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Research - What's New? 2008

Articles from the medical literature for 2008.

The majority of this material is obtained through Pubmed, sponsored by the United States national Library of medicine. When an article is of particular significance I try to excerpt relevant sections or diagrams to supplement the abstract provided by Pubmed. In some cases, I provide a link to the article as a PDF file.

Greek Letters Used: α (alpha) β (beta) γ (gamma) δ (delta) ε (epsilon) λ (lambda)

Please note: academic papers and portions thereof are used to illustrate educational concepts. These publications are generally copyright and the reader is asked to be aware of this. Publications are posted for the use of patients and their physicians, please do not redistribute them or use them for other purposes.

DOI: Digital object identifier. This is a new system that permanently identifies an electronic document. Articles displaying a DOI number can be located by entering the number into a locator ("resolver") at http://dx.doi.org Thank you.

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PubMed Link

Clin Neuropathol. 2008 Nov-Dec;27(6):424-9.
Altered distribution of lamin and emerin in muscle nuclei of sIBM patients.
Fidzianska A, Glinka Z, Kaminska A, Niebroj-Dobosz I.
Neuromuscular Unit, Medical Research Center, Polish Academy of Sciences, Pawinskiego 5 str., 02-106 Warsaw, Poland. neurmyol@cmdik.pan.pl
OBJECTIVE: Sporadic inclusion body myositis (sIBM) is a chronic acquired inflammatory myopathy. The cause of sIBM remains unknown and its pathogenesis is controversial. There is a hypothesis [Karpati and Carpenter 1993] that the rimmed vacuoles result from nuclear breakdown, and IBM filaments are formed from components of the nuclear matrix. MATERIAL AND METHODS: For nuclear membrane protein detection, six IBM patients were studied using immunohistochemical and immunochemical techniques. RESULTS: It was demonstrated that in the interior of 10-15% myonuclei emerin and lamin A/C inclusions appeared constantly. This finding indicated an abberant localization of lamin A/C epitopes, the presence of presumptive lamin A (67 KDu) and emerin as in the affected nuclei. CONCLUSION: We support the suggestion that truncated, changed lamin A protein takes part in nuclear disintegration and rimmed vacuole formation. PMID: 19130741

PubMed Link

Acta Neuropathol. 2008 Dec;116(6):583-95. Epub 2008 Oct 31.
Inclusion-body myositis: muscle-fiber molecular pathology and possible pathogenic significance of its similarity to Alzheimer's and Parkinson's disease brains.
Askanas V, Engel WK.

See paper here.

Department of Neurology, USC Neuromuscular Center, Good Samaritan Hospital, University of Southern California Keck School of Medicine, 637 South Lucas Avenue, Los Angeles, CA 90017-1912, USA. askanas@usc.edu
Sporadic inclusion-body myositis (s-IBM), the most common muscle disease of older persons, is of unknown cause and lacks successful treatment. Here we summarize diagnostic criteria and discuss our current understanding of the steps in the pathogenic cascade. While it is agreed that both degeneration and mononuclear-cell inflammation are components of the s-IBM pathology, how each relates to the pathogenesis remains unsettled. We suggest that the intra-muscle-fiber degenerative component plays the primary role, leading to muscle-fiber destruction and clinical weakness, since anti-inflammatory treatments are not of sustained benefit. We discuss possible treatment strategies aimed toward ameliorating a degenerative component, for example, lithium and resveratrol. Also discussed are the intriguing phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer and Parkinson's diseases, the most common neurodegenerative diseases associated with aging. Similarities include, in the respective tissues, cellular aging, mitochondrial abnormalities, oxidative and endoplasmic-reticulum stresses, proteasome inhibition and multiprotein aggregates. PMID: 18974994

Our current concepts of s-IBM pathogenesis

Characteristic features of s-IBM muscle-fiber degeneration

We consider s-IBM essentially a degenerative muscle disease: (a) occurring within an aged muscle cellular environment, (b) associated with intracellular accumulation and aggregation of a number of proteins, (c) in conjunction with oxidative and endoplasmic-reticulum (ER) stresses, and (d) involving abnormal signal transduction and transcription. Those together lead to the IBM-specific muscle-fiber degenerative process.

construction

Fig. 4 Proposed pathologic regulation of myostatin-precursor protein (MSTN-PP)/myostatin (MSTN) in s-IBM muscle fibers. Endoplasmic-reticulum (ER) stress induces MSNT-PP transcription through activation of NF-κB. Increased MSTN then leads to muscle fiber atrophy. Furthermore, increased AβPP/Aβ, which also causes proteasome inhibition, binds to MSTN-PP/MSTN and both accumulate in the form of probably insoluble aggregates

construction

Fig. 5 Proposed adverse effects of decreased SIRT1 deacetylase activity in s-IBM muscle fibers. Decreased deacetylase activity of SIRT1 activates NF-κB by increasing its acetylation (NF-κB-Ac). This leads to increased myostatin, and other detrimental consequences. Decreased SIRT1 activity also increases AβPP and Aβ, resulting in their known detrimental effects in s-IBM muscle fibers, as detailed in the text. Decreased SIRT1 activity might also inhibit autophagy, contributing to the accumulation of multiprotein aggregates

Intriguing similarities of the s-IBM muscle fiber phenotype to those of brains of AD and PD

Similarities to the AD brain include accumulation of Aβ, phosphorylated tau (p-tau) and more than 15 other Alzheimer-characteristic proteins [8, 10, 12, 13]. For years it was considered that the extracellular Aβ is exerting the main toxic, detrimental role in AD brain [83, 84]. However, more than a decade ago we proposed that our demonstrated intracellular increase and toxicity of AβPP and of its proteolytic fragment Aβ play the key cytotoxic role in the s-IBM pathogenic cascade [14, 15]; furthermore, we postulated that the same intracellular toxicity might be occurring in the AD pathogenesis [9]. This proposal regarding AD now seems to be gaining momentum, because more and more AD researchers discuss the possible importance of intracellular Aβ accumulation and toxicity in the AD pathogenesis [reviewed in 43, 58].

Interestingly, there are also phenotypic similarities of s-IBM muscle fibers to the PD brain, such as accumulation of α-syn, parkin and abnormalities of DJ-1, the latter also being present in AD brain [25]. These similarities suggest that the degenerative muscle and the brain diseases may share certain pathogenic steps and that knowledge of one disease might help elucidate the causes and treatments of the others. IBM, AD, and PD, including sporadic and hereditary forms of each, are all multifactorial and polygenetic. The respective cascade of events in each leading to their similar pathologic aspects is not well understood - cellular aging, protein misfolding, aggregation, proteasome inhibition, and mitochondrial abnormalities, as well as oxidative and ER stress have been proposed to be contributing in s-IBM, AD and PD [above, and reviewed in 1, 40, 48, 53, 56, 64, 74, 110]. Yet each disease category remains tissue- and region-specific, involving postmitotic-muscle fibers or postmitotic-neurons, thereby indicating that the mechanism of cellular-targeting is different in IBM, AD and PD. The tissue affected, muscle versus brain, may be influenced by: (1) etiologic agent (? a virus), (2) previous exposure to an environmental factor(s), (3) subtle differences of deficiency or toxicity factors, and (4) the patient's genetic background (the cellular microclimate). Easier availability of s-IBM patients' muscle biopsies, as compared to brain tissue, and the possibility of producing IBM experimental models by utilizing cultured human muscle fibers (which are the cells actually affected in the s-IBM disease process), might provide better understanding of some pathogenic aspects, not only related to s-IBM, but also to AD and PD, and facilitate development of treatments.

 


PubMed Link

Curr Opin Rheumatol. 2008 Nov;20(6):656-61.
Imaging tools for the clinical assessment of idiopathic inflammatory myositis.
Walker UA.
Department of Rheumatology, Basel University, Basel, Switzerland. ulrich.walker@fps-basel.ch
PURPOSE OF REVIEW: To summarize advances in the imaging of idiopathic inflammatory myopathies. RECENT FINDINGS: T2-weighted MRI with fat suppression or short tau inversion recovery sequences are the most sensitive and specific routine method of polymyositis and dermatomyositis imaging. MRI also represents an important aid in the identification of biopsy sites, with whole-body MRI sensitively visualizing the distribution of muscle involvement throughout the body. Ultrasound may be a cost-effective alternative to MRI, with contrast-enhanced ultrasound also permitting the assessment of muscle vascularization. PET sensitively detects increased muscle metabolism and simultaneously screens for underlying malignancies in dermatomyositis. Most scintigraphic techniques have a low sensitivity and specificity in the detection of muscle involvement, and it is unclear whether they provide an added benefit. New MRI techniques, such as T2 mapping, diffusion-weighted imaging and blood oxygenation level-dependent imaging, can provide information on muscle recruitment, myofibrillar structure and blood supply. SUMMARY: In suspected myositis, muscle imaging should be strongly considered prior to obtaining a muscle biopsy. Future research should prospectively study the use of muscle imaging in the evaluation of treatment response and muscle function. PMID: 18946324

PubMed Link

Clin Neuropathol. 2008 Nov-Dec;27(6):424-9.
Altered distribution of lamin and emerin in muscle nuclei of sIBM patients.
Fidzianska A, Glinka Z, Kaminska A, Niebroj-Dobosz I.
Neuromuscular Unit, Medical Research Center, Polish Academy of Sciences, Pawinskiego 5 str., 02-106 Warsaw, Poland. neurmyol@cmdik.pan.pl
OBJECTIVE: Sporadic inclusion body myositis (sIBM) is a chronic acquired inflammatory myopathy. The cause of sIBM remains unknown and its pathogenesis is controversial. There is a hypothesis [Karpati and Carpenter 1993] that the rimmed vacuoles result from nuclear breakdown, and IBM filaments are formed from components of the nuclear matrix. MATERIAL AND METHODS: For nuclear membrane protein detection, six IBM patients were studied using immunohistochemical and immunochemical techniques. RESULTS: It was demonstrated that in the interior of 10-15% myonuclei emerin and lamin A/C inclusions appeared constantly. This finding indicated an abberant localization of lamin A/C epitopes, the presence of presumptive lamin A (67 KDu) and emerin as in the affected nuclei. CONCLUSION: We support the suggestion that truncated, changed lamin A protein takes part in nuclear disintegration and rimmed vacuole formation. PMID: 19130741

PubMed Link

Arthritis Rheum. 2008 Nov;58(11):3600-8.
Human muscle cells express the costimulatory molecule B7-H3, which modulates muscle-immune interactions.
Waschbisch A, Wintterle S, Lochmüller H, Walter MC, Wischhusen J, Kieseier BC, Wiendl H.
University of Wuerzburg, Wuerzburg, Germany, and University of Erlangen, Erlangen, Germany.
OBJECTIVE: Interactions between the family of B7 ligands and their receptors are increasingly recognized as crucial for stimulation and/or inhibition of immune responses. The present study was undertaken to examine the expression and functional relevance of B7 homolog 3 (B7-H3), a novel B7 homolog attributed significant immunoregulatory functions, in human muscle cells in vivo and in vitro. METHODS: Thirty-five muscle biopsy specimens obtained from patients with polymyositis, dermatomyositis, inclusion body myositis, or noninflammatory myopathies and normal controls were analyzed by immunohistochemistry for B7-H3 expression. The expression of B7-H3 protein on primary human myoblasts and TE671 muscle rhabdomyosarcoma cells was studied by flow cytometry and Western blot analysis. B7-H3 small interfering RNA (siRNA) was used to study the impact of knockdown of B7-H3 on CD8+ cell-mediated lysis in skeletal muscle cells. RESULTS: B7-H3 was not detectable on normal muscle fibers. In contrast, its expression was markedly increased on muscle fibers from patients with inflammatory myopathies. Cell-surface staining was most prominent in the contact areas between muscle fibers and inflammatory cells. B7-H3 protein was detected on myoblasts cultured from control and myositis patient muscle tissue as well as in TE671 muscle rhabdomyosarcoma cells. Knockdown of B7-H3 by siRNA in TE671 cells enhanced CD8+ T cell-specific lysis, indicating a functional role of B7-H3 in the protection of skeletal muscle from immune-mediated lysis. CONCLUSION: Our results demonstrate that human muscle cells express B7-H3, a functional coinhibitory molecule of the B7 family. B7-H3 may play an important role in muscle-immune interactions, providing further evidence of the active role of muscle cells in local immunoregulatory processes. PMID: 18975328

PubMed Link

Neurotherapeutics. 2008 Oct;5(4):548-57.
Idiopathic inflammatory myopathies: current and future therapeutic options.
Wiendl H.
Department of Neurology, University of Wuerzburg, Wuerzburg, Germany. heinz.wiendl[at]klinik.uni-wuerzburg.de
Idiopathic inflammatory myopathies (notably polymyositis and dermatomyositis) are relatively uncommon diseases with a heterogeneous clinical presentation. Only a few randomized, double-blind, placebo-controlled trials have been performed, measures to assess outcome and response to treatment have to be validated. Initial treatment options of first choice are corticosteroids, although rarely tested in randomized, controlled trials. Unfortunately, not all patients respond to them and many develop undesirable side effects. Thus, second line agents or immunosuppressants given in combination with corticosteroids are used. For dermatomyositis/polymyositis, combination with azathioprine is most common. In case this combination is not sufficient or applicable, intravenous immunoglobulins are justified. Alternative or stronger immunosuppressants, such as cyclosporine A, cyclophosphamide, methotrexate, or mycophenolate are also used. There are no defined guidelines or best treatment protocols agreed on internationally; therefore, the medical approach must be individualized based on the severity of clinical presentation, disease duration, presence of extramuscular features, and prior therapy and contraindications to particular agents. Approximately 25% of patients are nonresponders and continue to experience clinical relapses. Those are candidates for alternative treatment options and experimental therapies. New immunoselective therapies directed toward cytokine modulation, immune cell migration, or modification of certain immune subsets (B- and T-cells) are a promising avenue of research and clinical application. Possible future therapeutic options are presented and discussed. PMID: 19019306

PubMed Link

Neurotherapeutics. 2008 Oct;5(4):633-7.
The hereditary inclusion body myopathy enigma and its future therapy.
Argov Z, Mitrani-Rosenbaum S.
Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. zohara@ekmd.huji.ac.il
Hereditary inclusion body myopathy (HIBM) is a genetic muscle disease due to mutations in the gene encoding the enzyme complex UDP-N-acetylglucosamine 2 epimerase-N-acetylmannosamine kinase (GNE), which catalyzes the rate-limiting step in sialic acid production. The review describes some of the disease features that may be relevant for further understanding of the metabolic impairment of HIBM and its future therapy. It also addresses the biochemical basis behind the substrate supplementation therapy designed for this condition. PMID: 19019317

PubMed Link

Web address: http://www.sciencedaily.com/releases/2008/12/ 081224215536.htm
Impaired Energy Metabolism Linked With Initiation Of Plaques In Alzheimer's Brain ScienceDaily (Jan. 3, 2009) Scientists have identified an initiating molecular mechanism in sporadic Alzheimer's disease (AD). The study, published by Cell Press in the December 26th issue of the journal Neuron, provides new information about generation of damaging amyloid β (Aβ) plaques within the AD brain and underscores the importance of developing new preventative and disease-modifying therapies for AD, especially those aimed at interrupting pathological Aβ-production. AD, the leading cause of dementia in the elderly, is a devastating neurological disorder characterized by accumulation and deposition of sticky clumps of A-beta protein. A-beta protein is generated from amyloid precursor protein (APP) by beta-site APP cleaving enzyme (BACE1). Previous research has suggested that BACE1 activity may play a key role in the initiation of AD pathogenesis and identified BACE1 as a promising target for AD therapeutics. Recently, BACE1 was linked to cellular stress responses in the brain. Importantly, the AD brain exhibits impaired energy metabolism (a stressful situation) and it has been suggested that diminished cerebral use of glucose and oxygen may be an early event in AD pathogenesis. Senior study author Dr. Robert Vassar from Northwestern University Feinberg School of Medicine has explored the link between energy inhibition and AD pathogenesis. "We have shown previously, using a pharmacological model of energy metabolism inhibition in pre-plaque transgenic mice with an excess of APP, that BACE1 and Aβ levels are elevated in the brain," says Dr. Vassar. Dr. Vassar and colleagues expanded on their previous work by using glucose deprivation to examine the molecular mechanisms underlying elevated BACE1 levels in response to energy inhibition. They found that glucose deprivation caused an increase in BACE1 levels and led to the phosphorylation of the stress-inducible translation initiation factor, eIF2α. Further, direct phosphorylation of eIF2α increased BACE1 levels and enhanced Aβ production while inhibition of eIF2α phosphorylation prevented energy-deprivation induced increases in BACE1. The researchers went on to show that energy inhibition increased eIF2α phosphorylation, BACE1 levels and amyloid plaque formation in APP transgenic mice. In addition, phosphorylated eIF2α and BACE1 were elevated in an aggressive Aβ plaque-forming mouse model and in humans with AD. "Here, for the first time we provide evidence linking impaired energy metabolism, an AD-relevant stress, with BACE1 translation mediated by eIF2α phosphorylation," says Dr. Vassar. "Our findings implicate phosphorylated eIF2α in both the initiation and progression of sporadic AD. Future experiments will determine whether inhibition of eIF2α phosphorylation could be an efficacious therapeutic approach for the prevention and treatment of AD." Impaired Energy Metabolism Linked With Initiation Of Plaques In Alzheimer's Brain. ScienceDaily. Retrieved January 4, 2009, from http://www.sciencedaily.com­ /releases/2008/12/081224215536.htm

PubMed Link

Hum Mol Genet. 2008 Dec 1;17(23):3663-74.
Epub 2008 Aug 23.Click here to read Links Mitochondrial processes are impaired in hereditary inclusion body myopathy.
Eisenberg I, Novershtern N, Itzhaki Z, Becker-Cohen M, Sadeh M, Willems PH, Friedman N, Koopman WJ, Mitrani-Rosenbaum S.
Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Hereditary inclusion body myopathy (HIBM) is an adult onset, slowly progressive distal and proximal myopathy. Although the causing gene, GNE, encodes for a key enzyme in the biosynthesis of sialic acid, its primary function in HIBM remains unknown. To elucidate the pathological mechanisms leading from the mutated GNE to the HIBM phenotype, we attempted to identify and characterize early occurring downstream events by analyzing the genomic expression patterns of muscle specimens from 10 HIBM patients carrying the M712T Persian Jewish founder mutation and presenting mild histological changes, compared with 10 healthy matched control individuals, using GeneChip expression microarrays. When analyzing the expression profile data sets by the intersection of three statistic methods (Student's t-test, TNoM and Info score), we found that the HIBM-specific transcriptome consists of 374 differentially expressed genes. The specificity of the HIBM transcriptome was assessed by the minimal transcript overlap found between HIBM and the transcriptome of nine additional muscle disorders including adult onset limb girdle myopathies, inflammatory myopathies and early onset conditions. A strikingly high proportion (18.6%) of the overall differentially expressed mRNAs of known function were found to encode for proteins implicated in various mitochondrial processes, revealing mitochondria pathways dysregulation. Mitochondrial morphological analysis by video-rate confocal microscopy showed a high degree of mitochondrial branching in cells of HIBM patients. The subtle involvement of mitochondrial processes identified in HIBM reveals an unexpected facet of HIBM pathophysiology which could at least partially explain the slow evolution of this disorder and give new insights in the disease mechanism. PMID: 18723858

PubMed Link

Neurobiol Aging. 2008 Dec 22. [Epub ahead of print]
Amyloid-beta protein impairs Ca(2+) release and contractility in skeletal muscle.
Shtifman A, Ward CW, Laver DR, Bannister ML, Lopez JR, Kitazawa M, Laferla FM, Ikemoto N, Querfurth HW.
Department of Neurology Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge St., Boston, MA 02135, United States.
Inclusion body myositis (IBM), the most common muscle disorder in the elderly, is partly characterized by dysregulation of β-amyloid precursor protein (βAPP) expression and abnormal, intracellular accumulation of full-length βAPP and β-amyloid epitopes. The present study examined the effects of β-amyloid accumulation on force generation and Ca(2+) release in skeletal muscle from transgenic mice harboring human betaAPP and assessed the consequence of Aβ(1-42) modulation of the ryanodine receptor Ca(2+) release channels (RyRs). β-Amyloid laden muscle produced less peak force and exhibited Ca(2+) transients with smaller amplitude. To determine whether modification of RyRs by β-amyloid underlie the effects observed in muscle, in vitro Ca(2+) release assays and RyR reconstituted in planar lipid bilayer experiments were conducted in the presence of Aβ(1-42). Application of Aβ(1-42) to RyRs in bilayers resulted in an increased channel open probability and changes in gating kinetics, while addition of Aβ(1-42) to the rabbit SR vesicles resulted in RyR-mediated Ca(2+) release. These data may relate altered βAPP metabolism in IBM to reductions in RyR-mediated Ca(2+) release and muscle contractility. PMID: 19108934
In summary, the present data demonstrate considerable alterations in SR Ca2+ release and contractility in skeletal muscle of IBM mice potentially arising from β-amyloid modulation of RyR function. Since Ca2+ handling is a major determinant of force generation in skeletal muscle, we suggest that better understanding of the mechanisms for β- amyloid-mediated changes in Ca2+ homeostasis may lead to improved therapeutic strategies for IBM.

PubMed Link

J Neurol Sci. 2008 Dec 19.
Inflammatory myopathies with mitochondrial pathology and protein aggregates.
Temiz P, Weihl CC, Pestronk A.
Celal Bayar University School of Medicine, Department of Pathology, Manisa, 45010, Turkey.
OBJECTIVES: To compare the clinical course and muscle biopsy features of polymyositis with mitochondrial pathology (PM-Mito) to inclusion body myositis (IBM) and steroid-responsive inflammatory myopathies (polymyositis). METHODS: We compared clinical, laboratory and myopathologic features in a retrospective study of patients with PM-Mito (23), IBM (26) and polymyositis (12). RESULTS: Selective weakness in the quadriceps or finger flexors was common in PM-Mito (62%) and IBM (87%). Weakness progressed more slowly in PM-Mito than in IBM. PM-Mito patients with more rapidly progressive weakness had more cytochrome oxidase negative muscle fibers. There was no history of benefit from corticosteroid treatment in any PM-Mito or IBM patients. B-cell foci were absent in IBM and PM-Mito. LC3, an autophagy marker, and alphaB-crystallin were common in aggregates in PM-Mito and IBM, but not polymyositis. SMI-31 and TDP-43 positive aggregates were common in IBM but not in PM-Mito or polymyositis. beta-amyloid showed no differences in aggregates among the three groups. CONCLUSIONS: PM-Mito and IBM may be part of the same disease spectrum. PM-Mito has more slowly progressive weakness than IBM and rarely has TDP-43 or SMI-31 staining aggregates in muscle fibers. The most frequent proteins in aggregates in both PM-Mito and IBM are LC3, an autophagy marker, and alphaB-crystallin. Alterations in autophagic degradation pathways may be a common pathogenic mechanism in PM-Mito and IBM. In pathologically typical polymyositis, staining for mitochondrial enzyme activity, aggregates and B-cells helps to distinguish PM-Mito from inflammatory myopathy syndromes that are more likely to respond to corticosteroid treatment. PMID: 19101700

PubMed Link

J Alzheimers Dis. 2008 Dec;15(4):673-84. Potential Mechanisms Linking Cholesterol to Alzheimer's Disease-like Pathology in Rabbit Brain, Hippocampal Organotypic Slices, and Skeletal Muscle.
Ghribi O.
Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, ND, USA.
Epidemiological, animal, and cellular studies suggest that abnormalities in cholesterol metabolism are important in the pathogenesis of Alzheimer's disease (AD), potentially by increasing amyloid-β (Aβ) peptide levels. Accumulation of Abeta in the brain is suggested to play a key role in the neurodegenerative processes by triggering the hyperphosphorylation of tau and the neuronal death that develop in the course of AD. However, the mechanisms by which cholesterol increases Aβ levels are still ill-defined. Previous and ongoing work from our laboratory indicates that hypercholesterolemia leads to the increased neuronal content of cholesterol and increased levels and processing of the amyloid-β protein precursor (AβPP). We also have found that the oxidized cholesterol metabolite, 27-hydroxycholesterol, increases Aβ levels in both organotypic hippocampal slices and in neuronal preparations cultured from adult rabbits. This cholesterol metabolite is predominantly formed in the circulation and, in contrast to cholesterol, has the ability to cross into the brain. These results may indicate that 27-hydroxycholesterol is the link between circulating cholesterol and AD-like pathology in the brain. We also have found pathological hallmarks in the skeletal muscle of cholesterol-fed rabbits that are suggestive of inclusion body myositis, a disease that shares some pathological similarities with AD. PMID: 19096164

PubMed Link

Ann Rheum Dis. 2008 Dec;67(12):1670-7. Epub 2008 Feb 13.
A high incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies.
Dastmalchi M, Grundtman C, Alexanderson H, Mavragani CP, Einarsdottir H, Helmers SB, Elvin K, Crow MK, Nennesmo I, Lundberg IE.
Rheumatology, Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Solna, SE-171 76 Stockholm, Sweden. maryam.dastmalchi@karolinska.se
OBJECTIVE: To investigate the effect of the tumour necrosis factor (TNF) blocking agent infliximab in patients with treatment-resistant inflammatory myopathies. METHODS: A total of 13 patients with refractory polymyositis (PM), dermatomyositis (DM), or inclusion body myositis (IBM) were treated with 4 infliximab infusions (5 mg/kg body weight) over 14 weeks. Outcome measures included myositis disease activity score with improvement defined according to The International Myositis Assessment and Clinical Studies Group (IMACS), and MRI. Repeated muscles biopsies were investigated for cellular infiltrates, major histocompatibility complex (MHC) class I and II, TNF, interleukin (IL)1alpha, IL6, high mobility group box chromosomal protein 1 (HMGB-1), interferon gamma (IFNgamma), myxovirus resistance protein A (MxA) and membrane attack complex (MAC) expression. Type I IFN activity was analysed in sera. RESULTS: Nine patients completed the study. Three patients discontinued due to adverse events and one due to a discovered malignancy. Three of the completers improved by >or=20% in three or more variables of the disease activity core set, four were unchanged and two worsened >or=30%. No patient improved in muscle strength by manual muscle test. At baseline, two completers had signs of muscle inflammation by MRI, and five at follow-up. T lymphocytes, macrophages, cytokine expression and MAC deposition in muscle biopsies were still evident after treatment. Type I IFN activity was increased after treatment. CONCLUSIONS: Infliximab treatment was not effective in refractory inflammatory myopathies. In view of radiological and clinical worsening, and activation of the type I IFN system in several cases, infliximab is not an alternative treatment in patients with treatment-resistant myositis. PMID: 18272672

PubMed Link

Arthritis Rheum. 2008 Oct;58(10):3216-23.
Expression of the CD85j (leukocyte Ig-like receptor 1, Ig-like transcript 2) receptor for class I major histocompatibility complex molecules in idiopathic inflammatory myopathies.
Schleinitz N, Cognet C, Guia S, Laugier-Anfossi F, Baratin M, Pouget J, Pelissier JF, Harle JR, Vivier E, Figarella-Branger D.
Department of Internal Medicine, CHU La Conception, Marseille, France. nicolas.schleinitz@ap-hm.fr
OBJECTIVE: Expression of class I major histocompatibility complex (MHC) molecules on the surface of muscle cells is a biologic feature of idiopathic inflammatory myopathies (IIM). Class I MHC-transgenic mouse models support a causative role for class I MHC expression by muscle cells in the pathogenesis of IIM. The muscle lesions are characterized by leukocyte infiltration. We undertook this study to analyze the expression in muscle lesions of various class I MHC-specific receptors on leukocytes and natural killer (NK) cells. METHODS: We generated a panel of cell transfectants to control the immunofluorescence analysis of class I MHC receptor expression. We then analyzed the expression of CD158 (killer cell Ig-like receptors [KIRs]) and CD85j (leukocyte Ig-like receptor 1, Ig-like transcript 2) on muscle sections prepared from 14 patients with IIM (5 with dermatomyositis [DM], 5 with polymyositis [PM], and 4 with sporadic inclusion body myositis [IBM]). RESULTS: We could not detect the presence of NK cells in inflammatory lesions. However, the class I MHC receptor CD85j, but no KIRs, was expressed by inflammatory cells infiltrating muscle lesions in IIM. CONCLUSION: CD85j is expressed in PM and sporadic IBM at the sites of partial invasion and in DM in perivascular inflammation, paving the way for dissecting the role of CD85j in the pathogenesis of inflammatory myopathies. PMID: 18821690

PubMed Link

Mol Neurobiol. 2008 Oct;38(2):178-98. Epub 2008 Sep 5.
Inclusion body myositis: a view from the Caenorhabditis elegans muscle.
Rebolledo DL, Minniti AN, Grez PM, Fadic R, Kohn R, Inestrosa NC.
Centro de Envejecimiento y Regeneración (CARE), Centro de Regulación Celular y Patología Joaquín V. Luco, MIFAB, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Alameda 340, Santiago, Chile.
Inclusion body myositis (IBM) is the most common myopathy in people over 50 years of age. It involves an inflammatory process that, paradoxically, does not respond to anti-inflammatory drugs. A key feature of IBM is the presence of amyloid-beta-peptide aggregates called amyloid deposits, which are also characteristic of Alzheimer's disease. The use of animals that mimic at least some characteristics of a disease has become very important in the quest to elucidate the molecular mechanisms underlying this and other pathogeneses. Although there are some transgenic mouse strains that recreate some aspects of IBM, in this review, we hypothesize that the great degree of similarity between nematode and human genes known to be involved in IBM as well as the considerable conservation of biological mechanisms across species is an important feature that must be taken into consideration when deciding on the use of this nematode as a model. Straightforward laboratory techniques (culture, transformation, gene knockdown, genetic screenings, etc.) as well as anatomical, physiological, and behavioral characteristics add to the value of this model. In the present work, we review evidence that supports the use of Caenorhabditis elegans as a biological model for IBM. PMID: 18773311

PubMed Link

Clin Rheumatol. 2008 Dec 6. [Epub ahead of print]
A case of inclusion body myositis responsive to prednisolone therapy.
Kalla R, Soumakiyan M, Tuck S.
Department of Rheumatology, James Cook University Hospitals, Marton Road, Middlesbrough, TS4 3BW, UK, kallarahul@gmail.com.
Inclusion body myositis, although rare, is the commonest cause of myopathy in patients aged over 50 years. The suggested pathogenesis remains uncertain and its prognosis remains poor. There have been select case reports of its association with an inflammatory etiology and it is postulated that this group of patients respond better to immunosuppressive therapy. We therefore report a rare case of inclusion body myositis that responded well to immunosuppressive therapy. We also report the possibility of its association with infliximab therapy.

Case report

A 61-year-old woman with a 44-year history of seropositive rheumatoid arthritis was electively admitted at James Cook University Hospital with a persistent cough and wheeze along with generalized weakness and worsening shortness of breath for the last 3 months. Her rheumatoid arthritis (RA) medications included methotrexate and a 4-year history of infliximab therapy. There was no prior history of myopathy or myositis. . . .

A further thorough neurological assessment revealed a 4-year history of gradually progressive distal muscle weakness and dysphagia which had begun after initiating infliximab therapy. Examination revealed no skin rashes and marked non-tender asymmetrical distal weakness in all four limbs with reduced tone and muscle wasting. The weakness was more marked in her hands distally and quadriceps muscles proximally. . . .

A right bicep muscle biopsy result was reported as being indicative of an inclusion body myositis (infiltration of lymphocytes and histiocytes along with rimmed vacuoles without inclusion bodies). In view of her RA history and a presentation of asymmetrical distal muscle weakness, an inflammatory myositis was thought to be the most likely diagnosis as a result of infliximab therapy. The patient was commenced on prednisolone [Prednisone] and mycophenolate mofetil [see note 1] and started to show clinical improvement in her swallowing and mobility. Since discharge, she has continued to improve and her steroid dose isbeing reduced. Two months later, she was able to eat normally, power in the upper limbs was full, and she was mobilizing independently.

From the discussion:

There is a general consensus amongst physicians that treatment in IBM in the majority of cases does not slow or reverse the progression of weakness. However, there are a few reports of clinical improvement in weakness and swallowing with prednisolone therapy [6]. There have also been select case reports of patients with concurrent autoimmune disorders such as rheumatoid arthritis, Sjogrens syndrome, and SLE that respond better to immunosuppressive therapy, highlighting a subset of IBM patients that may have a relatively better prognosis [7]. In our case, the patient had characteristic clinical findings and a muscle biopsy consistent with IBM, but showed clinical improvement with immunosuppressant.

This could be reported as a rare case of a subset of IBM patients that respond to immunosuppressive therapy. One could argue the diagnosis of IBM in this patient as she clinically improved on treatment and had a muscle biopsy which showed rimmed vacuoles without inclusion bodies. There is a possibility that this could be infliximab induced, as there is one case report of myositis induced by infliximab and she had developed new antibodies [9]. However, she fulfils the European Neuromuscular Centre Diagnostic Criteria (ENCDC) of IBM despite the biopsy result [10]. We therefore report a rare case of IBM that has shown significant clinical improvement with mycophenolate mofetil and prednisolone therapy. We also report the possibility of its association with infliximab therapy.
PMID: 19067104

Note 1: Mycophenolic acid (INN) or mycophenolate is an immunosuppressant drug used to prevent rejection in organ transplantation. It was initially marketed as the prodrug mycophenolate mofetil (abbreviated MMF) to improve oral bioavailability. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolic acid is commonly marketed under the trade names CellCept (mycophenolate mofetil; Roche) and Myfortic (mycophenolate sodium; Novartis). from: Mycophenolic acid. (2008, November 5). In Wikipedia, The Free Encyclopedia. Retrieved 03:25, December 12, 2008, from Mycophenolic acid. (2008, November 5). In Wikipedia, The Free Encyclopedia. Retrieved 03:25, December 12, 2008, from http://en.wikipedia.org/w/index.php?title=Mycophenolic_acid&oldid=249879302


PubMed Link

J Pathol. 2008 Sep 18.
Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques.
Wozniak M, Mee A, Itzhaki R.
Faculty of Life Sciences, University of Manchester, UK.
The brains of Alzheimer's disease sufferers are characterized by amyloid plaques and neurofibrillary tangles. However, the cause(s) of these features and those of the disease are unknown, in sporadic cases. We previously showed that herpes simplex virus type 1 is a strong risk factor for Alzheimer's disease when in the brains of possessors of the type 4 allele of the apolipoprotein E gene (APOE-epsilon4), and that β-amyloid, the main component of plaques, accumulates in herpes simplex virus type 1-infected cell cultures and mouse brain. The present study aimed to elucidate the relationship of the virus to plaques by determining their proximity in human brain sections. We used in situ polymerase chain reaction to detect herpes simplex virus type 1 DNA, and immunohistochemistry or thioflavin S staining to detect amyloid plaques. We discovered a striking localization of herpes simplex virus type 1 DNA within plaques: in Alzheimer's disease brains, 90% of the plaques contained the viral DNA and 72% of the DNA was associated with plaques; in aged normal brains, which contain amyloid plaques at a lower frequency, 80% of plaques contained herpes simplex virus type 1 DNA but only 24% of the viral DNA was plaque-associated (p less than 0.001). We suggest that this is because in aged normal individuals, there is a lesser production and/or greater removal of β-amyloid (Aβ), so that less of the viral DNA is seen to be associated with Abeta in the brain. Our present data, together with our finding of Abeta accumulation in herpes simplex virus type 1-infected cells and mouse brain, suggest that this virus is a major cause of amyloid plaques and hence probably a significant aetiological factor in Alzheimer's disease. They point to the usage of antiviral agents to treat the disease and possibly of vaccination to prevent it.

Discussion

Our major finding is the striking localization of HSV1 DNA within amyloid plaques in the temporal and frontal cortices: 90% of plaques in the brains of AD sufferers contained HSV1 DNA, and 80% in aged normal subjects in the fewer plaques present. In AD, 72% of viral DNA was plaque-associated; thus its localization within amyloid plaques reflects a specific association, not a background, random distribution. These results, when considered with our previous study showing that the virus causes a marked increase in Aβ within infected cells and in brain of infected mice [18], support the deduction that HSV1 is a major cause of plaque formation.. . .

Our current findings allow us to indicate the likely cascade of events leading from HSV1 infection to AD. We suggest that the virus enters the brain in the elderly as their immune systems decline and then establishes a latent infection, from which it is repeatedly reactivated by events such as stress, immunosuppression and brain inflammation induced during systemic infection (reviewed in [26]). The ensuing acute HSV1 infection causes up-regulation of enzymes involved in APP processing to Aâ and leads to prevention of abnormal protein degradation via the known inhibitory effect the virus has on autophagy [27]. Perhaps in aged normal subjects there is less production of amyloid and/or more amyloid cleared. The infected cell, after suffering severe structural damage, dies and disintegrates, releasing amyloid aggregates which then develop into classic plaques after other components of dying cells are deposited on them. Presumably, in APOE-å4 carriers, AD develops either as a consequence of HSV1-induced plaque accumulation or as a direct consequence of virusinduced cell death or inflammation.

In conclusion, the present data strongly implicate HSV1 in sporadic AD as an actual cause of, and a pathway for, amyloid plaque formation, and hence a likely major cause of the disease. Other pathogens can cause Aâ formation [28,29] but HSV1 is unique in being present in a high proportion of elderly brains and is therefore the only pathogen in a position to cause such damage. Our results add strong support to our proposal that antiviral agents be used to treat AD to prevent further deterioration by attacking a likely major cause, not just a single symptom, and that a vaccine against HSV1 be developed to prevent occurrence of the disease.

Copyright (c) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley and Sons, Ltd. PMID: 18973185


PubMed Link

Neurotherapeutics. 2008 Oct;5(4):633-637.
The Hereditary Inclusion Body Myopathy Enigma and its Future Therapy.
Argov Z, Mitrani-Rosenbaum S.
Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 91120. Hereditary inclusion body myopathy (HIBM) is a genetic muscle disease due to mutations in the gene encoding the enzyme complex UDP-N-acetylglucosamine 2 epimerase-N-acetylmannosamine kinase (GNE), which catalyzes the rate-limiting step in sialic acid production. The review describes some of the disease features that may be relevant for further understanding of the metabolic impairment of HIBM and its future therapy. It also addresses the biochemical basis behind the substrate supplementation therapy designed for this condition. PMID: 19019317

PubMed Link

Physiol Genomics. 2008 Sep 17;35(1):106-15. Epub 2008 Jul 15.
Muscle weakness correlates with muscle atrophy and precedes the development of inclusion body or rimmed vacuoles in the mouse model of DMRV/hIBM.
Malicdan MC, Noguchi S, Hayashi YK, Nishino I.
Department of Neuromuscular Research and Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Distal myopathy with rimmed vacuoles (DMRV), also called hereditary inclusion body myopathy (hIBM), is characterized clinically by weakness and atrophy that initially involves the distal muscles and pathologically by the presence of rimmed vacuoles (RVs) or intracellular protein deposits in myofibers. It is caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene that is important in sialic acid synthesis. Recently, we generated a mouse model (Gne(-/-)hGNED176VTg) that exhibits muscle weakness and pathological changes similar to DMRV patients. To gain better understanding of the pathomechanism of DMRV, we determined temporal changes in the overall motor performance of this model mouse for DMRV in correlation with the structure and function of isolated skeletal muscles and muscle pathology. These DMRV mice exhibited muscle weakness, decreased whole muscle mass and cross-sectional area (CSA), and reduced contractile power in an age-related manner. Single-fiber CSA further supported the finding of muscle atrophy that involved both type I and type II fibers. These results suggest that atrophy is highly correlated with reduced production of force at young age, both in vivo and ex vivo, thereby implicating the important role of atrophy in the pathomechanism of DMRV. In older age, and particularly in gastrocnemius muscles, RVs and intracellular inclusions were seen in type IIA fibers, further aggravating reduction of force and specific increase in twitch-tetanus ratio. PMID: 18628337

PubMed Link

Free Radic Biol Med. 2008 Sep 15;45(6):773-9. Epub 2008 Jun 14.
In inclusion-body myositis muscle fibers Parkinson-associated DJ-1 is increased and oxidized.
Terracciano C, Nogalska A, Engel WK, Wojcik S, Askanas V.
Department of Neurology, USC Neuromuscular Center, University of Southern California Keck School of Medicine, Good Samaritan Hospital, 637 S. Lucas Avenue, Los Angeles, CA 90017-1912, USA.
Sporadic inclusion-body myositis (s-IBM) is the most common muscle disease of older persons. The muscle-fiber molecular phenotype exhibits similarities to both Alzheimer-disease (AD) and Parkinson-disease (PD) brains, including accumulations of amyloid-beta, phosphorylated tau, alpha-synuclein, and parkin, as well as evidence of oxidative stress and mitochondrial abnormalities. Early-onset autosomal-recessive PD can be caused by mutations in the DJ-1 gene, leading to its inactivation. DJ-1 has antioxidative and mitochondrial-protective properties. In AD and PD brains, DJ-1 is increased and oxidized. We studied DJ-1 in 17 s-IBM and 18 disease-control and normal muscle biopsies by: (1) immunoblots of muscle homogenates and mitochondrial fractions; (2) real-time PCR; (3) oxyblots evaluating DJ-1 oxidation; (4) light- and electron-microscopic immunocytochemistry. Compared to controls, in s-IBM muscle fibers DJ-1 was: (a) increased in the soluble fraction, monomer 2-fold (P = 0.01), and dimer 2.8-fold (P = 0.004); (b) increased in the mitochondrial fraction; (c) highly oxidized; and (d) aggregated in about 15% of the abnormal muscle fibers. DJ-1 mRNA was increased 3.5-fold (P = 0.034). Accordingly, DJ-1 might play a role in human muscle disease, and thus not be limited to human CNS degenerations. In s-IBM muscle fibers, DJ-1 could be protecting these fibers against oxidative stress, including protection of mitochondria. PMID: 18601999

PubMed Link

Am J Phys Med Rehabil. 2008 Nov;87(11):883-9.
Dysphagia in inclusion body myositis: clinical features, management, and clinical outcome.
Oh TH, Brumfield KA, Hoskin TL, Kasperbauer JL, Basford JR.
Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, Minnesota 55905, USA.
OBJECTIVE: To evaluate the clinical features, treatment strategies, and outcome of dysphagia in patients with inclusion body myositis. DESIGN: Retrospective review of all 26 patients (20 women, 6 men, mean age of 72.2 yrs) with inclusion body myositis-associated dysphagia seen in 1997-2001 at our institution. RESULTS: Twenty-four patients (92%) had a dysphagia evaluation. Cricopharyngeal muscle dysfunction was noted in all nine patients who had barium swallow studies. Eighteen patients (69%) underwent one or more interventional procedures: cricopharyngeal myotomy (10), pharyngoesophageal dilation (6), percutaneous endoscopic gastrostomy (6), and botulinum injection of the upper esophageal sphincter (2). Dysphagia tended to worsen with time. Symptomatic improvement was noted with cricopharyngeal myotomy (63%) and pharyngoesophageal dilation (33%). The Mendelsohn maneuver seemed helpful in maintaining oral intake in the three patients in whom it was recommended. Thirteen patients died during follow-up at a mean age of 81 yrs. The cause of death was identified in eight and in all cases was because of the respiratory complications of aspiration. CONCLUSIONS: Dysphagia is a progressive condition in patients with inclusion body myositis and often leads to death from aspiration pneumonia. Treatment targeting cricopharyngeal muscle dysfunction, such as the Mendelsohn maneuver, will benefit from further investigation. PMID: 18936555
Rose MR, Dalakas M, Griggs R, Leong K, Miller J, Walter MC.
Treatment for inclusion body myositis. (Protocol)
Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD001555. DOI: 10.1002/14651858.CD001555.pub2.
Protocols provide place-markers for reviews that are currently being written. They summarize the background and the rationale of the review.

PubMed Link

Am J Physiol Regul Integr Comp Physiol. 2008 Mar;294(3):R829-35. Epub 2008 Jan 23.
Rabbits fed cholesterol-enriched diets exhibit pathological features of inclusion body myositis.
Chen X, Ghribi O, Geiger JD.
Department of Pharmacology, Physiology, and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, 501 N. Columbia Road, Grand Forks, North Dakota 58203, USA.
Sporadic inclusion body myositis (IBM) is the most common age-related muscle disease in humans; however, its etiology is unknown, there are few animal models for this disease, and effective treatments have not been identified. Similarities between pathological findings in Alzheimer's disease brain and IBM skeletal muscle include increased levels of amyloid precursor protein (APP) and amyloid beta-protein (Aβ). Moreover, there have been suggestions that elevated levels of free cholesterol might participate in the pathogenesis of Alzheimer's disease and IBM due, in part, to its role in Abeta generation. Here, we tested the hypothesis that rabbits fed cholesterol-enriched diets might faithfully exhibit human-like IBM pathological features. In skeletal muscle of one-third of the female rabbits fed cholesterol-enriched diet but not control diet, we found features of IBM, including vacuolated muscle fibers, increased numbers of mononuclear inflammatory cells, increased intramuscular deposition of Aβ, hyperphosphorylated tau, and increased numbers of muscle fibers immunopositive for ubiquitin. The cholesterol-enriched diet increased mRNA and protein levels of APP, increased the protein levels of βAPP cleaving enzyme, and shifted APP processing in favor of Aβ production. Our study has demonstrated that increased ingestion of high levels of dietary cholesterol can result in pathological features that resemble IBM closely and thus may serve as an important new model with which to study this debilitating disorder. PMID: 18216139

PubMed Link

Neurol India. 2008 Jul-Sep;56(3):263-70.
Inflammatory muscle diseases.
Mastaglia FL.
Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Queen Elizabeth II Medical Centre, Nedlands, 6009, Australia. flmast@cyllene.uwa.edu.au.
The three major immune-mediated inflammatory myopathies, dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM), each have their own distinctive clinical features, underlying pathogenetic mechanisms and patterns of muscle gene expression. In DM a complement-dependent humoral process thought to be initiated by antibodies to endothelial cells results in a microangiopathy with secondary ischemic changes in muscles. On the other hand, in PM and IBM there is a T-cell response with invasion of muscle fibers by CD8+ lymphocytes and perforin-mediated cytotoxic necrosis. In IBM degenerative changes are also a feature and comprise autophagia with rimmed vacuole formation and inclusions containing beta-amyloid and other proteins whose accumulation may be linked to impaired proteasomal function. The relationship between the inflammatory and degenerative component remains unclear, as does the basis for the selective vulnerability of certain muscles and the resistance to conventional forms of immunotherapy in most cases of IBM. Patients with DM or PM usually respond to treatment with glucocorticoids and immunosuppressive agents but their use remains largely empirical. Intravenous immunoglobulin therapy can be used to achieve disease control in patients with severe weakness or dysphagia, or in patients with immunodeficiency, but its use is limited by expense. Emerging therapies for resistant cases include TNFalpha inhibitors (etanercept, infliximab) and monoclonal antibodies (rituximab, alemtuzumab). However, experience with these therapies is still limited and there is a need for randomized trials to test their efficacy and establish guidelines for their use in clinical practice. PMID: 18974552

PubMed Link

Neurol India. 2008 Jul-Sep;56(3):363-7.
Major histocompatibility complex class I expression can be used as a diagnostic tool to differentiate idiopathic inflammatory myopathies from dystrophies.
Sundaram C, Uppin MS, Meena AK.
Department of Pathology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, India. challa_sundaram@yahoo.com.
Aim: Utility of major histocompatibility complex (MHC) Class I antigen immunostaining was studied to differentiate idiopathic inflammatory myopathies from dystrophies. Materials and Methods: Forty muscle biopsies including seven dermatomyositis (DM), six polymyositis (PM), two sporadic inclusion body myositis (sIBM), 20 dystrophies (one Duchenne, three Becker's, four alpha, one gamma sarcoglycanopathy, nine limb girdle, one myotonic and one fascioscapulohumeral muscular dystrophy) and five controls were stained with antibody for MHC Class I antigen (Novocastra clone W6/32 HL 1:100 dilution). Results: Polymyositis and sIBM showed MHC class I antigen positivity along sarcolemma of single and small groups of muscle fibers. The regenerating fibers in the perifascicular area in DM showed intense cytoplasmic positivity of MHC class I antigen. Muscle fibers in all dystrophies except regenerating fibers and control normal muscle were negative for MHC. Capillaries and lymphocytes were positive controls. There were no false positives in the study. Conclusion: MHC Class I immunostaining can be used as a complementary diagnostic tool for the diagnosis of idiopathic inflammatory myopathies. PMID: 18974565

PubMed Link

Acta Neuropathol. 2008 Oct 31.
Inclusion-body myositis: muscle-fiber molecular pathology and possible pathogenic significance of its similarity to Alzheimer's and Parkinson's disease brains.

Download article here.

Askanas V, Engel WK.
Department of Neurology, USC Neuromuscular Center, Good Samaritan Hospital, University of Southern California Keck School of Medicine, 637 South Lucas Avenue, Los Angeles, CA, 90017-1912, USA, askanas@usc.edu.
Sporadic inclusion-body myositis (s-IBM), the most common muscle disease of older persons, is of unknown cause and lacks successful treatment. Here we summarize diagnostic criteria and discuss our current understanding of the steps in the pathogenic cascade. While it is agreed that both degeneration and mononuclear-cell inflammation are components of the s-IBM pathology, how each relates to the pathogenesis remains unsettled. We suggest that the intra-muscle-fiber degenerative component plays the primary role, leading to muscle-fiber destruction and clinical weakness, since anti-inflammatory treatments are not of sustained benefit. We discuss possible treatment strategies aimed toward ameliorating a degenerative component, for example, lithium and resveratrol. Also discussed are the intriguing phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer and Parkinson's diseases, the most common neurodegenerative diseases associated with aging. Similarities include, in the respective tissues, cellular aging, mitochondrial abnormalities, oxidative and endoplasmic-reticulum stresses, proteasome inhibition and multiprotein aggregates. PMID: 18974994

Quotes.


We consider s-IBM essentially a degenerative muscle disease: (a) occurring within an aged muscle cellular environment, (b) associated with intracellular accumulation and aggregation of a number of proteins, (c) in conjunction with oxidative and endoplasmic-reticulum (ER) stresses, and (d) involving abnormal signal transduction and transcription. Those together lead to the IBM-specific muscle-fiber degenerative process. . . .

Also characteristic component of s-IBM muscle biopsies is a lymphocytic inflammation, mainly composed of cytotoxic CD8 cells [reviewed in 29]. Which component, degenerative or inflammatory, precedes the s-IBM pathogenesis [13, 29, 69] is a debated but unresolved issue.. . .

Relevant to treating patients, the main consideration in analyzing the s-IBM pathogenesis should focus less on whether inflammatory features are primary or secondary, and more on which of the pathologic abnormalities lead to muscle-fiber degeneration and weakness. It is now well-accepted that despite accumulation and activation of T-cells, s-IBM patients as a group respond poorly to anti-dysimmune treatment, in contrast to polymyositis patients, who have virtually identical immunopathologic abnormalities in their muscle biopsies [13, 29, 30, 35, 69]. This suggests that non-inflammatory factors are clinically more important.

We propose that the degenerative component within s-IBM muscle fibers is pathogenically more important and is responsible for lack of response to various immune-modulating treatments. Accordingly, therapeutic considerations should focus on reducing detrimental degenerative components .

. . .

Possible treatment avenues for s-IBM

Based on our studies, we propose that the most important general approach to developing treatment for s-IBM patients or to prevent progression of the disease is to stop deterioration and atrophy of the muscle fibers. The treatment approaches might be multifactorial, aiming toward various detrimental factors described above. Some approaches, based on our experimental IBM-culture models, appear promising. For example, our most recent studies demonstrated the following.

Resveratrol

Treatment with resveratrol of ER stress-induced cultured human muscle fibers (ER stress + IBM-culture-model) significantly decreased in them myostatin mRNA and protein, and was associated NF-kB de-acetylation (de-activation) [70]. Previously, resveratrol was shown to decrease Aβ and diminish AD neuropathology in AD mouse models [reviewed in 28]. Resveratrol (trans-3,4',5-trihydroxystilbene), is an antioxidant polyphenol and a potent activator of SIRT1 (reviewed in [27]). Accordingly, resveratrol, and/or other small molecules that activate SIRT1, activity of which is decreased in s-IBM muscle [71], might be beneficial in treating s-IBM patients. Recently, SIRT1 activity has been reported to increase autophagy [60]. Although the exact role of autophagy in s-IBM awaits further studies, resveratrol possibly could also benefit s-IBM patients through induction of autophagy.

Lithium

Lithium has previously been shown to diminish tau and Aβ pathologies in various experimental models of AD (reviewed in [34]), but its clinical efficacy in treating AD patients is not established. In a transgenic mouse model whose skeletal muscle bears some aspects of IBM muscle fibers, lithium was reported to decrease tau phosphorylation through decreasing activity of GSK-3β [54].

Recently, we have shown that treatment of AβPP-overexpressing cultured human muscle fibers (AβPP + culture-IBM-model) with lithium significantly decreased total AβPP, phosphorylated AβPP, and Aβ oligomers [92]. In addition, lithium significantly increased the inactive form of GSK-3β and increased expression of an autophagosome marker LC3-II [92]. Accordingly, treating of s-IBM patients with lithium possibly could be beneficial.

Other possible treatments

Other approaches may involve the following. (1) Stopping hyper-phosphorylation of tau, which leads to its self-aggregation into PHFs, or blocking the aggregation process itself (and blocking any hypothetical binding of hyper-phosphorylated tau to normal cellular components). (2) Diminishing adverse effects of intra-muscle fiber cholesterol. However, the use of statins is of uncertain benefit and potentially myotoxic. (3) Reducing oxidative stress with various antioxidants. (4) Protecting mitochondria, especially ones not yet affected, perhaps with very high dose Coenzyne Q10 and l-carnitine (neither of proven efficacy), and with better protective molecules as they are developed. Greater understanding of molecular mechanisms associated with human muscle-fiber aging could provide new avenues toward s-IBM therapy.

IBM, AD (Alzheimer's disease), and PD (Parkinson's disease), including sporadic and hereditary forms of each, are all multifactorial and polygenetic. The respective cascade of events in each leading to their similar pathologic aspects is not well understood; cellular aging, protein misfolding, aggregation, proteasome inhibition, and mitochondrial abnormalities, as well as oxidative and ER stress have been proposed to be contributing in s-IBM, AD and PD. Yet each disease category remains tissue- and region-specific, involving postmitotic-muscle fibers or postmitotic-neurons, thereby indicating that the mechanism of cellular-targeting is different in IBM, AD and PD. The tissue affected, muscle versus brain, may be influenced by: (1) etiologic agent (? a virus), (2) previous exposure to an environmental factor(s), (3) subtle differences of deficiency or toxicity factors, and (4) the patient's genetic background (the cellular microclimate). Easier availability of s-IBM patients' muscle biopsies, as compared to brain tissue, and the possibility of producing IBM experimental models by utilizing cultured human muscle fibers (which are the cells actually affected in the s-IBM disease process), might provide better understanding of some pathogenic aspects, not only related to s-IBM, but also to AD and PD, and facilitate development of treatments.


PubMed Link

Arthritis Rheum. 2008 Oct 30;58(11):3600-3608.

Human muscle cells express the costimulatory molecule B7-H3, which modulates muscle-immune interactions.
Waschbisch A, Wintterle S, Lochmüller H, Walter MC, Wischhusen J, Kieseier BC, Wiendl H.
University of Wuerzburg, Wuerzburg, Germany, and University of Erlangen, Erlangen, Germany.
OBJECTIVE: Interactions between the family of B7 ligands and their receptors are increasingly recognized as crucial for stimulation and/or inhibition of immune responses. The present study was undertaken to examine the expression and functional relevance of B7 homolog 3 (B7-H3), a novel B7 homolog attributed significant immunoregulatory functions, in human muscle cells in vivo and in vitro. METHODS: Thirty-five muscle biopsy specimens obtained from patients with polymyositis, dermatomyositis, inclusion body myositis, or noninflammatory myopathies and normal controls were analyzed by immunohistochemistry for B7-H3 expression. The expression of B7-H3 protein on primary human myoblasts and TE671 muscle rhabdomyosarcoma cells was studied by flow cytometry and Western blot analysis. B7-H3 small interfering RNA (siRNA) was used to study the impact of knockdown of B7-H3 on CD8+ cell-mediated lysis in skeletal muscle cells. RESULTS: B7-H3 was not detectable on normal muscle fibers. In contrast, its expression was markedly increased on muscle fibers from patients with inflammatory myopathies. Cell-surface staining was most prominent in the contact areas between muscle fibers and inflammatory cells. B7-H3 protein was detected on myoblasts cultured from control and myositis patient muscle tissue as well as in TE671 muscle rhabdomyosarcoma cells. Knockdown of B7-H3 by siRNA in TE671 cells enhanced CD8+ T cell-specific lysis, indicating a functional role of B7-H3 in the protection of skeletal muscle from immune-mediated lysis. CONCLUSION: Our results demonstrate that human muscle cells express B7-H3, a functional coinhibitory molecule of the B7 family. B7-H3 may play an important role in muscle-immune interactions, providing further evidence of the active role of muscle cells in local immunoregulatory processes. PMID: 18975328

Quote: Identifying positive and negative regulators of muscle - immune interactions and learning about the mechanisms that balance these regulatory influences are crucial for understanding cellular processes in muscle inflammation. Emerging evidence will help us not only to unravel the pathogenesis of inflammatory muscle disorders, but also to further the development of therapies that rely on muscle, such as techniques involving gene therapy, DNA vaccination, or myoblast transplantation.


PubMed Link

Curr Opin Rheumatol. 2008 Nov;20(6):681-5.
Animal models in myositis.
Katsumata Y, Ascherman DP.
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan. katsumata@ior.twmu.ac.jp
PURPOSE OF REVIEW: The etiology of the idiopathic inflammatory myopathies remains elusive. Delineation of pathogenic mechanisms in humans is hindered by the heterogeneity of different patient populations as well as the complexity and chronicity of the disease. Therefore, appropriate animal models are required to help clarify the immunopathogenesis of these disorders and to explore promising new therapies. The purpose of this review is to discuss recently published animal models in myositis, with a particular focus on idiopathic inflammatory myopathy. RECENT FINDINGS: Over the last few years, there has been considerable progress in the development of animal models for polymyositis and inclusion body myositis, but reports focusing on dermatomyositis have been limited. Although some of these systems are entirely novel, others have elucidated pathogenic mechanisms of existing models. SUMMARY: Several new animal models of myositis have emerged over the last few years that have revealed new insights regarding the pathophysiology of idiopathic inflammatory myopathy and that should set the foundation for development of new, more effective therapies against this often intractable disease. PMID: 18946328

PubMed Link

Curr Opin Rheumatol. 2008 Nov;20(6):669-74.
Dendritic cells and the immunopathogenesis of idiopathic inflammatory myopathies.
de Padilla CM, Reed AM.
Division of Rheumatology, Departments of Medicine, Pediatrics, and Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
PURPOSE OF REVIEW: Mechanisms driving the autoimmune process in idiopathic inflammatory myopathies (IIMs) have not been unraveled, despite extensive studies. In recent times, it has become apparent that heterogeneous populations of dendritic cells have specialized roles in IIM. Here, we will discuss the role of dendritic cells in the induction of adaptive immune response in IIM and review the recent literature addressing the role of dendritic cells in the cause and pathogenesis of inflammatory myopathies. RECENT FINDINGS: Different subsets of immature and mature dendritic cells have been recently identified in skeletal muscle in IIM. Dendritic cells present in inclusion body myositis and polymyositis are primarily myeloid dendritic cells. In contrast, plasmacytoid dendritic cells, a subset of dendritic cells and considered the main source of the interferon-alpha/beta (IFN-alpha/beta), have been found abundantly in muscle tissue of adult dermatomyositis and juvenile dermatomyositis. SUMMARY: Dendritic cells are associated with the chronic infiltration of mononuclear cells in the inflammatory muscle tissue of IIM patients. Increasing evidences point out that dendritic cells are not only crucially involved in the initiation of anti-self immune response but are also essential for the maintenance of autoimmune lesions in inflammatory myopathies. PMID: 18946326

PubMed Link

Curr Opin Rheumatol. 2008 Nov;20(6):662-8.
Inclusion body myositis: new insights into pathogenesis.
Garlepp MJ, Mastaglia FL.
School of Pharmacy, Curtin University of Technology, Australia. mgarlepp@ichr.uwa.edu.au
PURPOSE OF REVIEW: The pathogenesis of sporadic inclusion body myositis is complex and the disease has a relentless course. Recent observations regarding possible mechanisms of disease may provide targets for therapy. RECENT FINDINGS: Evidence is strengthening that specific T-cell and B-cell responses are ongoing in skeletal muscle in sporadic inclusion body myositis and that cytokines and chemokines generated by an autoimmune response are likely to influence antigen presentation by intramuscular dendritic cells and muscle cells, expression of amyloid precursor protein and the endoplasmic reticulum stress response. Early beta-amyloid expression and perhaps aberrant expression of protein processing enzymes, such as E3 ligases, seem to be involved in the myopathic process. NF-kappaB activation by endoplasmic reticulum stress and cytokine action further stimulates amyloid precursor protein production, exacerbates endoplasmic reticulum stress and increases myostatin content in muscle contributing to muscle atrophy. SUMMARY: Understanding the paradoxes in sporadic inclusion body myositis is important in determining rational therapy for the disease. Amyloid precursor protein is expressed in muscle in other inflammatory muscle diseases but the cellular distribution differs and inclusions do not form so that other metabolic defects seem to be important. Intramuscular immune cells influence muscle function and viability in inclusion body myositis but immunotherapy is ineffective. A useful target for therapy may be restoration of muscle regenerating capacity.
Conclusion
T-cell-mediated autoimmunity is a key factor in the pathogenesis of s-IBM and it is likely that soluble mediators such as IL-1β contribute to the endoplasmic reticulum stress and aberrant protein accumulation. The myopathy is unlikely to be solely due to infammatory mediator interaction with muscle and evidence is mounting to support a role for aberrant expression of enzymes involved in the endoplasmic reticulum stress and ubiquitination responses early in disease. Overexpression of APP and accumulation of ubiquinated proteins per se are not suffcient to explain the pathological features of s-IBM so that a genetic predisposition to autoimmunity may be necessary for manifestation of the disease.
PMID: 18946325

PubMed Link

Neurobiol Aging. 2008 Oct 13. [Epub ahead of print]

Decreased SIRT1 deacetylase activity in sporadic inclusion-body myositis muscle fibers.
Nogalska A, D'Agostino C, Engel WK, Davies KJ, Askanas V.
Department of Neurology, USC Neuromuscular Center, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA 90017-1912, USA.
SIRT1 belongs to the sirtuin family of NAD(+)-dependent histone/protein deacetylases. Experimentally, increased activity of SIRT1 facilitates calorie-restricted longevity, and decreases NF-kappaB activation and the amount of the amyloid-beta (Abeta). We studied SIRT1 in an aging-associated muscle disease, sporadic inclusion-body myositis (s-IBM), whose muscle fibers contain increased NF-kappaB activation and abnormal accumulation of Abeta. We show that, as compared to the age-matched controls, in s-IBM muscle fibers: (1) SIRT1 activity and deacetylation of SIRT1 targets, H4, NF-kappaB and p53 were decreased; (2) SIRT1 mRNA and protein were significantly increased; (3) in the cytoplasm, SIRT1 protein was accumulated in the form of cytoplasmic aggregates; (4) in the nuclei, SIRT1 protein was decreased. To our knowledge, this is the first demonstration of SIRT1 abnormalities, including decreased SIRT1 deacetylase activity, in human disease associated with aging. We propose that in s-IBM muscle fibers, inadequate activity of SIRT1 may be detrimental by increasing NF-kappaB activation and contributing to abnormal Abeta accumulation. Improving SIRT1 action by treatment with known SIRT1 activators might benefit s-IBM patients. PMID: 18922603

related article [thanks to Bob Albrecht for this reference]

PubMed Link

Eur J Cell Biol. 2008 Oct 13. [Epub ahead of print]
Sirt1 increases skeletal muscle precursor cell proliferation.
Rathbone CR, Booth FW, Lees SJ.
Department of Biomedical Sciences, University of Missouri-Columbia, Columbia, MO 65211, USA.
It is important to understand the mechanisms that control muscle precursor cell (MPC) proliferation for the development of countermeasures to offset the deleterious effects of the aging-related loss of skeletal muscle mass (and myonuclei) and the impaired ability of old muscle to regrow and regenerate. Over-expression of the NAD(+)-dependent histone deacetylase Sirt1 increased MPC proliferation and cell cycle progression as evidenced by increased 5-bromo-2'-deoxyuridine (BrdU) incorporation, an increase in cell number, proliferating cell nuclear antigen expression, and the phosphorylation of retinoblastoma protein. Associated with the Sirt1-mediated increase in MPC cycle progression were the bidirectional decreases and increases in the expression of the cyclin-dependent kinase inhibitors p21(Waf/Cip1) and p27(Kip1), respectively. Based upon our recent observation that lowering oxygen (O(2)) in culture from ambient (20%) to estimated physiological levels (5%) increased MPC proliferation, we next measured Sirt1 protein at 5% and 20% O(2). Interestingly, in addition to increased proliferation in MPCs cultured at 5% O(2), Sirt1 expression increased, compared to 20% O(2). Using O(2) levels as a platform to modulate basal Sirt1 protein, activation of Sirt1 activity with resveratrol in 20% O(2) increased MPC proliferation while inhibition of Sirt1 with nicotinamide in 5% O(2) lowered proliferation. For the first time, Sirt1 has been shown to increase MPC proliferation. These findings could have clinical significance since MPC proliferation has important implications in regulating skeletal muscle growth, maintenance, and repair, and the aging-related loss of skeletal muscle mass. PMID: 18922599

PubMed Link

J Neurol Neurosurg Psychiatry. 2008 Oct;79(10):1186-9.
TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia.
Weihl CC, Temiz P, Miller SE, Watts G, Smith C, Forman M, Hanson PI, Kimonis V, Pestronk A.
Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA. weihlc@neuro.wustl.edu
TAR DNA binding protein-43 (TDP-43) is found in ubiquitinated inclusions (UBIs) in some frontotemporal dementias (FTD-U). One form of FTD-U, due to mutations in the valosin containing protein (VCP) gene, occurs with an inclusion body myopathy (IBMPFD). Since IBMPFD brain has TDP-43 in UBIs, we looked for TDP-43 inclusions in IBMPFD muscle. In normal muscle, TDP-43 is present in nuclei. In IBMPFD muscle, TDP-43 is additionally present as large inclusions within UBIs in muscle cytoplasm. TDP-43 inclusions were also found in 78% of sporadic inclusion body myositis (sIBM) muscles. In IBMPFD and sIBM muscle, TDP-43 migrated with an additional band on immunoblot similar to that reported in FTD-U brains. This study adds sIBM and hereditary inclusion body myopathies to the growing list of TDP-43 positive inclusion diseases.

comment added by the webmaster-- there's an interesting cross-reference to IBM here: HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNA genome that produces a chromosomally integrated DNA during the replicative cycle. Activation of HIV-1 gene expression by the transactivator Tat is dependent on an RNA regulatory element (TAR) located downstream of the transcription initiation site. The protein encoded by this gene is a transcriptional repressor that binds to chromosomally integrated TAR DNA and represses HIV-1 transcription. In addition, this protein regulates alternate splicing of the CFTR gene. A similar pseudogene is present on chromosome 20. TDP-43 is a cellular protein that binds specifically to pyrimidine-rich motifs in HIV-1 double-stranded TAR DNA and represses transcription from the HIV-1 LTR promoter in both the presence and absence of HIV-1 Tat source


PubMed Link

J Clin Neurosci. 2008 2008 Dec;15(12):1350-3. Prevalence of sporadic inclusion body myositis and factors contributing to delayed diagnosis.
Needham M, Corbett A, Day T, Christiansen F, Fabian V, Mastaglia FL. Centre for Neuromuscular and Neurological Disorders, Australian Neuromuscular Research Institute (ANRI), Level 4, A-Block, University of Western Australia, Queen Elizabeth II Medical Centre, Nedlands, Perth 6009, Western Australia.
The prevalence of sporadic inclusion body myositis (sIBM) is variable in different populations and ethnic groups. A previous survey in Western Australia in 2000 found a prevalence of 9.3 per million population. We have now performed a follow-up survey to determine whether there has since been any change in prevalence. The current prevalence was found to be 14.9 per million population, with a prevalence of 51.3 per million population in people over 50 years of age. This is the highest reported prevalence of sIBM and correlates with a high frequency of HLA-DR3 and the 8.1 major histocompatibility complex ancestral haplotype in this population. Review of a combined cohort of 57 sIBM cases from three Australian centres revealed a high rate of initial misdiagnosis and a mean time to diagnosis of 5.2 years, which suggests that even the latest prevalence figure may be an underestimate, and emphasising the need to increase the level of awareness of the condition among the medical community. PMID: 18815046

PubMed Link

Arthritis Rheum. 2008 Sep 29;58(10):3216-3223.
Expression of the CD85j (leukocyte Ig-like receptor 1, Ig-like transcript 2) receptor for class I major histocompatibility complex molecules in idiopathic inflammatory myopathies.
Schleinitz N, Cognet C, Guia S, Laugier-Anfossi F, Baratin M, Pouget J, Pelissier JF, Harle JR, Vivier E, Figarella-Branger D. CHU La Conception, Marseille, France.
OBJECTIVE: Expression of class I major histocompatibility complex (MHC) molecules on the surface of muscle cells is a biologic feature of idiopathic inflammatory myopathies (IIM). Class I MHC-transgenic mouse models support a causative role for class I MHC expression by muscle cells in the pathogenesis of IIM. The muscle lesions are characterized by leukocyte infiltration. We undertook this study to analyze the expression in muscle lesions of various class I MHC-specific receptors on leukocytes and natural killer (NK) cells. METHODS: We generated a panel of cell transfectants to control the immunofluorescence analysis of class I MHC receptor expression. We then analyzed the expression of CD158 (killer cell Ig-like receptors [KIRs]) and CD85j (leukocyte Ig-like receptor 1, Ig-like transcript 2) on muscle sections prepared from 14 patients with IIM (5 with dermatomyositis [DM], 5 with polymyositis [PM], and 4 with sporadic inclusion body myositis [IBM]). RESULTS: We could not detect the presence of NK cells in inflammatory lesions. However, the class I MHC receptor CD85j, but no KIRs, was expressed by inflammatory cells infiltrating muscle lesions in IIM. CONCLUSION: CD85j is expressed in PM and sporadic IBM at the sites of partial invasion and in DM in perivascular inflammation, paving the way for dissecting the role of CD85j in the pathogenesis of inflammatory myopathies. PMID: 18821690

PubMed Link

Neurobiol Aging. 2008 Sep 25.

Please cite this article in press as: Morosetti, R., et al., Increased aging in primary muscle cultures of sporadic inclusion-body myositis. Neurobiol Aging (2008), doi:10.1016/j.neurobiolaging.2008.08.011

Increased aging in primary muscle cultures of sporadic inclusion-body myositis.
Morosetti R, Broccolini A, Sancricca C, Gliubizzi C, Gidaro T, Tonali PA, Ricci E, Mirabella M. Department of Neuroscience, Catholic University, Rome, Italy; Fondazione Don Carlo Gnocchi, Rome, Italy.
Ageing is thought to participate to the pathogenesis of sporadic inclusion-body myositis (s-IBM). Although the regenerative potential of s-IBM muscle is reduced in vivo, age-related abnormalities of satellite cells possibly accounting for the decline of muscle repair have not been demonstrated. Here we show that proliferation rate and clonogenicity of s-IBM myoblasts are significantly lower and doubling time is longer than normal age-matched controls, indicating that proliferative capacity of s-IBM muscles becomes exhausted earlier. Telomere shortening is detected in s-IBM cells suggesting premature senescence. Differently from controls, s-IBM myoblasts show increased active β-catenin mainly localized within myonuclei, indicating active Wnt stimulation. After many rounds of muscle growth, only s-IBM myoblasts accumulate congophilic inclusions and immunoreactive Aβ(1-40) deposits. Therefore, s-IBM myoblasts seem to have a constitutively impaired regenerative capacity and the intrinsic property, upon sufficient aging in vitro, to accumulate Aβ. Our results might be valuable in understanding molecular mechanisms associated with muscle aging underlying the defective regeneration of s-IBM muscle and provide new clues for future therapeutic strategies. PMID: 18823681

The cause and the pathogenesis of s-IBM are unknown and its histopathology is characterized by the presence of lymphocytic infiltrates combined with degenerative features such as formation of vacuoles, intracellular inclusions and accumulation of amyloid-β protein (Aβ) and other related molecules (Engel and Askanas, 2006). s-IBM may be considered an age-related myopathy (Askanas and Engel, 2007) and various muscle changes occurring in normal aging may be exacerbated in s-IBM muscle, thus participating in its pathogenesis. It is known that primary s-IBM myoblasts do not show evident morphological abnormalities, are capable of normally differentiating and can be properly innervated (McFerrin et al., 1999). Although the regenerative potential of s-IBM muscle is apparently greatly reduced in vivo, characteristic age-related abnormalities of satellite cells, that might account for the decline in muscle repair ability, have not been demonstrated so far.

4. Discussion

s-IBM is the most common acquired muscle disease of older persons and, because of its generally unsatisfactory response to antidysimmune treatments, has a progressive course leading to severe disability. Ageing is considered a crucial aspect contributing to the pathogenesis of s-IBM and to the development of its characteristic molecular phenotype. In s-IBM muscle the presence of degenerative features, such as vacuolated fibers containing Aβ and amyloid-related proteins (Askanas and Engel, 2006), reflects a complex multifactorial pathogenesis involving misfolded and unfolded proteins and increased oxidative stress in the context of a cellular 'aged' milieau which act in concert with chronic inflammation (Askanas and Engel, 2003). Degenerating muscle fibers display progressive vacuolization, atrophy and accumulation of multiprotein aggregates accompanied by proteasome inhibition and endoplasmic reticulum stress (Askanas and Engel, 2007). In particular, the increased intracellular expression ofAβPP and its toxic proteolitic fragment Aβ is thought to play a key upstream role in the pathogenic cascade leading to muscle degeneration (Askanas and Engel, 2006). It has also been postulated that the aging environment of s-IBM with its characteristic muscle degenerative changes may elicit a T-cell inflammatory reaction facilitating the establishment of the chronic lymphocytic inflammation (Askanas and Engel, 2007). Satellite cell-dependent regeneration occurs also in s-IBM muscle wherein multiple metabolic pathways normally involved in muscle development are activated (Broccolini et al., 2004, 2006). However, in s-IBM muscle, despite the activation of potentially repairing mechanisms and an apparently normal representation of satellite cells (M. Mirabella, personal observation), regenerating muscle fibers are scarce in comparison to other myopathies and, overall regeneration is insufficient to counterbalance the ongoing muscle fibers degeneration. Our studydemonstrates that it is possible to isolate myoblasts from s-IBM muscle biopsies to a lesser extent compared to agematched controls. In fact, two of the s-IBM biopsies were not able to produce myoblasts beyond R3, whereas in the other six biopsies, myoblast proliferation was steady, although quantitatively less pronounced compared with normal aged controls, up to R7 and then abruptly stopped at R8. Proliferation rate and clonogenicity of s-IBM myoblasts were significantly lower and doubling time significantly longer than normal controls, even from young cultures obtained from R2, indicating that these findings do not simply reflect replicative senescence due to extended proliferation in culture and suggesting that the regenerative capacity of s-IBM satellite cells might be constitutively impaired. These observations were also supported by the detection of telomere shortening in s-IBM samples already at R2-P5, thus indicating premature senescence even in 'young' s-IBM cultures. Our results may be valuable in understanding the molecular mechanisms underlying the defective regeneration of muscle fibers observed in s-IBM muscle. As a matter of fact, we do believe that promoting in culture the outgrow of myoblasts directly from the muscle explant, rather than obtaining them through direct dissociation of the specimen, more closely resembles the physiologic mechanism of myoblast proliferation that takes place in muscle. This probably because the myogenic cells, that are resident in the muscle fragment and give rise to the outgrowing muscle cells, remain in their tissue micro-environment when experimentally promoted to replicate. In addition, in the cultured monolayer, muscle cells coexist with fibroblasts that also emerge from the muscle fragments, thus resembling more the in vivo situation, where muscle fibers are surrounded by non-muscle cells (Askanas and Engel, 1992). Using this experimental approach, we have shown aging-related phenotypic abnormalities that seem exclusive of s-IBM cultures and would have been missed if the observation was conducted only on myoblasts obtained right after the initial plating of the muscle fragment in the culturing dish. Overall, our evidence strongly argues in favor of the fact that the proliferation capacity of s-IBM muscles becomes exhausted at an earlier stage compared with their age-matched normal counterparts. . . .

Our observation suggests that the modulation of Wnt signaling pathway may be relevant in designing therapeutic strategies directed to ameliorate the impairment of muscle regeneration in s-IBM and to reduce the effects of the aged environment on myogenic progenitor cells fate. . . .

Our study confirms that relatively short-term cultures of s-IBM appear morphologically indistinguishable from normal muscle cultures and do not show Aβ accumulation, congophilic inclusions or structural abnormalities.. . .

Therefore, we can speculate that, in our in vitro system, the abnormal metabolic changes caused by the aging process of myoblasts in culture lead to an impairment of the cellular Aβ clearing system, thus promoting the accumulation of Aβ1-40 despite a normal level of expression of its precursor. Based on the results of our study, the possibility exists that, in s-IBM muscle, an impairment of the Aβ clearing system, due to abnormal mechanisms of increased aging, is indeed primarily responsible for the initial deposition of Aβ within muscle fibers. This would possibly activate a 'vicious-circle' scenario where the increased accumulation of Aβ leads to increased oxidative stress, which inturn causes over-expression of specific transcription factors capable of increase the AβPP production, thus creating a self-perpetuating cellular destructive mechanism. However, further studies are necessary to clarify this issue. In our opinion these data bear two important consequences. First, satellite cells of s-IBM from which cultured myoblasts are derived, have the intrinsic property, upon sufficient aging in vitro, to accumulate Aβ, manifesting at least some of the aspect of the phenotype of mature muscle fibers. . . .The second main consideration, which is a direct consequence of this line of evidence, is that s-IBM cultured cells have an increased susceptibility to undergo degenerative changes in response to various stressors and the occurrence of spontaneous accumulation ofAβ in aged s-IBM cultures indicates that this is indeed a primary aging-related mechanism contributing to s-IBM muscle degeneration in vivo.

In view also of possible future application of myogenic stem cells-based therapies, it is of paramount importance to look for pharmacological or molecular strategies trying to protect transplanted cells from the pathogenic factors promoting excessive aging which operate in the s-IBM muscle environment in vivo and that may also affect them, thus greatly reducing their muscle regenerative potential and clinical usefulness.

Article available here.



PubMed Link

J Neuropathol Exp Neurol. 2008 Jul;67(7):711-9.
Endothelial and myogenic differentiation of hematopoietic progenitor cells in inflammatory myopathies.
Hollemann D, Budka H, Löscher WN, Yanagida G, Fischer MB, Wanschitz JV.
Department of Blood Group Serology and Transfusion Medicine, Institute of Neurology, Medical University Vienna, Austria.
Incorporation of circulating hematopoietic progenitor cells (HPCs) into damaged skeletal muscle has been proposed as a novel mechanism of tissue repair complementary to satellite cell-dependent regeneration. We studied the occurrence and myoendothelial differentiation of HPCs in muscle of patients with inflammatory myopathies. Muscle biopsies from untreated patients with dermatomyositis, polymyositis, inclusion body myositis, and controls were investigated for the expression of endothelial (CD31, von Willebrand factor, vascular endothelial growth factor receptor 2), hematopoietic (CD34, CD133, CD45), and myogenic (Pax7, MyoD) markers by immunohistochemistry and reverse-transcriptase-polymerase chain reaction. Confocal laser scanning microscopy was used to visualize coexpression of CD34, CD133, von Willebrand factor, or Pax7 on individual cells. Morphometric analysis revealed significantly increased numbers of CD133 cells per square millimeter in polymyositis and inclusion body myositis compared with controls (p < 0.001); this correlated with the density of CD45 infiltrates (p < 0.001). By confocal laser scanning microscopy, we detected several mononuclear cells that coexpressed either CD34/von Willebrand factor or CD133/Pax7 with or without CD34 reactivity, indicating endothelial or myogenic commitment of some HPCs in skeletal muscle. Rarely, CD133/CD34/Pax7 cells seemed to occupy satellite cell niches or to incorporate into preexisting myofibers. Our findings suggest that circulating HPCs colonize skeletal muscle in inflammatory conditions and provide evidence for in situ myoendothelial differentiation of some of these cells. PMID: 18596542

In IBM, the most frequent IM in elderly patients, chronic inflammation occurs in conjunction with a degenerative process that is related to protein misfolding and deposition of β-amyloid and is associated with a poor response to current immunotherapies and progressive disability of most patients.

Although rarely observed in human tissue, our study is in accordance with experimental data supporting the concept that circulating myoendothelial progenitors can colonize skeletal muscle after injury, creating a 'steady state' of equilibrium with resident satellite cells and EPCs and participating in the permanent restoration of damaged muscle. These complementary mechanisms of tissue regeneration seemed to be particularly enhanced in patients with IBM, which might reflect an attempt to compensate for the failure to rebuild muscle after sustained degeneration and regeneration cycles in the context of an aged milieu of IBM muscle.



Brain. 2008 Jul 24; Page E1 of E2 Inflammation interrelates to APP in sIBM: IL-1{beta} induces accumulation of {beta}-amyloid.
Jens Schmidt, Marinos C Dalakas
Letter: reply to Greenberg (see below).

PubMed Link

J Neurol. 2008 Jul;255 Suppl 3:12-6.
IVIg in other autoimmune neurological disorders: current status and future prospects.
Dalakas M.
Neuromuscular Division, Dept. of Neurology, 900 Walnut St., 2nd Floor, Philadelphia, PA 19107, USA. marinos.dalakas@jefferson.edu
A number of autoimmune disorders have been identified in which IVIg treatment may be beneficial. Evidence for the use of IVIg in inflammatory myopathies comes from controlled trials in dermatomyositis (DM) and sporadic-inclusion body myositis (s-IBM). In DM, muscle strength was increased and neuromuscular scores and skin rashes improved. Results for s-IBM have not been as encouraging as those observed for DM. Subsequently, IVIg should be recommended as a second-line therapy in DM and used for life-threatening dysphagia in s-IBM. Using an animal model of experimental autoimmune myasthenia gravis (MG), studies also indicate that IVIg can significantly improve clinical symptoms and affect pathogenic idiotypic antibodies. In human MG, studies indicate that IVIg exhibited equal efficacy compared to plasmapheresis. IVIg can therefore be recommended for use in an MG crisis or in lieu of plasmapheresis. The role of IVIg in the chronic management of MG has not been studied. IVIg has also been investigated in autoimmune CNS disorders. In a controlled study in patients with stiff person syndrome IVIg was effective, with improvements in the distribution of stiffness index and heightened sensitivity scores. For neurodegenerative diseases such as Alzheimer's disease, post-polio syndrome, pain, fibrosis, and autoimmune sleep disorders, some early promising results for the use of IVIg are emerging, but remain to be fully investigated. In conclusion, IVIg appears to be an effective treatment for a number of autoimmune disorders, however, optimal dosing and pharmacogenetic studies are necessary. PMID: 18685921

PubMed Link

J Neurol Neurosurg Psychiatry. 2008 Oct;79(10):1186-9.
TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia.
Weihl CC, Temiz P, Miller SE, Watts G, Smith C, Forman M, Hanson PI, Kimonis V, Pestronk A. Dr C C Weihl, Department of Neurology, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA; weihlc@neuro.wustl.edu.
TAR DNA binding protein-43 (TDP-43) is found in ubiquitinated inclusions (UBIs) in some frontotemporal dementias (FTD-U). One form of FTD-U, due to mutations in the valosin containing protein (VCP) gene, occurs with an inclusion body myopathy (IBMPFD). Since IBMPFD brain has TDP-43 in UBIs, we looked for TDP-43 inclusions in IBMPFD muscle. In normal muscle, TDP-43 is present in nuclei. In IBMPFD muscle, TDP-43 is additionally present as large inclusions within UBIs in muscle cytoplasm. TDP-43 inclusions were also found in 78% of sporadic inclusion body myositis (sIBM) muscles. In IBMPFD and sIBM muscle, TDP-43 migrated with an additional band on immunoblot similar to that reported in FTD-U brains. This study adds sIBM and hereditary inclusion body myopathies to the growing list of TDP-43 positive inclusion diseases. PMID: 18796596


PubMed Link
Mol Neurobiol. 2008 Sep 5. [Epub ahead of print]
Inclusion Body Myositis: A View from the Caenorhabditis elegans Muscle.
Rebolledo DL, Minniti AN, Grez PM, Fadic R, Kohn R, Inestrosa NC. Centro de Envejecimiento y Regeneración (CARE), Centro de Regulación Celular y Patología "Joaquín V. Luco" (CRCP), MIFAB, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Alameda, 340, Santiago, Chile.
Inclusion body myositis (IBM) is the most common myopathy in people over 50 years of age. It involves an inflammatory process that, paradoxically, does not respond to anti-inflammatory drugs. A key feature of IBM is the presence of amyloid-beta-peptide aggregates called amyloid deposits, which are also characteristic of Alzheimer's disease. The use of animals that mimic at least some characteristics of a disease has become very important in the quest to elucidate the molecular mechanisms underlying this and other pathogeneses. Although there are some transgenic mouse strains that recreate some aspects of IBM, in this review, we hypothesize that the great degree of similarity between nematode and human genes known to be involved in IBM as well as the considerable conservation of biological mechanisms across species is an important feature that must be taken into consideration when deciding on the use of this nematode as a model. Straightforward laboratory techniques (culture, transformation, gene knockdown, genetic screenings, etc.) as well as anatomical, physiological, and behavioral characteristics add to the value of this model. In the present work, we review evidence that supports the use of Caenorhabditis elegans as a biological model for IBM.


PubMed Link
Curr Opin Neurol. 2008 Oct;21(5):596-600.
Recent advances in distal myopathy with rimmed vacuoles (DMRV) or hIBM: treatment perspectives.
Malicdan MC, Noguchi S, Nishino I.
National Institute of Neurosciences, National Center of Neurology and Psychiatry, Tokyo, Japan.
PURPOSE OF REVIEW: Distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy is an adult-onset autosomal recessive, slowly progressive and debilitating myopathy due to mutations in the gene that regulates the synthesis of sialic acid. This review aims to update our knowledge of this myopathy and to review studies about pathomechanism and therapeutic strategies. RECENT FINDINGS: Owing to the mutated gene, it was expected that the pathomechanism of this myopathy would be based on hyposialylation, a highly controversial phenomenon. This concept has been supported by findings in two recently generated animal models. In addition, the intracellular amyloid-beta accumulation in a distal myopathy with rimmed vacuole mouse model is relevant to similar findings in patients. SUMMARY: Clarifying the role of hyposialylation in distal myopathy with rimmed vacuole/hereditary inclusion body myopathy could potentially lead to a therapeutic strategy for this progressive myopathy. In addition, strategies aimed at preventing amyloid-beta deposition or enhancing its clearance could also be beneficial, as this epiphenomenon is now known to occur early in the course of the disease. PMID: 18769255
"As GNE is involved in sialic acid biosynthesis, it follows that decreased sialic acid, or hyposialylation, should be considered to play a role in the symptomatology or disease progression in DMRV/hIBM."
"Conclusion From these recent studies, it is clear that hyposialylation has a central role in the pathogenesis of this myopathy, though specific details are lacking as to how this phenomenon causes disease. Of greater practical importance, this phenomenon should not be disregarded because it opens an avenue to therapy, and trials addressing this step in the DMRV/hIBM mouse are much anticipated. Another issue that may beworth exploring is the early epiphenomenon of amyloidogenesis, which can be targeted for therapy."


Brain Advance Access published July 24, 2008
Brain (2008) Page E1 of E2
Letter: Comment on 'Interrelation of inflammation and APP in sIBM: IL-1β induces accumulation of b-amyloid in skeletal muscle' by Steven A. Greenberg
It therefore seems uncertain as to whether any b-amyloid protein is being seen in IBM myofibres in these experiments. More generally, given that no western blot study of IBM muscle demonstrating a 4 kDa band (the approximate mass of β -amyloid) immunoreactive with any anti-β -amyloid antibody has ever been published, together with multiple immunohistochemical studies that have failed to see β -amyloid in IBM muscle and the inability of any antibodies that have been used to discriminate β-amyloid from APP, it is important to consider the possibility that no β -amyloid protein has ever been demonstrated in any IBM patient muscle sample, let alone demonstration that its presence is disease specific. These issues should be kept in mind with regard to the view that the accumulation of β-amyloid is an IBM 'hallmark'.
Comment on Schmidt J, Barthel K, Wrede A, Salajegheh M, Ba¨hr M, Dalakas MC. Interrelation of inflammation and APP in sIBM: IL-1β induces accumulation of β-amyloid in skeletal muscle. Brain 2008; 131: 1228-40.

PubMed Link

J Neurol Neurosurg Psychiatry. 2008 Sep;79(9):1056-60. Epub 2008 Feb 7.
Sporadic inclusion body myositis: phenotypic variability and influence of HLA-DR3 in a cohort of 57 Australian cases.
Needham M, James I, Corbett A, Day T, Christiansen F, Phillips B, Mastaglia FL.
Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australian Neuromuscular Research Institute (ANRI), Queen Elizabeth II Medical Centre, Nedlands, Perth 6009, WA, Australia. needhm01@student.uwa.edu.au
BACKGROUND AND AIMS: There have been few studies of the variability in the clinical phenotype in sporadic inclusion body myositis (sIBM) and it is not known whether the human leucocyte antigen (HLA) haplotype influences the phenotype and course of the disease. We studied a large cohort of patients with sIBM in order to determine the degree of phenotypic variability and different modes of presentation, as well as the influence of HLA haplotypes. METHOD: A cross-sectional study of 57 biopsy-proven sIBM cases from three Australian centres was performed. Patients were interviewed and examined by a single investigator, and had HLA typing and autoantibody studies. RESULTS: Although the initial symptoms in the majority of cases were attributable to quadriceps weakness (79%), a proportion of patients presented due to finger weakness (12%), foot drop (7%) or dysphagia (1.8%). Although the majority had the classic combination of quadriceps and forearm muscle involvement, some patients had predominantly forearm weakness with sparing of the quadriceps, or severe involvement of the anterior tibial muscles. Asymmetrical involvement was common (82%), particularly of the forearm muscles, with the non-dominant side being more severely affected in most cases. Carriage of the HLA-DRB1*0301 (DR3) allele was associated with lower quadriceps muscle strength and a more rapid decline in strength. CONCLUSIONS: The findings emphasise the variability in the mode of presentation, patterns of muscle involvement and clinical course of sIBM in this population, and indicate that the HLA-DRB1*0301 (DR3) allele may influence the rate of progression as well as susceptibility to the disease. PMID: 18258695

ApoE Gene - a gene on chromosome 19 involved in making ApoE, a substance that helps carry cholesterol in the bloodstream. The APOE gene comes in several different forms, or alleles, but three occur most frequently: APOE ε2, APOE ε3, and APOE ε4. The APOE ε4 gene is considered a "risk factor" gene for AD and appears to influence the age of onset of the disease.

APOE alleles have been investigated in sIBM to determine whether they might contribute to disease susceptibility or have a disease-modifying role. Previous studies of APOE yielded conflicting results in different populations. Conclusion: [we] have confirmed that APOE ε4 is a not a susceptibility factor for the development of sIBM. Although the APOE genotype does not appear to influence the risk of developing sIBM, it does not exclude a role for the apoE protein in the pathogenesis of the disease. The present findings also argue against a role for APOE alleles in conferring susceptibility to sIBM. However, it is of interest that there was a trend towards an earlier age of onset in patients with the ε2 allele. Thus, while the apoE protein may play a role in the pathogenesis of sIBM by influencing β-amyloid deposition and possibly muscle regeneration, the evidence indicates that possession of APOE ε4 per se is not a susceptibility factor or disease modifying factor for sIBM, although a possible disease modifying effect of ε2 may warrant further investigation in a larger cohort of cases.


PubMed Link

J Clin Neuromuscul Dis. 2008 Jun;9(4):397-401.
Hypogonadism is common in men with myopathies.
Al-Harbi TM, Bainbridge LJ, McQueen MJ, Tarnopolsky MA.
division of Neurology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
BACKGROUND: Hypogonadism has been described in patients with myotonic muscular dystrophy type 1 but has not been evaluated in other myopathies. METHODS: We measured total and free serum testosterone levels in 59 men with myotonic muscular dystrophy type 1 (N = 12), facioscapulohumeral muscular dystrophy (N = 11), dystrophinopathy (N = 12), metabolic myopathy (N = 7), and inclusion body myositis (N = 17) and compared these with the normal reference interval. RESULTS: Thirty-two of the 59 (54%) participants had low total testosterone, 23 (39%) had low total and free values, and 5 (8%) had low free with normal total levels. There were no significant differences in the prevalence of hypogonadism between those with myotonic muscular dystrophy type 1 and the other groups even after considering age as a confounder. CONCLUSIONS: Hypogonadism is common in men with myopathies, and with the importance of testosterone in the maintenance of muscle mass, treatment of hypogonadism should be considered. PMID: 18525423

See Table 2 Here


PubMed Link

Hum Mol Genet. 2008 Aug 23. [Epub ahead of print]
Mitochondrial processes are impaired in hereditary inclusion body myopathy.
Eisenberg I, Novershtern N, Itzhaki Z, Becker-Cohen M, Sadeh M, Willems PH, Friedman N, Koopman WJ, Mitrani-Rosenbaum S. Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Hereditary inclusion body myopathy (HIBM) is an adult onset, slowly progressive distal and proximal myopathy. Although the causing gene, GNE, encodes for a key enzyme in the biosynthesis of sialic acid, its primary function in HIBM remains unknown. To elucidate the pathological mechanisms leading from the mutated GNE to the HIBM phenotype, we attempted to identify and characterize early occurring downstream events by analyzing the genomic expression patterns of muscle specimens from 10 HIBM patients carrying the M712T Persian Jewish founder mutation and presenting mild histological changes, compared to 10 healthy matched control individuals, using GeneChip expression microarrays. When analyzing the expression profile datasets by the intersection of three statistic methods (Student's t-test, TNoM and Info score) we found that the HIBM specific transcriptome consists of 374 differentially expressed genes. The specificity of the HIBM transcriptome was assessed by the minimal transcript overlap found between HIBM and the transcriptome of 9 additional muscle disorders including adult onset limb girdle myopathies, inflammatory myopathies and early onset conditions. A strikingly high proportion (18.6%) of the overall differentially expressed mRNAs of known function were found to encode for proteins implicated in various mitochondrial processes, revealing mitochondria pathways dysregulation. Mitochondrial morphological analysis by video-rate confocal microscopy showed a high degree of mitochondrial branching in cells of HIBM patients. The subtle involvement of mitochondrial processes identified in HIBM reveals an unexpected facet of HIBM pathophysiology which could at least partially explain the slow evolution of this disorder and give new insights in the disease mechanism. PMID: 18723858

PubMed Link

J Biol Chem. 2008 Aug 20. [Epub ahead of print]
Impaired protein aggregate handling and clearance underlie the pathogenesis of p97/VCP associated disease.
Ju JS, Miller SE, Hanson PI, Weihl CC. Neurology, Washington University, Saint Louis, MO 63110.
Mutations in p97/VCP cause the multisystem disease, IBMPFD or inclusion body myopathy, Paget's disease of the bone and fronto-temporal dementia. p97/VCP is a member of the AAA+ (ATPase associated with a variety of activities) protein family and has been implicated in multiple cellular processes. One pathologic feature in IBMPFD is ubiquitinated inclusions, suggesting that mutations in p97/VCP may affect protein degradation. The present study shows that IBMPFD mutant expression increases ubiquitinated proteins and susceptibility to proteasome inhibition. Co-expression of an aggregate prone protein such as expanded polyglutamine in IBMPFD mutant cells results in an increase in aggregated protein that localizes to small inclusions instead of a single perinuclear aggresome. These small inclusions fail to co-localize with autophagic machinery. IBMPFD mutants avidly bind to these small inclusions and may not allow them to traffic to an aggresome. This is rescued by HDAC6, a p97/VCP binding protein that facilitates the autophagic degradation of protein aggregates. Expression of HDAC6 improves aggresome formation and protects IBMPFD mutant cells from polyglutamine induced cell death. Our study emphasizes the importance of protein aggregate trafficking to inclusion bodies in degenerative diseases and the therapeutic benefit of inclusion body formation.

PubMed Link

Aminoacyl tRNA synthetases and their connections to disease
PNAS 2008 105: 11043-11049.
Sang Gyu Park, Paul Schimmel, and Sunghoon Kim
AARSs in Autoimmune Diseases:
Autoantibodies Directed Against a Subset of Synthetases in Autoimmune Disorders. Autoantibodies against different AARSs (aminoacyl tRNA synthetases) including histidyl-tRNA synthetase (hrS), threonyl-tRNA synthetase (TRS), ARS, IRS, FRS, GRS and asparaginyl-tRNA synthetase (NRS) have been found in about 30% of all autoimmune patients (69, 70). The 'antisynthetase syndrome' includes, among others, idiopathic inflammatory myopathies (IIM), interstitial lung diseases (ILD), rheumatoid and erosive arthritis, and Reynaud's phenomenon. IIM is a group of systemic diseases characterized by chronic muscle inflammation and can be classified into three distinct clinicopathologic subgroups - polymyositis (PM), dermatomyositis (DM) and inclusion bodymyositis (IBM). Both PM and DM patients slowly develop proximal and often symmetrical muscle weakness over weeks to months. The frequent disease types correlated with anti-synthetase antibodies are PM and DM. hrS (Jo-1) is the most frequently targeted autoantigen in PM. Anti-hrS autoantibodies are produced in 15 to 25% of all patients with PM. The patients identified with anti-NRS antibodies have ILD.
Wall Street Journal Online
Flurizan's Failure Leaves Key Alzheimer's Theory Unresolved
Posted By Shirley S. Wang On June 30, 2008
Though Myriad Genetics was hoping its experimental Alzheimer's drug Flurizan would surprise naysayers in the scientific and investment communities, the company instead announced that its Phase III clinical trial did indeed fail. The company said Monday that the 18-month, 1,684-patient study - the largest Alzheimer's-treatment study to date - showed Flurizan failed to improve cognitive functioning or activities of daily living, and added that Myriad is abandoning further efforts to develop the drug. This leaves Elan and Wyeth's bapineuzumab and Eli Lilly's gamma secretase inhibitor as the two leading candidates among disease-modifying Alzheimer's drugs in development. Flurizan worked by inhibiting enzymes that produce one form of amyloid, the sticky substance in the brain that many scientists believe is responsible for the disease. But there isn't clear data to show that removing amyloid improves cognitive functioning; the hope was that Flurizan would provide the best human evidence to date. Its failure to deliver prolongs uncertainty about the wisdom of targeting amyloid to treat or even prevent Alzheimer's. Myriad will still present full data from the study later in July at a major Alzheimer's conference. Myriad, primarily a diagnostics company with about $157 million of revenue last year, has spent about $200 million on research and development for Flurizan, Myriad Pharmaceuticals President Adrian Hobden told the Health Blog a few weeks ago. It spent $60 million of that during the current fiscal year. In midday trading, the stock is down more than 5.5%. However, as the Flurizan R & D costs come off the books, Myriad is likely to achieve profitability next year, said Peter Meldrum, Myriad's president and CEO in a statement today. The company hasn't turned a profit since at least 2003 because of these costs. Myriad's Danish partner, Lundbeck, which would have co-marketed the drug in Europe, announced it will write down the $100 million it paid for rights to the drug. Lundbeck's shares closed down 10% in European trading. Alzheimer's brain by Associated Press
Article printed from Health Blog: http://blogs.wsj.com/health
URL to article: http://blogs.wsj.com/health/2008/06/30/flurizans-failure-leaves-key-alzheimers-theory-unresolved/

PubMed Link

Arch Biochem Biophys. 2008 Jun 1;474(1):15-21. Epub 2008 Mar 26.
Amyloid toxicity in skeletal myoblasts: Implications for inclusion-body myositis.
Jayaraman M, Kannayiram G, Rajadas J.
Bioorganic and Neurochemistry Laboratory, Central Leather Research Institute, Adyar, Chennai 600 020, India.
Skeletal muscle disorder, inclusion-body myositis (IBM) has been known for accumulation of amyloid characteristic proteins in muscle. To understand the biophysical basis of IBM, the interaction of amyloid fibrils with skeletal myoblast cells (SMC) has been studied in vitro. Synthetic insulin fibrils and Abeta(25-35) fibrils were used for this investigation. From the saturation binding analysis, the calculated dissociation constant (K(d)) for insulin fibril and Abeta(25-35) fibrils were 69.37+/-11.17nM and 115.60+/-12.17nM, respectively. The fibrillar insulin comparatively has higher affinity binding to SMC than Abeta fibrils. The competitive binding studies with native insulin showed that the amount of bound insulin fibril was significantly decreased due to displacement of native insulin. However, the presence of native insulin is not altered the binding of beta-amyloid fibril. The cytotoxicity of insulin amyloid intermediates was measured. The pre-fibrillar intermediates of insulin showed significant toxicity (35%) as compared to matured fibrils. Myoblast treated with beta-amyloid fibrils showed more oxidative damage than the insulin fibril. Cell differentiating action of amyloidic insulin was assayed by creatine kinase activity. The insulin fibril treated cells differentiated more slowly compared to native insulin. However, beta-amyloid fibrils do not show cell differentiation property. These findings reinforce the hypothesis that accumulation of amyloid related proteins is significant for the pathological events that could lead to muscle degeneration and weakness in IBM.

There are number of pathologic similarities exists between Alzheimer's disease brain and inclusion-body myositis (IBM) muscle, such as accumulation of β-amyloid and phosphorylated tau [8-10]. In general, more than 20 unrelated proteins, including β-amyloid, prion, tau, insulin and transthyretin can abnormally unfold and self-aggregate to form β-pleated-sheet amyloid [11]. Although matured amyloid fibrils were previously considered to be cytotoxic, current experimental evidence suggest that pre-amyloid oligomeric complexes and/or protofibrillar aggregates are more cytotoxic [12,13].

We hypothesize that in the IBM muscle, elevated amyloid peptide levels results in deposition of amyloid on the myoblast membrane.

In conclusion, we have shown that Aβ25-35 and insulin fibrils bind to myoblast membrane. The present data support the hypothesis that oxidative stress-mediated amyloid cytotoxicity in skeletal myoblast through reducing efficiency of antioxidant system. Thus, oxidative stress coupled cytotoxicity and impaired cell differentiation are the possible amyloid induced pathologies observed in myoblasts associated with IBM.


PubMed Link

Acta Myol. 2007 Dec;26(3):171-5.
Perspectives on distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy: contributions from an animal model. Lack of sialic acid, a central determinant in sugar chains, causes myopathy?
Malicdan MC, Noguchi S, Nishino I.
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, Japan.
Distal myopathy with rimmed vacuoles (DMRV) or hereditary inclusion body myopathy (hIBM) is an adult onset slowly progressive myopathy secondary to mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene that encodes a bifunctional enzyme which catalyzes the rate-limiting step in sialic acid biosynthesis. Many hypotheses have been proposed to explain why patients develop weakness and atrophy, but are most views are obscure and thus are still considered controversial, partly because of the lack of an appropriate model with which these theories could be clarified. In this review, we briefly summarize the progress in DMRV research, and highlight efforts of researchers in generating the animal model for this myopathy. PMID:

Web address:

http://www.sciencedaily.com/releases/2008/07/080717140438.htm
Discovery Of A New Signaling Mechanism May Lead To Novel Anti-inflammatory Therapy

ScienceDaily (July 18, 2008) A team of researchers at the University of California, San Diego School of Medicine has uncovered a new signaling mechanism used to activate protein kinases that are critical for the body's inflammatory response. Their work will be published in the July 18 online edition of Science.

"In addition to helping explain the basic mechanisms of transmembrane receptor signaling, these results may identify a potential therapy for interfering with inflammation," said Michael Karin, Ph.D., professor of pharmacology and pathology in UC San Diego's Laboratory of Gene Regulation and Signal Transduction.

The tumor necrosis factor (TNF) receptor (TNFR) family codes for a large number of cell surface receptors of great biomedical importance, and its signaling mechanisms have been the subject of intense investigation during the past decade. Specific inhibitors of TNF receptor 1 (TNFR1) activation are being used in the treatment of rheumatoid arthritis, psoriasis and inflammatory bowel disease, and receptor activator of NF-?B (RANK) inhibitors were recently found to be effective in the treatment of osteoporosis and other bone loss diseases.

Now Atsushi Matsuzawa, Ph.D., and Ping-Hui Tseng, Ph.D., postdoctoral fellows in the Karin laboratory, describe how engagement of CD40, a member of the TNFR family, results in assembly of multiprotein signaling complexes at the receptor. However, according to the researchers -- and contrary to previous expectations -- signaling cascades that lead to activation of Jun Kinases (JNK) and p38 MAP Kinases (MAPK) are not initiated until these complexes dissociate from the receptor.

The authors found that complex translocation from the cell surface receptor to the cytoplasm, which is required for JNK and p38 activation, depends on degradation of a signaling protein called TRAF3. This process can be inhibited by a class of compounds known as Smac mimics.

"As Smac mimic compounds do not interfere with the activation of NF-?B-dependent innate immunity but do prevent the induction of JNK- and p38- dependent inflammatory mediators, they may serve as the prototypes for new anti-inflammatory therapy," said Karin, who also noted that current drugs that work by interfering with TNFR signaling exceed $5 billion a year in revenue.

Additional contributors include Sivakumar Vallabhapurapu, Jun-Li Luo and Weizhou Zhang, Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, UCSD School of Medicine; Haopeng Wang and Dario A. A. Vignali, Department of Immunology, St. Jude Children's Research Hospital, Memphis; and Ewen Gallagher, Department of Immunology, Imperial College, London, Faculty of Medicine, Norfolk Place, London. Work was supported by grants from the National Institutes of Health, the Leukemia and Lymphoma Society, The Mochida Memorial Foundation for Medical and Pharmaceutical Research, American Lung Association of California and Life Science Foundation; a Cancer Center Support CORE grant and the American Lebanese Syrian Associated Charities (ALSAC.). Karin is an American Cancer Society Research Professor.


PubMed Link

Cell. 2008 Jul 11;134(1):37-47.
Highly efficient, functional engraftment of skeletal muscle stem cells in dystrophic muscles.
Cerletti M, Jurga S, Witczak CA, Hirshman MF, Shadrach JL, Goodyear LJ, Wagers AJ.
Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02115, USA.
Satellite cells reside beneath the basal lamina of skeletal muscle fibers and include cells that act as precursors for muscle growth and repair. Although they share a common anatomical localization and typically are considered a homogeneous population, satellite cells actually exhibit substantial heterogeneity. We used cell-surface marker expression to purify from the satellite cell pool a distinct population of skeletal muscle precursors (SMPs) that function as muscle stem cells. When engrafted into muscle of dystrophin-deficient mdx mice, purified SMPs contributed to up to 94% of myofibers, restoring dystrophin expression and significantly improving muscle histology and contractile function. Transplanted SMPs also entered the satellite cell compartment, renewing the endogenous stem cell pool and participating in subsequent rounds of injury repair. Together, these studies indicate the presence in adult skeletal muscle of prospectively isolatable muscle-forming stem cells and directly demonstrate the efficacy of myogenic stem cell transplant for treating muscle degenerative disease.

This article has received a fair bit of media attention but it is not readily apparent what is new here. The interested reader may consult: 16051152 | 17218401 | 17878281 | 17631448 | 16930987


PubMed Link

Physiol Genomics. 2008 Jul 15. [Epub ahead of print]
Muscle weakness correlates with muscle atrophy and precedes the development of inclusion body or rimmed vacuoles in the mouse model of DMRV/hIBM.
Malicdan MC, Noguchi S, Hayashi YK, Nishino I.
National Institutes of Neuroscience, NCNP. Distal myopathy with rimmed vacuoles (DMRV), also called hereditary inclusion body myopathy (hIBM), is characterized clinically by weakness and atrophy that initially involves the distal muscles, and pathologically by the presence of rimmed vacuoles (RVs) or intracellular protein deposits in myofibers. It is caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene that is important in sialic acid synthesis. Recently, we have generated a mouse model (Gne(-/-)hGNED176VTg) that exhibited muscle weakness and pathological changes similar to DMRV patients. To gain better understanding on the pathomechanism of DMRV, we determined the temporal changes in the overall motor performance of this model mouse for DMRV in correlation with the structure and function of isolated skeletal muscles and muscle pathology. These DMRV mice exhibited muscle weakness, decreased whole muscle mass and cross-sectional area (CSA), and reduced contractile powers in an age-related manner. Single fiber CSA further supported the finding of muscle atrophy which involved both type 1 and type 2 fibers. These results suggest that atrophy is highly correlated with reduced production of force at young age, both in vivo and ex vivo, thereby implicating the important role of atrophy in the pathomechanism of DMRV. In the older age, and particularly in the gastrocnemius muscles RVs and intracellular inclusions were seen in type IIA fibers, further aggravating reduction of force and specific increase in twitch-tetanus ratio. Key words: skeletal muscle force, sialic acid, amyloid, Nonaka myopathy, muscular dystrophy. PMID: 18628337

PubMed Link

J Neuropathol Exp Neurol. 2008 Jun;67(6):624-32.
The kinesin superfamily motor protein KIF4 is associated with immune cell activation in idiopathic inflammatory myopathies.
Bernasconi P, Cappelletti C, Navone F, Nessi V, Baggi F, Vernos I, Romaggi S, Confalonieri P, Mora M, Morandi L, Mantegazza R.
Neurology IV, Foundation Neurological Institute Carlo Besta, Department of Medical Pharmacology, Milan, Italy. pbernasconi@instituto-besta.it
The idiopathic inflammatory myopathies (IIMs) dermatomyositis, polymyositis, and inclusion body myositis are characterized by myofiber degeneration and inflammation. The triggering factors of muscle autoaggression in these disorders are unknown, but infiltrating T cells may be activated locally and proliferate in situ. T-cell polarization involving reorientation of cytoskeleton and microtubule-organizing centers mediated by motor proteins may occur within inflammatory cells in the muscle. We therefore analyzed ubiquitous and neuronal kinesin superfamily (KIF) members KIF-5, dynein, and KIF4 in IIM muscle biopsies and in activated peripheral blood lymphocytes from healthy donors. Only KIF-4 was altered. Transcript levels were significantly higher in IIM muscle than in controls, and KIF4 inflammatory cells were found in IIM muscles. In polymyositis and inclusion body myositis, KIF4 cells were mainly located around individual muscle fibers, whereas in dermatomyositis, they were also near blood vessels. KIF4 cells were not specific to any immune lineage, and some were Ki67. In peripheral blood lymphocytes stimulated with mitogens, interleukin 2 or anti-CD3/CD28 antibodies, KIF4 expression was upregulated, and the protein was localized in the cytoplasm in association with lysosome-associated membrane protein 1 and perforin lysosomal vesicles. These results imply that KIF4 is associated with activated T cells, irrespective of their functional phenotype, and that it is likely involved in cytoskeletal modifications associated with in situ T-cell activation in IIM. PMID: 18520780

PubMed Link

Ann Rheum Dis. 2008 Jul 15. [Epub ahead of print]
Increased serum levels of B-cell activating factor (BAFF) in subsets of patients with idiopathic inflammatory myopathies.
Krystufkova O, Vallerskog T, Barbasso Helmers S, Mann H, Pùtová I, Belácek J, Malmström V, Trollmo C, Vencovsky J, Lundberg IE.
Institute of Rheumatology, Prague, Czech Republic.
OBJECTIVE: To investigate serum levels of B-cell activating factor (BAFF) in patients with myositis and correlate these to autoantibody profile, clinical phenotype and treatment. METHODS: BAFF levels in sera from 49 patients with dermatomyositis, 44 with polymyositis, 6 with inclusion body myositis and 30 matched controls were measured by enzyme-linked immunosorbent assay (ELISA). Specific autoantibodies were detected by line-blot and western blot assays. RESULTS: Serum levels of BAFF were significantly higher in patients compared to healthy controls (p=0.003). Patients with anti-Jo-1 autoantibodies had higher BAFF levels than control individuals (p<0.003) or patients without any specific autoantibodies (p<0.05). Patients with dermatomyositis had higher BAFF levels compared to polymyositis (p<0.05). Patients with interstitial lung disease (ILD) had higher BAFF levels than patients without ILD (p<0.05) or controls (p<0.01) but this could be explained by presence of anti-Jo-1 autoantibodies. BAFF levels correlated with serum CK (rs=0.365, p=0.0005) but not with CRP levels. A negative correlation of BAFF levels with glucocorticoid daily dose for all patients (rs=-0.292, p=0.003) and with cumulative glucocorticoid doses in early myositis cases (rs=-0.659, p=0.0002) was recorded. CONCLUSION: Our finding of elevated serum levels of BAFF in myositis patients with described phenotypes together with the correlations between levels of BAFF and CK and a negative correlation with dose of glucocorticoids, indicate that BAFF could be a potential therapeutic target in such cases.
PubMed Link

Annals of Neurology

Published Online: 14 Jul 2008

Editorial
Interplay between inflammation and degeneration: Using inclusion body myositis to study neuroinflammation.

Marinos C. Dalakas, MD

In primary inflammatory or autoimmune neurological disorders, such as primary or secondary progressive multiple sclerosis and chronic inflammatory neuropathies and myopathies, the chronic persistent inflammation leads to degeneration and irreversible cell loss. In other disorders considered neurodegenerative, such as Alzheimer's disease or amyotrophic lateral sclerosis, there is "neuroinflammation" characterized by gliosis, macrophage activation, and cytokine upregulation. Although in most of these conditions inflammatory mediators coexist even from the outset with cell stress and degeneration, the interrelationship between inflammatory and degeneration-associated molecules has not been studied in vivo, and the clinically relevant markers connected with disease progression remain unclear.

Perhaps one of the typical human neurological disorders in which inflammation and degeneration coexist from the outset is inclusion body myositis (IBM), the most common acquired myopathy for individuals older than 50 years.[1-3] The muscles of IBM patients have the following characteristics: (1) clonal expansion of CD8+ cells that invade major histocompatibility complex class I (MHC-I)-expressing muscle fibers; (2) persistent upregulation of cytokines, chemokines, adhesion molecules, and MHC-I, which induces cell stress; (3) vacuolization; (4) mitochondrial and nuclear abnormalities; (5) promiscuous deposits of degeneration-associated molecules, identical to those seen in Alzheimer's disease, such as β-amyloid, tau, ubiquitin, presenilin, α-synuclein, and apolipoprotein E; and (6) involvement of the ubiquitin-proteasome system, including the disposal of unwanted proteins by macroautophagy, as seen in neurodegenerative disorders.[4] Because of these features, the IBM muscle is a useful tool to investigate in vivo the interplay between inflammatory and degenerative molecules.

. . . these two new studies[5][6] provide strong evidence that in IBM proinflammatory cytokines not only correlate with the intramuscular accumulation of amyloid, phosphorylated tau, ubiquitin, and αB-crystallin,[6] but also induce tau phosphorylation and amyloid aggregates. construction

Viral or inflammatory triggers lead to clonal expansion of CD8+ T cells and T-cell-mediated cytotoxicity via the perforin pathway. The released cytokines upregulate major histocompatibility complex (MHC) class I molecules and increase levels of the MHC-peptide loading complex, because the abundance of generated peptides cannot be conformationally assembled with the MHC to exit the endoplasmic reticulum (ER).

Because effective antidegenerative agents as treatment options are not in the offing, focusing on antiinflammatory mediators is more realistic. The results from the trial with alemtuzumab, a T-cell-depleting monoclonal antibody against CD52, in the treatment of IBM patients, support this view.[17] Alemtuzumab significantly reversed disease progression, improved the strength of some patients, and reduced the inflammatory and degeneration-associated molecules in the patients' muscles.[17] The observations are encouraging and necessitate further study.

References used:

5 Kitazawa. Ann Neurol 2008; 63.
6 Schmidt J, Barthel K, Wrede A, et al. Interrelation of inflammation and APP in sIBM: IL-1 induces accumulation of -amyloid in skeletal muscle. Brain 2008; 131: 1228-1240.
17 Dalakas MC, Rakocevic G, McElroy B, et al. Alemtuzumab (CAMPATH 1-H) therapy in sporadic Inclusion Body Myositis (sIBM) alters disease progression and suppresses endomysial inflammation. Ann Neurol 2007; 62: 560-565. [this reference is misleading - here is a more accurate reference to this program note -- Annals of Neurology Vol 62 (suppl 11) page: S60 2007 ANA and CNS Meeting Programs ANA T1-T136

DOI Link:10.1002/ana.11641


PubMed Link

Rheumatology (Oxford). 2008 Jul 8. [Epub ahead of print]
Sarcoidosis and inclusion body myositis.
Vattemi G, Tonin P, Marini M, Guadagnin ML, Dal Pra B, Simonati A, Filosto M, Tomelleri G.
[letter]
The association of IBM and muscular sarcoidosis is probably casual, nevertheless, our observation, together with previous reports [3-5], raises the likelihood of a link between these two apparently unrelated diseases. From 2952 consecutive muscle biopsies performed in our department, we identified six patients with pulmonary sarcoidosis (0.20%) and 27 patients with IBM who represent 0.91% of our patient population, a frequency that ranges between those reported by other authors (0.4-1.3%) [6]. Among the six patients with pulmonary sarcoidosis, two had muscular sarcoidosis and IBM, two patients had a non-specific myopathy and two a normal muscle. In addition, 7.4% of our IBM patients had sarcoidosis; this is a considerable frequency compared with previous papers reporting the association of IBM with other autoimmune disorders in 1-4% of the cases [7,8]. It is relevant to underline that IBM and sarcoidosis are mediated by Th1-driven immune reactions [9]. Interestingly, in our first patient the histological features of both sarcoidosis and IBM were clearly demonstrated only at the second muscle biopsy thus suggesting that sarcoid myopathy may have promoted IBM. Also the clinical course supports this hypothesis since the asymmetrical muscle weakness that can be observed in IBM is not usually reported in chronic sarcoid myopathy. Even though we cannot exclude that the discrepancy observed between the first and the second muscle biopsy may be due to the different muscles chosen for the pathological examination, we consider it unlikely since IBM features are usually present at the four limbs [10]. Another possibility is that the presentation of the two diseases occurs at different times, as it frequently happens in autoimmune disorders; alternatively IBM could represent a common phenotypic end-point of muscular sarcoidosis [11].

PubMed Link

Free Radic Biol Med. 2008 Jun 14. [Epub ahead of print]
In inclusion-body myositis muscle fibers Parkinson-associated DJ-1 is increased and oxidized.
Terracciano C, Nogalska A, Engel WK, Wojcik S, Askanas V.
Department of Neurology, USC Neuromuscular Center, University of Southern California Keck School of Medicine, Good Samaritan Hospital, 637 S. Lucas Avenue, Los Angeles, CA 90017-1912, USA.

Sporadic inclusion-body myositis (s-IBM) is the most common muscle disease of older persons. The muscle-fiber molecular phenotype exhibits similarities to both Alzheimer-disease (AD) and Parkinson-disease (PD) brains, including accumulations of amyloid-β(beta), phosphorylated tau, α (alpha)-synuclein, and parkin, as well as evidence of oxidative stress and mitochondrial abnormalities. Early-onset autosomal-recessive PD can be caused by mutations in the DJ-1 gene, leading to its inactivation. DJ-1 has antioxidative and mitochondrial-protective properties. In AD and PD brains, DJ-1 is increased and oxidized. We studied DJ-1 in 17 s-IBM and 18 disease-control and normal muscle biopsies by: (1) immunoblots of muscle homogenates and mitochondrial fractions; (2) real-time PCR; (3) oxyblots evaluating DJ-1 oxidation; (4) light- and electron-microscopic immunocytochemistry. Compared to controls, in s-IBM muscle fibers DJ-1 was: (a) increased in the soluble fraction, monomer 2-fold (P = 0.01), and dimer 2.8-fold (P = 0.004); (b) increased in the mitochondrial fraction; (c) highly oxidized; and (d) aggregated in about 15% of the abnormal muscle fibers. DJ-1 mRNA was increased 3.5-fold (P = 0.034). Accordingly, DJ-1 might play a role in human muscle disease, and thus not be limited to human CNS degenerations. In s-IBM muscle fibers, DJ-1 could be protecting these fibers against oxidative stress, including protection of mitochondria. PMID: 18601999 [


Web address: http://www.sciencedaily.com/releases/2008/06/080619120657.htm
Potential New Way To Block Inflammation In Autoimmune Disease Discovered
ScienceDaily (June 24, 2008) -
Researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the National Institutes of Health (NIH), have identified a promising new target for autoimmune disease treatment -- a cell-surface receptor called DR3. Their research in mice suggests that blocking this receptor could slow or stop the damaging inflammation characteristic of autoimmune diseases, potentially without leaving the body vulnerable to serious infections, as many current therapies do. DR3 is a protein on the surface of cells. It is a member of the tumor necrosis factor (TNF) family of receptors, which bind to molecules related to TNF, a cell-signaling protein that promotes inflammation. Many of today's most potent treatments for inflammatory diseases, such as rheumatoid arthritis and psoriasis, interfere with the action of TNF, thereby blocking inflammation. Since current anti-TNF therapies don't work in all autoimmune diseases, however, the researchers turned to the study of DR3, which is a close relative of TNFR1, the main receptor for TNF. Working with mouse models of asthma and multiple sclerosis, both immune system diseases, the researchers found that mice engineered to lack DR3 were resistant to those diseases. "The implication is that blocking DR3 in mice, and possibly in humans, is a potential therapy for these diseases and perhaps others in which the immune system goes awry," said Richard Siegel, M.D., Ph.D., a scientist in the NIAMS' Immunoregulation Group, who led the research effort. While closely related to TNFR1, DR3 is expressed in T cells, a different kind of immune cell (a white blood cell that identifies and fights infection) than those that express TNFR1, Dr. Siegel said. The NIAMS group collaborated with a laboratory in Cardiff, Wales, which had generated genetically engineered mice deficient in DR3, as well as with a research group at the NIH's National Institute of Allergy and Infectious Diseases (NIAID), which has developed mouse models of disease with strong T cell components, such as asthma and multiple sclerosis. "These findings open up new avenues for therapy of these two diseases as well as to other autoimmune diseases in which T cells play a role in causing or perpetuating the disease," said Siegel. The researchers hope that DR3-blocking agents will be effective anti-inflammatory treatments someday. Siegel noted that if they were to be used in rheumatic diseases, they would be a complement to strategies that block TNF because they hit a different arm of the immune system. "It could be potentially synergistic or complementary," he said. Of critical importance, the NIAMS scientists found that removing DR3 did not appear to suppress the immune response or the ability to fight infection within the mice -- a problem with many other treatments for autoimmune disease. "We could see the effect of DR3 deficiency in the diseased organ, but when we looked systemically at the immune response at other places in the mouse, it was barely affected," said Dr. Siegel. The group's findings suggest that DR3-blocking agents might be more effective at specifically treating autoimmune disease without breaking down the body's defenses against infections, a long-sought goal of researchers in the field. Journal reference: 1. Meylan F, et al. The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases. Immunity, 29, 1-11, July 2008

NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (2008, June 24). Potential New Way To Block Inflammation In Autoimmune Disease Discovered. ScienceDaily.

Retrieved June 24, 2008, from http://www.sciencedaily.com­ /releases/2008/06/080619120657.htm


PubMed Link

PLoS ONE. 2008 Jun 18;3(6):e2477.
UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) binds to α (alpha)-actinin 1: novel pathways in skeletal muscle?
Amsili S, Zer H, Hinderlich S, Krause S, Becker-Cohen M, MacArthur DG,
North KN, Mitrani-Rosenbaum S. I Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
BACKGROUND: Hereditary inclusion body myopathy (HIBM) is a rare neuromuscular disorder caused by mutations in GNE, the key enzyme in the biosynthetic pathway of sialic acid. While the mechanism leading from GNE mutations to the HIBM phenotype is not yet understood, we searched for proteins potentially interacting with GNE, which could give some insights about novel putative biological functions of GNE in muscle. METHODOLOGY/PRINCIPAL FINDINGS: We used a Surface Plasmon Resonance (SPR)-Biosensor based assay to search for potential GNE interactors in anion exchanged fractions of human skeletal muscle primary culture cell lysate. Analysis of the positive fractions by in vitro binding assay revealed α (alpha)-actinin 1 as a potential interactor of GNE. The direct interaction of the two proteins was assessed in vitro by SPR-Biosensor based kinetics analysis and in a cellular environment by a co-immunoprecipitation assay in GNE overexpressing 293T cells. Furthermore, immunohistochemistry on stretched mouse muscle suggest that both GNE and α (alpha)-actinin 1 localize to an overlapping but not identical region of the myofibrillar apparatus centered on the Z line. CONCLUSIONS/SIGNIFICANCE: The interaction of GNE with α (alpha)-actinin 1 might point to its involvement in α (alpha)-actinin mediated processes. In addition these studies illustrate for the first time the expression of the non-muscle form of α (and ifalpha)-actinin, α (alpha)-actinin 1, in mature skeletal muscle tissue, opening novel avenues for its specific function in the sarcomere. Although no significant difference could be detected in the binding kinetics of α (alpha)-actinin 1 with either wild type or mutant GNE in our SPR biosensor based analysis, further investigation is needed to determine whether and how the interaction of GNE with α (alpha)-actinin 1 in skeletal muscle is relevant to the putative muscle-specific function of α (alpha)-actinin 1, and to the muscle-restricted pathology of HIBM. PMID: 18560563
PubMed Link

Brain. 2008 May;131(Pt 5):1228-40. Epub 2008 Apr 17.
Interrelation of inflammation and APP in sIBM: IL-1 β(beta) induces accumulation of β(beta)-amyloid in skeletal muscle.
Schmidt J, Barthel K, Wrede A, Salajegheh M, Bähr M, Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. j.schmidt@gmx.org
Distinct interrelationships between inflammation and β(beta)-amyloid-associated degeneration, the two major hallmarks of the skeletal muscle pathology in sporadic inclusion body myositis (sIBM), have remained elusive. Expression of markers relevant for these pathomechanisms were analysed in biopsies of sIBM, polymyositis (PM), dermatomyositis (DM), dystrophic and non-myopathic muscle as controls, and cultured human myotubes. By quantitative PCR, a higher upregulation was noted for the mRNA-expression of CXCL-9, CCL-3, CCL-4, IFN-γ (gamma), TNF-α (alpha) and IL-1 β(beta) in sIBM muscle compared to PM, DM and controls. All inflammatory myopathies displayed overexpression of degeneration-associated markers, yet only in sIBM, expression of the mRNA of amyloid precursor protein (APP) significantly and consistently correlated with inflammation in the muscle and mRNA-levels of chemokines and IFN-γ(gamma). Only in sIBM, immunohistochemical analysis revealed that inflammatory mediators including IL-1 β(beta) co-localized to β(beta)-amyloid depositions within myofibres. In human myotubes, exposure to IL-1 β(beta) caused upregulation of APP with subsequent intracellular aggregation of β(beta)-amyloid. Our data suggest that, in sIBM muscle, production of high amounts of pro-inflammatory mediators specifically induces β(beta)-amyloid-associated degeneration. The observations may help to design targeted treatment strategies for chronic inflammatory disorders of the skeletal muscle.

From the paper:
Collectively, these data show that, in sIBM, degeneration associated molecules were overexpressed at the level of mRNA and protein. A co-localization of several of these molecules could be demonstrated by immunohistochemistry.

We here demonstrate that highly upregulated proinflammatory cytokines and chemokines in sIBM muscle correlate and co-localize with the expression of β(beta)-amyloid-associated proteins. In contrast to PM and DM, the other two inflammatory myopathies used as comparative controls, in sIBM, the majority of the signal for inflammatory and degenerative markers localized strongly to muscle fibres.

Given the similar magnitude of upregulation of the degeneration-associated molecules including APP, ubiquitin, desmin and α(alpha)β(beta)-crystallin that we observed in all three inflammatory myopathies, one could argue that a chronic inflammation in muscle always results in overexpression of pathways associated with degenerative pathomechanisms. In line with this, a high expression of the mRNA of APP was noted in patients with a chronic disease course of DM or PM. However, only in sIBM, there was a significant and consistent correlation between the mRNA expression of β(beta)-amyloid-associated molecules and the major inflammatory markers. Moreover, only in sIBM, the inflammatory molecules CXCL-9, MHC-I and IL-1β(beta) co-localized with APP and b-amyloid within the fibres, which suggests some association between inflammation and degeneration in sIBM muscle. It is conceivable that a so far unknown underlying condition in sIBM may cause a higher baseline expression of APP as well as its extensive upregulation under inflammatory conditions.

In summary, our data demonstrate a striking upregulation of inflammatory chemokines and cytokines in sIBM muscle and a specific interplay between inflammatory and β(beta)-amyloid-associated pathomechanisms. Ubiquitous upregulation of IL-1β(beta) in muscle fibres may aggravate an overexpression of APP and lead to an accumulation of β(beta)-amyloid. The data further our understanding of the pathology not only of sIBM, but also of other neuroinflammatory and neurodegenerative conditions where interactions between inflammation and accumulation of β(beta)-amyloid contribute to the pathology.

See Greenberg, July 24, 2008 (above).


PubMed Link

Genet Test. 2008 Mar;12(1):101-9.
Validation of GNE:p.M712T identification by melting curve analysis.
Valles-Ayoub Y, Saechao C, Haghighatgoo A, Neshat MS, Esfandiarifard S, Pietruszka M, Darvish D. HIBM Research Group, Encino, California, USA.
Hereditary inclusion body myopathy/distal myopathy with rimmed vacuoles is an adult onset autosomal recessive muscle-wasting disease common in people of Iranian-Jewish descent, due to the founder allelic variant GNE:p.M712T. High correlation of disease susceptibility with GNE:p.M712T allows its use as a molecular marker for diagnosis. In this study, we applied and validated the use of melting curve analysis using SimpleProbe technology for detection of this mutation using specimens obtained by mouthwash, buccal swab, and whole blood. The assay was then applied to 43 clinical specimens, and results were validated by additional methods. A probe spanning this mutation in exon 12 accurately discerns two Tm corresponding to its hybridization to wild-type and M712T-derived amplicons. A 10 degrees C divergence in Tm allowed rapid single-tube genotyping of reference and patient samples with 100% accuracy. Distal myopathy constitutes a large heterogeneous group of pathologies with similar physiological manifestations and little molecular markers for distinguishing subtypes. Application of SimpleProbes for detection of GNE:p.M712T on genomic DNA obtained from buccal epithelial cells allows accurate, rapid, and cost-effective identification of this allele in individuals at risk. This procedure is amenable to automated high-throughput applications and can be extended to both clinical and research applications.


PubMed Link

J Clin Neurosci. 2008 Apr;15(4):440-4. Epub 2008 Feb 6.
Two-dimensional gel electrophoresis in inclusion body myositis.
Hutchinson DO, Jongbloed B.
Department of Neurology, Auckland Hospital, Auckland, New Zealand. dhutch@adhb.govt.nz
Inclusion body myositis (IBM) is an acquired inflammatory myopathy in which a wide range of proteins is deposited within the cytoplasm of muscle fibres. To explore the possibility that this deposition occurs due to uncontrolled protein production arising from a defect at the nuclear level, we studied muscle samples from IBM and control subjects using two-dimensional gel electrophoresis. Twenty-seven gels from five controls and 24 gels from six patients with IBM were exhaustively compared using image analysis software and visual inspection. We found significant intra- and inter-subject variability in the number of protein spots on the gels. From 2272 to 4522 spots were found in different control gels, and from 2821 to 4153 spots in the IBM gels. No unique spots were identified in the IBM gels. When viewed with other work, the results of this study suggest that widespread, uncontrolled activation of genes is unlikely to be a component of the pathogenesis in IBM.

PubMed Link

Neuromuscul Disord. 2008 Feb;18(2):150-2. Epub 2007 Dec 3.
Apolipoprotein ε(epsilon) alleles in sporadic inclusion body myositis: a reappraisal.
Needham M, Hooper A, James I, van Bockxmeer F, Corbett A, Day T, Garlepp MJ, Mastaglia FL.
Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Queen Elizabeth II Medical Centre, Perth, Australia. Needhm01@student.uwa.edu.au
Previous studies have differed as to whether APOE ε(epsilon)4 is a susceptibility factor for developing sporadic inclusion body myositis (sIBM), with a positive association being found only in an Australian cohort of cases. We have now re-examined this in a larger cohort of 57 sIBM cases and have also carried out a meta-analysis of all the published studies looking for evidence of a risk association or effect of APOE alleles on disease expression. Our findings argue against a specific role for any APOE alleles in conferring susceptibility to sIBM but have demonstrated a non-significant trend towards an earlier age-of-onset in patients with the ε(epsilon)2 allele. PMID: 18060780

PubMed Link

J Rheumatol. 2008 Mar;35(3):445-7. Epub 2008 Jan 15.
Epidemiology of sporadic inclusion body myositis and polymyositis in Olmsted County, Minnesota.
Wilson FC, Ytterberg SR, St Sauver JL, Reed AM.
division of Rheumatology, Mayo Clinic, College of Medicine, Rochester, Minnesota 55905, USA. wilson.floranne@mayo.edu
OBJECTIVE: To determine the incidence and prevalence of sporadic inclusion body myositis (sIBM) and polymyositis (PM) in a population-based study. METHODS: Charts of patients with myositis in Olmsted County, Minnesota, USA, from 1981 to 2000 were reviewed. RESULTS: For sIBM, the age- and sex-adjusted incidence rates per 100,000 were 0.79 (95% confidence interval = 0.24-1.35), and for PM, 0.41 (95% CI 0.08-0.73). The age- and sex-adjusted prevalence rates per 100,000 were 7.06 (95% CI 0.87-13.24) for sIBM and 3.45 (95% CI 0.00-7.35) for PM. CONCLUSION: The incidence and prevalence rates for sIBM are higher than previously reported.

PubMed Link

J Clin Neuromuscul Dis. 2008 Jun;9(4):397-401.
Hypogonadism is common in men with myopathies.
Al-Harbi TM, Bainbridge LJ, McQueen MJ, Tarnopolsky MA.
division of Neurology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
BACKGROUND: Hypogonadism has been described in patients with myotonic muscular dystrophy type 1 but has not been evaluated in other myopathies. METHODS: We measured total and free serum testosterone levels in 59 men with myotonic muscular dystrophy type 1 (N = 12), facioscapulohumeral muscular dystrophy (N = 11), dystrophinopathy (N = 12), metabolic myopathy (N = 7), and inclusion body myositis (N = 17) and compared these with the normal reference interval. RESULTS: Thirty-two of the 59 (54%) participants had low total testosterone, 23 (39%) had low total and free values, and 5 (8%) had low free with normal total levels. There were no significant differences in the prevalence of hypogonadism between those with myotonic muscular dystrophy type 1 and the other groups even after considering age as a confounder. CONCLUSIONS: Hypogonadism is common in men with myopathies, and with the importance of testosterone in the maintenance of muscle mass, treatment of hypogonadism should be considered. PMID: 18525423

PubMed Link

Neuromuscul Disord. 2008 Jun 3. [Epub ahead of print]
Distal inflammatory myopathy: Unusual presentation of polymyositis or new entity?
Dimitri D, Dubourg O, Maisonobe T, Fournier E, Ranque B, Laforêt P, Mussini JM, Pagnoux C, Behin A, Papo T, Benveniste O, Eymard B, Herson S.
Centre de Reference des Maladies Neuromusculaires 'Garches-Necker-Mondor-Hendaye', APHP, INSERM U841, CHU Henri Mondor, 51 boulevard du Marechal de Lattre de Tassigny, 94010 Creteil, France.
New classification of idiopathic inflammatory myopathy (IIM) defined three major entities, polymyositis (PM), dermatomyositis (DM) and sporadic inclusion body myositis (s-IBM). We report the clinical, electrophysiological and pathological characteristics of three patients with a rare form of IIM not fulfilling the diagnostic criteria for any of these three major entities. The three patients presented with a subacute, distal asymmetrical weakness in upper limbs. Muscle biopsy showed an active myositis, with necrosis and regeneration, T cell infiltrates with invasion of non-necrotic fibers, without rimmed vacuoles, and diffuse major histocompatibility complex-I (MHC-I) immunostaining in muscle fibers. All patients responded to immunosuppressive agents. Seven others cases were identified in the literature. It is important to recognize this atypical presentation as it seems to respond to immunosuppressive agents. PMID: 18534849

PubMed Link

J Neuropathol Exp Neurol. 2008 Jun;67(6):624-632.
The Kinesin Superfamily Motor Protein KIF4 Is Associated With Immune Cell Activation in Idiopathic Inflammatory Myopathies.
Bernasconi P, Cappelletti C, Navone F, Nessi V, Baggi F, Vernos I, Romaggi S, Confalonieri P, Mora M, Morandi L, Mantegazza R.
From the Neurology IV (PB, CC, VN, FB, SR, PC, MM, LM, RM), Foundation Neurological Institute "Carlo Besta"; CNR Institute of Neuroscience, Cellular and Molecular Pharmacology Laboratory (FN), Department of Medical Pharmacology, Milan, Italy; and ICREA and Centro de Regulación Genómica, Cell and Developmental Biology Program (IV), Barcelona, Spain.
The idiopathic inflammatory myopathies (IIMs) dermatomyositis, polymyositis, and inclusion body myositis are characterized by myofiber degeneration and inflammation. The triggering factors of muscle autoaggression in these disorders are unknown, but infiltrating T cells may be activated locally and proliferate in situ. T-cell polarization involving reorientation of cytoskeleton and microtubule-organizing centers mediated by motor proteins may occur within inflammatory cells in the muscle. We therefore analyzed ubiquitous and neuronal kinesin superfamily (KIF) members KIF-5, dynein, and KIF4 in IIM muscle biopsies and in activated peripheral blood lymphocytes from healthy donors. Only KIF-4 was altered. Transcript levels were significantly higher in IIM muscle than in controls, and KIF4 inflammatory cells were found in IIM muscles. In polymyositis and inclusion body myositis, KIF4 cells were mainly located around individual muscle fibers, whereas in dermatomyositis, they were also near blood vessels. KIF4 cells were not specific to any immune lineage, and some were Ki67. In peripheral blood lymphocytes stimulated with mitogens, interleukin 2 or anti-CD3/CD28 antibodies, KIF4 expression was upregulated, and the protein was localized in the cytoplasm in association with lysosome-associated membrane protein 1 and perforin lysosomal vesicles. These results imply that KIF4 is associated with activated T cells, irrespective of their functional phenotype, and that it is likely involved in cytoskeletal modifications associated with in situ T-cell activation in IIM. PMID: 18520780 [PubMed - as supplied by publisher]

PubMed Link

Pathol Res Pract. 2008 May 29. [Epub ahead of print]
Myopathology of non-infectious inflammatory myopathies - The current status.
Hewer E, Goebel HH. Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
Besides the classical inflammatory myopathies (IM), dermatomyositis (DM), polymyositis, and inclusion body myositis, the much larger spectrum of IM includes focal and nodular myositis, granulomatous myositis, macrophagic myofasciitis, graft vs. host myositis, eosinophilic myositis, and other immune-associated conditions, some of them only recently described. In addition, paraneoplastic, statin-induced and critical illness myopathies have been considered immune-associated IM. Infectious, i.e., bacterial, viral, and parasitic IM are much less frequent in the northern hemisphere. In IM, muscle biopsy is an essential diagnostic procedure to initiate therapy. The myopathological spectrum encompasses disease-specific histopathological features, such as perifascicular atrophy in DM, non-necrotizing granulomas in sarcoid myopathy, autophagic vacuoles with tubulofilamentous inclusions in inclusion body myositis, rarely electron microscopic criteria, such as undulating tubules in endothelial cells of DM specimens, and, foremost, immunohistochemical findings. These latter features concern inflammatory infiltrates, the muscle parenchyma, the interstitial compartment, and the vasculature with varying involvement of each component in the different IM. Differences in immunohistochemical parameters among the IM, such as major histocompatibility complexes I and II, cytokines, cell adhesion molecules, different types of inflammatory cells, metalloproteinases, and complement factors procure a large gamut of data, the individual patterns of which characterize the myopathology of individual IM.

PubMed Link

Semin Neurol. 2008 Apr;28(2):241-9.
Inflammatory myopathies: evaluation and management.
Greenberg SA.
Department of Neurology, Brigham and Women's Hospital, Department of Neurology, division of Neuromuscular Disease, Brigham and Women'sHospital, and Harvard Medical School, Boston, MA 02115, USA. sagreenberg@partners.org
The inflammatory myopathies, including dermatomyositis, inclusion body myositis, and polymyositis, are poorly understood autoimmune diseases affecting skeletal muscle. Dermatomyositis is a disease mainly of skin and muscle, but may affect lung and other tissues. Proximal or generalized weakness or skin rash are the typical presenting features. Inclusion body myositis has a specific clinical pattern of weakness that generally distinguishes it from other inflammatory myopathies, with prominent involvement of wrist and finger flexors, and quadriceps. Polymyositis generally presents with proximal or generalized weakness. Typical dermatomyositis muscle pathology is quite distinct, with perivascular inflammatory cells that include plasmacytoid dendritic cells, and abnormal capillaries and perimysial perifascicular myofibers. Both inclusion body myositis and polymyositis usually have infiltration into muscle of large numbers of inflammatory cells, typically surrounding and displacing, and sometimes invading, myofibers. Inclusion body myositis is refractory to corticosteroids and to several immunomodulating therapies that have been used. Dermatomyositis and polymyositis are treated with corticosteroids and a variety of agents. Osteoporosis and opportunistic infections pose a significant risk during treatment of patients. This review discusses the clinical manifestations, pathology, and treatment approaches for the inflammatory myopathies.

PubMed Link

Arch Biochem Biophys. 2008 Mar 26 [Epub ahead of print]
Amyloid toxicity in skeletal myoblasts: Implications for inclusion-body myositis.
Jayaraman M, Kannayiram G, Rajadas J.
Bioorganic and Neurochemistry Laboratory, Central Leather Research Institute, Adyar, Chennai 600 020, India.
Skeletal muscle disorder, inclusion-body myositis (IBM) has been known for accumulation of amyloid characteristic proteins in muscle. To understand the biophysical basis of IBM, the interaction of amyloid fibrils with skeletal myoblast cells (SMC) has been studied in vitro. Synthetic insulin fibrils and Aβ(beta)(25-35) fibrils were used for this investigation. From the saturation binding analysis, the calculated dissociation constant (K(d)) for insulin fibril and Aβ(beta)(25-35) fibrils were 69.37+/-11.17nM and 115.60+/-12.17nM, respectively. The fibrillar insulin comparatively has higher affinity binding to SMC than Aβ(beta) fibrils. The competitive binding studies with native insulin showed that the amount of bound insulin fibril was significantly decreased due to displacement of native insulin. However, the presence of native insulin is not altered the binding of β(beta)-amyloid fibril. The cytotoxicity of insulin amyloid intermediates was measured. The pre-fibrillar intermediates of insulin showed significant toxicity (35%) as compared to matured fibrils. Myoblast treated with β(beta)-amyloid fibrils showed more oxidative damage than the insulin fibril. Cell differentiating action of amyloidic insulin was assayed by creatine kinase activity. The insulin fibril treated cells differentiated more slowly compared to native insulin. However, beta-amyloid fibrils do not show cell differentiation property. These findings reinforce the hypothesis that accumulation of amyloid related proteins is significant for the pathological events that could lead to muscle degeneration and weakness in IBM.
A Pilot Trial of Lithium in Inclusion Body Myositis (IBM)
Trial Status Open for Enrollment What is the Purpose of this Study? There is currently no effective treatment for IBM and its pathogenesis remains uncertain. This study is designed to test the hypothesis that treatment of patients with IBM with Lithium can improve muscle strength and reduce the markers of disease activity believed to be important in the disease pathogenesis.
Who is Eligible to Participate? Patients diagnosed with Inclusion Body Myositis above the age of 30 who have adequate muscle function for quantitative muscle testing. Patients must also meet all other inclusion and exclusion criteria explained in further detail by study coordinator
What's the matter What is involved in this Study? This is an open label trial of the effects of Li on muscle strength. Procedures consist of a baseline muscle biopsy, and blood work. Two weeks later patients are given Li at 30 mg twice a day. Every two weeks patients return to for study visits for EKGs, Li level labs, questionnaires, and muscle strength testing. At the end of the study, patients will receive another muscle biopsy.
How long is the Study? It is approximately 6 months long.
For More Information Contact: Nicole C. Hank, MHSM, study coordinator, at 602-258-3354 ext 137 or nhank@pnal.net or call the Main line at 602-258-3354

PubMed Link

Neurosci Lett. 2008 Jan 31;431(2):141-5. Epub 2007 Dec 15.
Casein kinase 1 α (alpha) associates with the tau-bearing lesions of inclusion body myositis.
Kannanayakal TJ, Mendell JR, Kuret J.
Center for Molecular Neurobiology, Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, 1060 Carmack Road, Columbus, OH 43210, United States.
Inclusion body myositis and Alzheimer's disease are age-related disorders characterized in part by the appearance of intracellular lesions composed of filamentous aggregates of the microtubule-associated protein tau. Abnormal tau phosphorylation accompanies tau aggregation and may be an upstream pathological event in both diseases. Enzymes implicated in tau hyperphosphorylation in Alzheimer's disease include members of the casein kinase 1 family of phosphotransferases, a group of structurally related protein kinases that frequently function in tandem with the ubiquitin modification system. To determine whether casein kinase 1 isoforms associate with degenerating muscle fibers of inclusion body myositis, muscle biopsy sections isolated from sporadic disease cases were subjected to double-label fluorescence immunohistochemistry using selective anti-casein kinase 1 and anti-phospho-tau antibodies. Results showed that the α(alpha) isoform of casein kinase 1, but not the δ(delta) or ε(epsilon) isoforms, stained degenerating muscle fibers in all eight inclusion body myositis cases examined. Staining was almost exclusively localized to phospho-tau-bearing inclusions. These findings, which extend the molecular similarities between inclusion body myositis muscle and Alzheimer's disease brain, implicate casein kinase 1 α(alpha) as one of the phosphotransferases potentially involved in tau hyperphosphorylation.
PubMed Link
J Clin Invest. 2008 Mar;118(3):904-12.
Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy.
Schessl J, Zou Y, McGrath MJ, Cowling BS, Maiti B, Chin SS, Sewry C, Battini R, Hu Y, Cottle DL, Rosenblatt M, Spruce L, Ganguly A, Kirschner J, Judkins AR, Golden JA, Goebel HH, Muntoni F, Flanigan KM, Mitchell CA, Bönnemann CG
Reducing body myopathy (RBM) is a rare disorder causing progressive muscular weakness characterized by aggresome-like inclusions in the myofibrils. Identification of genes responsible for RBM by traditional genetic approaches has been impossible due to the frequently sporadic occurrence in affected patients and small family sizes. As an alternative approach to gene identification, we used laser microdissection of intracytoplasmic inclusions identified in patient muscle biopsies, followed by nanoflow liquid chromatography-tandem mass spectrometry and proteomic analysis. The most prominent component of the inclusions was the Xq26.3-encoded four and a half LIM domain 1 (FHL1) protein, expressed predominantly in skeletal but also in cardiac muscle. Mutational analysis identified 4 FHL1 mutations in 2 sporadic unrelated females and in 2 families with severely affected boys and less-affected mothers. Transfection of kidney COS-7 and skeletal muscle C2C12 cells with mutant FHL1 induced the formation of aggresome-like inclusions that incorporated both mutant and wild-type FHL1 and trapped other proteins in a dominant-negative manner. Thus, a novel laser microdissection/proteomics approach has helped identify both inherited and de novo mutations in FHL1, thereby defining a new X-linked protein aggregation disorder of muscle.

We have thus established FHL1 as the protein mutated in RBM, classifying this condition as a novel sporadic and familial X-linked progressive protein aggregation disorder of skeletal and cardiac muscle. To our knowledge our report also represents the first example in which a proteomic approach has directly led to the identification of a disease gene. This technique may become important in the molecular characterization of other rare or mostly sporadic disorders with cellular morphological alterations, such as inclusions, for which traditional genetic approaches have been unsuccessful.


PubMed Link

Brain. 2008 Apr 17 [Epub ahead of print]
Interrelation of inflammation and APP in sIBM: IL-1{β(beta)} induces accumulation of {β(beta)}-amyloid in skeletal muscle.
Schmidt J, Barthel K, Wrede A, Salajegheh M, Bähr M, Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA, Department of Neurology and Department of Experimental and Clinical Neuroimmunology, Department of Neuropathology, University of Göttingen, Germany and Neuromuscular division, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA.

Distinct interrelationships between inflammation and β(beta)-amyloid-associated degeneration, the two major hallmarks of the skeletal muscle pathology in sporadic inclusion body myositis (sIBM), have remained elusive. Expression of markers relevant for these pathomechanisms were analysed in biopsies of sIBM, polymyositis (PM), dermatomyositis (DM), dystrophic and non-myopathic muscle as controls, and cultured human myotubes. By quantitative PCR, a higher upregulation was noted for the mRNA-expression of CXCL-9, CCL-3, CCL-4, IFN-γ(gamma), TNF-α (alpha) and IL-1β(beta) in sIBM muscle compared to PM, DM and controls. All inflammatory myopathies displayed overexpression of degeneration-associated markers, yet only in sIBM, expression of the mRNA of amyloid precursor protein (APP) significantly and consistently correlated with inflammation in the muscle and mRNA-levels of chemokines and IFN-γ(gamma). Only in sIBM, immunohistochemical analysis revealed that inflammatory mediators including IL-1β(beta) co-localized to β(beta)-amyloid depositions within myofibres. In human myotubes, exposure to IL-1β(beta) caused upregulation of APP with subsequent intracellular aggregation of β(beta)-amyloid. Our data suggest that, in sIBM muscle, production of high amounts of pro-inflammatory mediators specifically induces β(beta)-amyloid-associated degeneration. The observations may help to design targeted treatment strategies for chronic inflammatory disorders of the skeletal muscle.


PubMed Link
J Neurol Sci. 2008 Jan 15;264(1-2):77-86. Epub 2007 Sep 12.
Non-pathogenic protein aggregates in skeletal muscle in MLF1 transgenic mice.
Li ZF, Wu X, Jiang Y, Liu J, Wu C, Inagaki M, Izawa I, Mizisin AP, Engvall E, Shelton GD.
Burnham Institute for Medical Research, La Jolla, CA 92037, United States.

Protein aggregate formation in muscle is thought to be pathogenic and associated with clinical weakness. Over-expression of either wild type or a mutant form of myeloid leukemia factor 1 (MLF1) in transgenic mouse skeletal muscle and in cultured cells resulted in aggregate formation. Aggregates were detected in MLF1 transgenic mice at 6 weeks of age, and increased in size with age. However, histological examination of skeletal muscles of MLF1 transgenic mice revealed no pathological changes other than the aggregates, and RotaRod testing did not detect functional deficits. MLF1 has recently been identified as a protein that could neutralize the toxicity of intracellular protein aggregates in a Drosophila model of Huntington's disease (HD). We also demonstrate that MLF1 interacts with MRJ, a heat shock protein, which can independently neutralize the toxicity of intracellular protein aggregates in the Drosophila HD model. Our data suggest that over-expression of MLF1 has no significant impact on skeletal muscle function in mice; that progressive formation of protein aggregates in muscle are not necessarily pathogenic; and that MLF1 and MRJ may function together to ameliorate the toxic effects of polyglutamine or mutant proteins in myodegenerative diseases such as inclusion body myositis and oculopharyngeal muscular dystrophy, as well as neurodegenerative disease.


RING Finger Protein 5 May Guide Treatment for Muscle Disease in Older Adults

A new mouse model for the study of Inclusion Body Myositis (IBM), a type of muscular dystrophy, has been developed by Dr. Ze'ev Ronai and a worldwide team of researchers. The protein RNF5 is over-produced in the mice, resulting in extensive muscle damage similar to that seen in IBM patients. The IBM mouse model will allow researchers to further study the mechanisms underlying development of the disease, as well as test potential new therapies.

(April 2, 2008 - La Jolla, CA) Researchers at the Burnham Institute for Medical Research (Burnham) have discovered a new player in the development of a disorder called Sporadic Inclusion Body Myositis (sIBM). sIBM is a muscle disease that affects predominantly older men, causing muscles to gradually weaken and waste away. The number of people living with sIBM is unknown, but it is the most common muscle disease among those over the age of 50, and due to its unfamiliarity, it is probably underdiagnosed. This discovery provides a potential avenue for future diagnostic and therapeutic opportunities for this disease.

In muscles, proteins are continuously made and broken down by the endoplasmic reticulum (ER), a protein factory in the cell. To assure that proteins produced pass quality control, a set of ER-based inspectors identify and remove those proteins that are not properly folded. Ubiquitin ligase RNF5 (or RING Finger Protein 5) acts much like one of these quality-control inspectors at the end of the assembly line by tagging defective protein products so that they can be recycled. Burnham scientists have found that RNF5 plays a key role in the progression of IBM. While the causes of sIBM or how it progresses are still mostly unknown, and there is no cure or standard treatment, this finding offers a new understanding for the mechanism underlying development of sIBM and points to possible use of new markers for diagnosis and mouse models to test for novel therapeutics. The results of this study appeared in PLoS ONE on February 13.

The Burnham research team was led by Ze'ev Ronai, Ph.D., and included Agnes Delaunay, PhD., and P. Lorenzo Puri, M.D., Ph.D., with Diane Shelton, D.V.M. Ph.D of UCSD and international collaborators from Japan and Italy. Dr. Ronai had previously shown that RNF5 is important for muscle maintenance in the worm model C. elegans; now the team discovered that RNF5 is up-regulated in biopsies from sIBM patients.

Following this discovery, the team developed three mouse models: one knockout model in which the RNF5 gene was missing, and two in which cells could be triggered to overproduce RNF5, with expression either limited to skeletal muscle, -or within muscle and a variety of other organs.

A comparison of normal and knockout mice exposed to muscle-damaging toxin showed slower healing in the knockouts compared with the normal mice, demonstrating the importance of RNF5 in muscle repair.

Pathologic changes within muscles of the transgenic models with RNF5 overexpression were similar to those found in muscle biopsies from patients with sIBM. Overproduction of RNF5 caused a rapid and significant muscle degeneration, weight loss and muscle weakness. Followed by extensive muscle regeneration. Similar to what is often seen in patients with IBM, muscle specimens from RNF5 overexpressing animals revealed the presence of structures known as rimmed vacuoles and congophilic inclusions, hallmarks of this disease.

The researchers also found increased levels of markers characteristic of ER stress, a phenomenon that has been linked with a variety of human diseases, including sIBM. It is believed that ER stress is a response to misfolded-protein buildup; sensing the backlog, the ER recruits helpers through the Unfolded Protein Response (UPR) chaperonins that increase the export of misfolded proteins to enable their breakdown and recycling. But, with prolonged stress, the UPR eventually fails to handle the overload, resulting in the accumulation of misfolded proteins in the cytoplasmic vacuoles, structures within the cell cytoplasm which are characteristic of sIBM patients.

Whether RNF5 is the primary cause for sIBM, or an important contributor in the development of this muscle disorder is yet to be determined. Dr. Ronai, lead author of the study, says the link established between ER stress, RNF5 and sIBM strengthen one theory stating that ER stress is causative for the disease and will now allow further study of the mechanisms underlying this disabling and all too common muscle disease.

-We now have a great mouse model that can be used to screen for drugs that might alleviate symptoms of sIBM,- says Dr. Ronai. But questions about what may interact with RNF5 in the cell to cause the symptoms of sIBM, he explains, still need to be addressed. 'We know the substrates for this ubiquitin ligase in C. elegans, but not yet in human muscle.'

This research is supported by a grant from the National Cancer Institute of the National Institutes of Health.

About Burnham Institute for Medical Research
Burnham Institute for Medical Research uses an entrepreneurial, collaborative approach to medical research to reveal the fundamental molecular causes of disease and devise the innovative therapies of tomorrow. The Institute is organized into five research centers: a National Cancer Institute-designated Cancer Center; the Del E. Webb Center for Neurosciences, Aging and Stem Cell Research; an Infectious and Inflammatory Disease Research Center; a Diabetes and Obesity Research Center; and the Sanford Children's Health Research Center. Thanks to the quality of its faculty members, Burnham ranks among the top 25 organizations worldwide (according to the Institute for Scientific Information) for its research impact and among the top four research institutes nationally for NIH grant funding. Burnham is a nonprofit, public benefit corporation headquartered in La Jolla, California, with campuses in Orlando, Florida and Santa Barbara, California. For more information, please visit http://www.burnham.org/.

Web address: http://www.sciencedaily.com/releases/2008/04/ 080404094547.htm
RING Finger Protein 5 May Guide Treatment For Muscle Disease In Older Adults ScienceDaily (Apr. 8, 2008) -
Researchers at the Burnham Institute for Medical Research (Burnham) have discovered a new player in the development of a disorder called Sporadic Inclusion Body Myositis (sIBM). sIBM is a muscle disease that affects predominantly older men, causing muscles to gradually weaken and waste away. The number of people living with sIBM is unknown, but it is the most common muscle disease among those over the age of 50, and due to its unfamiliarity, it is probably underdiagnosed. This discovery provides a potential avenue for future diagnostic and therapeutic opportunities for this disease. In muscles, proteins are continuously made and broken down by the endoplasmic reticulum (ER), a 'protein factory' in the cell. To assure that proteins produced pass quality control, a set of ER-based inspectors identify and remove those proteins that are not properly folded. Ubiquitin ligase RNF5 (or RING Finger Protein 5) acts much like one of these quality-control inspectors at the end of the assembly line by tagging defective protein products so that they can be recycled. Burnham scientists have found that RNF5 plays a key role in the progression of IBM. While the causes of sIBM or how it progresses are still mostly unknown, and there is no cure or standard treatment, this finding offers a new understanding for the mechanism underlying development of sIBM and points to possible use of new markers for diagnosis and mouse models to test for novel therapeutics.

The results of this study appeared in PLoS One on February 13. The Burnham research team was led by Ze'ev Ronai, Ph.D., and included Agnes Delaunay, PhD., and P. Lorenzo Puri, M.D., Ph.D., with Diane Shelton, D.V.M. Ph.D of UCSD and international collaborators from Japan and Italy. Dr. Ronai had previously shown that RNF5 is important for muscle maintenance in the worm model C. elegans; now the team discovered that RNF5 is up-regulated in biopsies from sIBM patients. Following this discovery, the team developed three mouse models: one knockout model in which the RNF5 gene was missing, and two in which cells could be triggered to overproduce RNF5, with expression either limited to skeletal muscle, -or within muscle and a variety of other organs. A comparison of normal and knockout mice exposed to muscle-damaging toxin showed slower healing in the knockouts compared with the normal mice, demonstrating the importance of RNF5 in muscle repair. Pathologic changes within muscles of the transgenic models with RNF5 overexpression were similar to those found in muscle biopsies from patients with sIBM. Overproduction of RNF5 caused a rapid and significant muscle degeneration, weight loss and muscle weakness. Followed by extensive muscle regeneration. Similar to what is often seen in patients with IBM, muscle specimens from RNF5 overexpressing animals revealed the presence of structures known as rimmed vacuoles and congophilic inclusions, hallmarks of this disease. The researchers also found increased levels of markers characteristic of ER stress, a phenomenon that has been linked with a variety of human diseases, including sIBM. It is believed that ER stress is a response to misfolded-protein buildup; sensing the backlog, the ER recruits helpers through the Unfolded Protein Response (UPR)-chaperonins that increase the export of misfolded proteins to enable their breakdown and recycling. But, with prolonged stress, the UPR eventually fails to handle the overload, resulting in the accumulation of misfolded proteins in the cytoplasmic vacuoles, structures within the cell cytoplasm which are characteristic of sIBM patients. Whether RNF5 is the primary cause for sIBM, or an important contributor in the development of this muscle disorder is yet to be determined. Dr. Ronai, lead author of the study, says the link established between ER stress, RNF5 and sIBM strengthen one theory stating that ER stress is causative for the disease and will now allow further study of the mechanisms underlying this disabling and all too common muscle disease. 'We now have a great mouse model that can be used to screen for drugs that might alleviate symptoms of sIBM,' says Dr. Ronai. But questions about what may interact with RNF5 in the cell to cause the symptoms of sIBM, he explains, still need to be addressed. 'We know the substrates for this ubiquitin ligase in C. elegans, but not yet in human muscle.'This research is supported by a grant from the National Cancer Institute of the National Institutes of Health. Adapted from materials provided by Burnham Institute.

PubMed Link

Delaunay A, Bromberg KD, Hayashi Y, Mirabella M, Burch D, et al. (2008) The ER-Bound RING Finger Protein 5 (RNF5/RMA1) Causes Degenerative Myopathy in Transgenic Mice and Is Deregulated in Inclusion Body Myositis. PLoS ONE 3(2): e1609. doi:10.1371/journal.pone.0001609 Web address: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001609
Abstract
Growing evidence supports the importance of ubiquitin ligases in the pathogenesis of muscular disorders, although underlying mechanisms remain largely elusive. Here we show that the expression of RNF5 (aka RMA1), an ER-anchored RING finger E3 ligase implicated in muscle organization and in recognition and processing of malfolded proteins, is elevated and mislocalized to cytoplasmic aggregates in biopsies from patients suffering from sporadic-Inclusion Body Myositis (sIBM). Consistent with these findings, an animal model for hereditary IBM (hIBM), but not their control littermates, revealed deregulated expression of RNF5. Further studies for the role of RNF5 in the pathogenesis of s-IBM and more generally in muscle physiology were performed using RNF5 transgenic and KO animals. Transgenic mice carrying inducible expression of RNF5, under control of ?-actin or muscle specific promoter, exhibit an early onset of muscle wasting, muscle degeneration and extensive fiber regeneration. Prolonged expression of RNF5 in the muscle also results in the formation of fibers containing congophilic material, blue-rimmed vacuoles and inclusion bodies. These phenotypes were associated with altered expression and activity of ER chaperones, characteristic of myodegenerative diseases such as s-IBM. Conversely, muscle regeneration and induction of ER stress markers were delayed in RNF5 KO mice subjected to cardiotoxin treatment. While supporting a role for RNF5 Tg mice as model for s-IBM, our study also establishes the importance of RNF5 in muscle physiology and its deregulation in ER stress associated muscular disorders.
. . . Here, we have established and characterized inducible transgenic mouse over-expressing RNF5 either ubiquitously or in a muscle specific manner. We show that general as well as tissue specific overexpression of RNF5 induces myofiber degeneration associated with an alteration of endoplasmic reticulum (ER) function. Conversely, RNF5 KO mice exhibit delayed repair of muscle damage associated with attenuated ER stress response. Screening for RNF5 expression in muscle biopsies from patients suffering from muscular disorders including classical myopathies such as Duchenne and Becker myopathy as well as other myopathies with unknown etiology identified upregulation and mislocalization of RNF5 to aggregates in muscles from sIBM patients, as well as in a mouse model for hereditary IBM. Our findings establishes the importance of RNF5 in muscle physiology and in ER stress associated muscular disorders while pointing to the possible use of RNF5 transgenic mouse as a unique model to study the role of ER function in the pathogenesis of degenerative muscle diseases.

. . . In conclusion, the characterization of the RNF5 transgenic and KO mouse models establishes an undisclosed link between impaired ER stress response and the early changes in degenerative myopathies, shown here for sIBM, while offering a novel model for studying the complex function of the ER in global muscle physiology.


Genet Test. 2008 Spring;12(1):101-9.
Validation of GNE:p.M712T Identification by Melting Curve Analysis.
Valles-Ayoub Y, Saechao C, Haghighatgoo A, Neshat MS, Esfandiarifard S, Pietruszka M, Darvish D.
HIBM Research Group, Encino, California.

Hereditary inclusion body myopathy/distal myopathy with rimmed vacuoles is an adult onset autosomal recessive muscle-wasting disease common in people of Iranian-Jewish descent, due to the founder allelic variant GNE:p.M712T. High correlation of disease susceptibility with GNE:p.M712T allows its use as a molecular marker for diagnosis. In this study, we applied and validated the use of melting curve analysis using SimpleProbe((R)) technology for detection of this mutation using specimens obtained by mouthwash, buccal swab, and whole blood. The assay was then applied to 43 clinical specimens, and results were validated by additional methods. A probe spanning this mutation in exon 12 accurately discerns two Tm corresponding to its hybridization to wild-type and M712T-derived amplicons. A 10 degrees C divergence in Tm allowed rapid single-tube genotyping of reference and patient samples with 100% accuracy. Distal myopathy constitutes a large heterogeneous group of pathologies with similar physiological manifestations and little molecular markers for distinguishing subtypes. Application of SimpleProbes((R)) for detection of GNE:p.M712T on genomic DNA obtained from buccal epithelial cells allows accurate, rapid, and cost-effective identification of this allele in individuals at risk. This procedure is amenable to automated high-throughput applications and can be extended to both clinical and research applications.


Original Article
Ann Neurol 2008 early view
Inflammation induces tau pathology in inclusion body myositis model via glycogen synthase kinase-3
Masashi Kitazawa, PhD, Dan N. Trinh, BS, Frank M. LaFerla, PhD *
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA

email: Frank M. LaFerla (laferla@uci.edu) *Correspondence to Frank M. LaFerla, Department of Neurobiology and Behavior, 1109 Gillespie Neuroscience Facility, University of California, Irvine, Irvine, CA 92697-4545

Objective

Inclusion body myositis (IBM) is an inflammatory muscle disease, although the role of inflammation remains to be elucidated. Here, we address the mechanisms by which inflammation modulates A and tau, two hallmark features of this disease.

Methods

A transgenic mouse model of IBM was utilized in which acute and chronic inflammation was induced via lipopolysaccharide. The effects of inflammation were assessed by analyzing the myopathological and the behavioral phenotype. Human IBM skeletal muscle biopsies were investigated to determine concordance with data from the animal model.

Results

Both acute and chronic lipopolysaccharide exposure augmented infiltration by CD8+ cytotoxic T cells and increased amyloid precursor protein steady-state levels in skeletal muscle, whereas increased A generation was observed only in chronically treated mice. Both acute and chronic inflammation enhanced tau phosphorylation in skeletal muscle. The mechanism underlying this effect was mediated by the tau kinase, glycogen synthase kinase-3 (GSK-3). Suppression of GSK-3 activity using either a specific inhibitor or lithium chloride significantly reduced tau phosphorylation and partially rescued motor impairment. In human IBM muscle, GSK-3 and phospho-tau were colocalized, further supporting the pathogenic role of GSK-3 in this disease. Using C2C12 myoblast cultures, we found that GSK-3 was activated by proinflammatory cytokines (interleukin-1, interleukin-6, tumor necrosis factor-), leading to enhanced tau phosphorylation.

Interpretation

Our results identify a molecular mechanism by which proinflammatory stimuli affect tau pathology via the GSK-3 signaling pathway in skeletal muscle. Ann Neurol 2008

Received: 6 June 2007; Revised: 20 November 2007; Accepted: 27 November 2007

Mar 18 2008, 11:47 AM EST

Lithium chloride slows onset of skeletal muscle disorder

University of California - Irvine Study first to show biopolar drug could effectively treat inclusion body myositis
Irvine, Calif., March 18, 2008 --

A new UC Irvine study finds that lithium chloride, a drug used to treat bipolar disorder, can slow the development of inclusion body myositis, a skeletal muscle disease that affects the elderly. In the study by scientists Frank LaFerla and Masashi Kitazawa, mice genetically engineered to have IBM demonstrated markedly better motor function six months after receiving daily doses of lithium chloride, compared with non-treated mice. The muscles in treated mice also had lower levels of a protein that the study linked to muscle inflammation associated with IBM. These data are the first to show that lithium chloride is a potential IBM therapy. "Lithium chloride is an approved drug for treating humans. We already know it is safe and can be used by people," said LaFerla, professor of neurobiology and behavior at UCI and co-author of the study. "Given our findings, we believe a clinical trial that tests the effectiveness of lithium chloride on IBM patients should be conducted as soon as possible." Results of the study appear online this month in the journal Annals of Neurology. IBM is the most common skeletal muscle disorder among people older than 50. People with IBM experience weakness, inflammation and atrophy of muscles in their fingers, wrists, forearms and quadriceps. There is no cure for IBM, nor is there an effective treatment, according to the National Institutes of Health. LaFerla, a noted Alzheimer's disease researcher, began studying IBM about 10 years ago after learning the disorders have similar tissue characteristics. In the brain, a buildup of phosphorylated tau protein leads to the development of tangles, one of the two lesions that are hallmarks of Alzheimer's disease. High phospho-tau levels also are present in IBM, though patients do not experience dementia or memory loss. In a previous study, LaFerla found that lithium chloride reduced phospho-tau levels in mice genetically engineered to develop Alzheimer's disease. LaFerla and his research team then wondered: Could lithium chloride also reduce phospho-tau levels and symptoms in mice with IBM? First, they sought to determine how the inflammation affects the skeletal muscle fibers. They injected the mice with a drug to trigger muscle inflammation, then put them on tiny treadmills to test their motor function. As expected, mice with inflammation could not keep up with the control mice, indicating reduced motor function. Examining their brain tissue, the scientists discovered the mice with muscle inflammation also had higher levels of phospho-tau. Through additional testing, they discovered an enzyme called GSK-3 β(beta) was responsible for increasing the tau phosphorylation. Previous studies have shown that same enzyme to cause tau buildup in the Alzheimer's brain. Next, the scientists sought to block the accumulation of phospho-tau in the IBM mice with the goal of curbing motor function loss. In mice six months of age, one group was fed lithium chloride-laced food for six months, and a second group was fed regular food. At 12 months of age, mice in the first group performed on the treadmill as if they were six months of age, while mice in the second group had reduced motor function. Lithium chloride, the scientists found, blocked the GSK-3 β(beta) enzyme that caused higher levels of phospho-tau. "The older animals were performing as if they were younger animals," said Kitazawa, a postgraduate researcher of neurobiology and behavior at UCI and co-author of the study. "Lithium chloride was delaying their rate of decline." The scientists then sought evidence that their results in mice might translate to humans with IBM. They performed tests on human muscle tissue samples and found the GSK-3 β(beta) enzyme again played a role in the phosphorylation of tau. That was not the case, though, in patients with other muscle disorders. "This suggests that our IBM mouse model may have the same skeletal muscle mechanism as in human cases," LaFerla said.

Comment: I was contacted by a senior researcher who made the following comment on this press release "The press release states outright that lithium can slow progression of inclusion body myositis. The study referred to did not administer lithium to any patients with IBM; the mistake reflects an exageration in which people claim that a manipulated animal has the disease when it in fact is only a model. In this case, the model is grossly inaccurate, but that is another story, and the press release grossly exagerating; it also claims that "mice genetically engineered to have IBM demonstrated markedly better motor function six months after receiving daily doses of lithium chloride, compared with non-treated mice." In fact, the actual results reported in the publication of this study showed no statistically significant difference in motor function in six-month treated mice."


Neurology. 2008 Feb 5;70(6):418-24. Epub 2007 Sep 19.
Comment in: Neurology. 2008 Feb 5;70(6):414-5.
Correlation of muscle biopsy, clinical course, and outcome in PM and sporadic IBM.
Chahin N, Engel AG.
Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
OBJECTIVE: To correlate muscle biopsy findings with prebiopsy and postbiopsy clinical course and response to therapy in polymyositis (PM) and sporadic inclusion body myositis (IBM). BACKGROUND: Existence of pure PM has recently been questioned; subsequently, the definition and criteria for diagnosing PM were debated. METHODS: Patient records, follow-up information, and muscle biopsies were analyzed in 107 patients whose biopsies were initially read as PM and IBM. RESULTS: The patients fell into three groups by combined biopsy and clinical criteria: PM, 27 patients; IBM, 64 patients; PM/IBM, 16 patients with biopsy diagnosis of PM but clinical features of IBM. For the three groups, the respective mean periods from disease onset to end of follow-up were 5.9, 8.5, and 9.6 years. Another autoimmune disease was present in 4 of 27 PM, 8 of 64 IBM, and 1 of 16 PM/IBM cases. An autoimmune serologic marker occurred in one-third of each group. Nineteen PM patients had no associated autoimmune disease or marker. Nonnecrotic fiber invasion by mononuclear cells appeared in all IBM, 17 of 27 PM, and 13 of 16 PM/IBM patients. The density of both invaded fibers and cytochrome-c oxidase-negative fibers was higher in IBM and PM/IBM than in PM. Immunotherapy improved 22 of 27 PM patients but had only transient beneficial effects in 2 of 32 IBM and 1 of 14 PM/IBM patients. CONCLUSIONS: 1) Sixteen of 43 patients (37%) with biopsy features of polymyositis (PM) had clinical features of inclusion body myositis (IBM). 2) Absence of canonical biopsy features of IBM from clinically affected muscles of IBM patients challenges biopsy criteria for IBM, or the IBM markers appear late in some patients, or their distribution in muscle is patchy and restricted compared with that of the inflammatory exudate. 3) The muscle biopsy is a reliable instrument in the diagnosis of PM and IBM in close to 85% of the patients. Errors of diagnosis in the remaining 15% can be avoided or reduced by combined evaluation of the clinical and pathologic findings.
J Neuropathol Exp Neurol. 2008 Jan;67(1):41-9.
Inclusion body myositis associated with human T-lymphotropic virus-type I infection: eleven patients from an endemic area in Japan.
Matsuura E, Umehara F, Nose H, Higuchi I, Matsuoka E, Izumi K, Kubota R, Saito M, Izumo S, Arimura K, Osame M.
Department of Neurology and Geriatrics, Center for Chronic Viral Diseases, Graduate School of Kagoshima University, Kagoshima, Japan.
The objective of this study was to investigate the association of human T-lymphotropic virus-type I (HTLV-I) infection with sporadic inclusion body myositis in 11 patients from an endemic area in Japan. The clinical features were consistent with sporadic inclusion body myositis, and anti-HTLV-I antibodies were present in the sera of all patients. Their muscle biopsies showed the diagnostic features of inclusion body myositis, including endomysial T-cell infiltration, rimmed vacuoles, deposits of phosphorylated tau, and abnormal filaments in the nuclei and cytoplasm of the myofibers. The fibers expressed major histocompatibility complex class I antigens and were invaded by CD8 and CD4 cells. In a single human leukocyte antigen-A2-positive patient, in situ human leukocyte antigen-A*0201 / Tax11-19-pentamer staining showed pentamer-positive cells surrounding the muscle fibers. Double-immunogold silver staining and polymerase chain reaction in situ hybridization revealed that HTLV-I proviral DNA was localized on helper-inducer T cells, but not on muscle fibers. Human T-lymphotropic virus-type I proviral loads in peripheral blood mononuclear cells from each patient were similar to those in HTLV-I-associated myelopathy/tropical spastic paraparesis. This study suggests that HTLV-I infection may be one of the causes of sporadic inclusion body myositis, as has been reported in human immunodeficiency virus type-1 infection.
Ann Neurol. 2008 Mar 4 [Epub ahead of print] Ann Neurol. 2008 Jul;64(1):15-24.
Inflammation induces tau pathology in inclusion body myositis model via glycogen synthase kinase-3β(beta).
Kitazawa M, Trinh DN, Laferla FM.
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA.
OBJECTIVE: Inclusion body myositis (IBM) is an inflammatory muscle disease, although the role of inflammation remains to be elucidated. Here, we address the mechanisms by which inflammation modulates Aβ(beta) and tau, two hallmark features of this disease. METHODS: A transgenic mouse model of IBM was utilized in which acute and chronic inflammation was induced via lipopolysaccharide. The effects of inflammation were assessed by analyzing the myopathological and the behavioral phenotype. Human IBM skeletal muscle biopsies were investigated to determine concordance with data from the animal model. RESULTS: Both acute and chronic lipopolysaccharide exposure augmented infiltration by CD8(+) cytotoxic T cells and increased amyloid precursor protein steady-state levels in skeletal muscle, whereas increased Aβ(beta) generation was observed only in chronically treated mice. Both acute and chronic inflammation enhanced tau phosphorylation in skeletal muscle. The mechanism underlying this effect was mediated by the tau kinase, glycogen synthase kinase-3β(beta) (GSK-3β(beta)). Suppression of GSK-3β(beta) activity using either a specific inhibitor or lithium chloride significantly reduced tau phosphorylation and partially rescued motor impairment. In human IBM muscle, GSK-3β(beta) and phospho-tau were colocalized, further supporting the pathogenic role of GSK-3β(beta) in this disease. Using C2C12 myoblast cultures, we found that GSK-3β(beta) was activated by proinflammatory cytokines (interleukin-1β(beta), interleukin-6, tumor necrosis factor-α (alpha)), leading to enhanced tau phosphorylation. INTERPRETATION: Our results identify a molecular mechanism by which proinflammatory stimuli affect tau pathology via the GSK-3β(beta) signaling pathway in skeletal muscle.
Neuromuscular Disorders Volume 18, Issue 2, February 2008, Pages 150-152
Case report
Apolipoprotein ε alleles in sporadic inclusion body myositis: A reappraisal
Merrilee Needhama, Corresponding Author Contact Information, E-mail The Corresponding Author, Amanda Hooperb, Ian Jamesc, Frank van Bockxmeerb, d, Alastair Corbette, Timothy Dayf, Michael J. Garleppg and Frank L. Mastaglia
Abstract
Previous studies have differed as to whether APOEε4 is a susceptibility factor for developing sporadic inclusion body myositis (sIBM), with a positive association being found only in an Australian cohort of cases. We have now re-examined this in a larger cohort of 57 sIBM cases and have also carried out a meta-analysis of all the published studies looking for evidence of a risk association or effect of APOE alleles on disease expression. Our findings argue against a specific role for any APOE alleles in conferring susceptibility to sIBM but have demonstrated a non-significant trend towards an earlier age-of-onset in patients with the ?2 allele.
Science 15 February 2008: Vol. 319. no. 5865, pp. 916 - 919 DOI: 10.1126/science.1141448
Adapting Proteostasis for Disease Intervention
William E. Balch,1 Richard I. Morimoto,2 Andrew Dillin,3 Jeffery W. Kelly4*
The protein components of eukaryotic cells face acute and chronic challenges to their integrity. Eukaryotic protein homeostasis, or proteostasis, enables healthy cell and organismal development and aging and protects against disease. Here, we describe the proteostasis network, a set of interacting activities that maintain the health of proteome and the organism. Deficiencies in proteostasis lead to many metabolic, oncological, neurodegenerative, and cardiovascular disorders. Small-molecule or biological proteostasis regulators that manipulate the concentration, conformation, quaternary structure, and/or the location of protein(s) have the potential to ameliorate some of the most challenging diseases of our era.

Slowing the Emergence of Complex Age-Onset Diseases

Aging challenges proteome homeostasis because of decreasing cellular proteostasis capacity and increasing protein damage (14-17). Given the central role of the proteome in physiology, proteostasis regulators may alleviate some of the defects facing the proteome of aged individuals and indirectly delay the onset of complex diseases of unknown etiology, such as a subset of autoimmune diseases and disorders like inclusion body myositis. Perhaps more intriguing is the possibility that restoring proteostasis capabilities to young-adult levels could reverse age-dependent imbalances that have very subtle phenotypes. In support of this idea, up-regulating proteostasis activities by the HSF-1 and DAF-16 transcription factors results in both an increased longevity of worms harboring misfolding-prone proteins and an increased ability to prevent aggregation-associated proteotoxicity (6, 20). Even if longevity is not increased in humans, restoring or maintaining proteostasis should increase the quality of life by delaying the onset and/or decreasing the impact of late-onset diseases.


Acta Neuropathol. 2007 Nov;114(5):537-42. Epub 2007 Mar 29.
Myopathy with tubulin-reactive inclusions in two cats.
Shelton GD, Sturges BK, Lyons LA, Williams DC, Aleman M, Jiang Y, Mizisin AP.
Department of Pathology 0709, University of California, San Diego, La Jolla, CA 92093-0709, USA. gshelton@ucsd.edu
Many types of inclusions have been described in human myopathies including but not limited to nemaline rod bodies, cylindrical spirals, tubular aggregates, cytoplasmic bodies, reducing bodies, and fingerprint bodies, and hyaline inclusions in myofibrillar myopathy and inclusion body myositis. There are very few reports describing inclusions in spontaneously occurring myopathies in cats, and these reports are limited to nemaline rod myopathy. A myopathy with tubulin-reactive crystalline inclusions has recently been reported in a human patient with a clinical presentation of myalgia and fatigue. Similarly, a myopathy with chronic, slowly progressive muscle weakness has been identified here in two unrelated cats. Inclusions were the only pathological change in skeletal muscle biopsies and, ultrastructurally, groups of crystalline structures were evident that had a subsarcolemmal or central location, rhomboid or rectangular shapes, lacked orientation, and were not membrane bound. The crystalline structures reacted positively with an antibody against tubulin. This feline myopathy may be the equivalent of the human myopathy with tubulin-positive crystalline inclusions.
Acta Neuropathol. 2007 Nov;114(5):517-26. Epub 2007 Aug 31.
NOGO is increased and binds to BACE1 in sporadic inclusion-body myositis and in A β(beta) PP-overexpressing cultured human muscle fibers.
Wojcik S, Engel WK, Yan R, McFerrin J, Askanas V.
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, 637 S. Lucas Ave, Los Angeles, CA 90017-1912, USA.
Increased amyloid-β(beta) precursor protein (A β(beta) PP) and amyloid-β(beta) (A β(beta)) accumulation appear to be upstream steps in the pathogenesis of sporadic inclusion-body myositis (s-IBM). BACE1, participating in A β(beta) production is also increased in s-IBM muscle fibers. Nogo-B and Nogo-A belong to a family of integral membrane reticulons, and Nogo-B binding to BACE1 blocks BACE1 access to A β(beta) PP, decreasing A β(beta) production. We studied Nogo-B and Nogo-A in s-IBM muscle and in our IBM muscle culture models, based on A β(beta) PP-overexpression or ER-stress-induction in cultured human muscle fibers (CHMFs). We report that: (1) in biopsied s-IBM fibers, Nogo-B is increased, accumulates in aggregates, is immuno-co-localized with BACE1, and binds to BACE1; Nogo-A is undetectable. (2) In CHMFs, (a) A β(beta) PP overexpression increases Nogo-B, Nogo-A, and BACE1, (b) ER stress increases BACE1 but decreases Nogo-B and Nogo-A, (c) Nogo-B and Nogo-A associate with BACE1. Accordingly, two novel mechanisms, A β(beta) PP overexpression and ER stress, are involved in Nogo-B and Nogo-A expression in human muscle. We propose that in s-IBM muscle the Nogo-B increase may represent an attempt by muscle fiber to decrease A β(beta) production. However, the increase of Nogo-B seems insufficient because A β(beta) continues to accumulate and the disease progresses. We propose that manipulations, which increase Nogo-B in s-IBM muscle might offer a new therapeutic opportunity.
[also see above]
PLoS ONE. 2008 Feb 13;3(2):e1609.
The ER-Bound RING Finger Protein 5 (RNF5/RMA1) Causes Degenerative Myopathy in Transgenic Mice and Is Deregulated in Inclusion Body Myositis.
Delaunay A, Bromberg KD, Hayashi Y, Mirabella M, Burch D, Kirkwood B, Serra C, Malicdan MC, Mizisin AP, Morosetti R, Broccolini A, Guo LT, Jones SN, Lira SA, Puri PL, Shelton GD, Ronai Z.
Signal Transduction, The Burnham Institute for Medical Research, La Jolla, California, United States of America.
Growing evidence supports the importance of ubiquitin ligases in the pathogenesis of muscular disorders, although underlying mechanisms remain largely elusive. Here we show that the expression of RNF5 (aka RMA1), an ER-anchored RING finger E3 ligase implicated in muscle organization and in recognition and processing of malfolded proteins, is elevated and mislocalized to cytoplasmic aggregates in biopsies from patients suffering from sporadic-Inclusion Body Myositis (sIBM). Consistent with these findings, an animal model for hereditary IBM (hIBM), but not their control littermates, revealed deregulated expression of RNF5. Further studies for the role of RNF5 in the pathogenesis of s-IBM and more generally in muscle physiology were performed using RNF5 transgenic and KO animals. Transgenic mice carrying inducible expression of RNF5, under control of β(beta)-actin or muscle specific promoter, exhibit an early onset of muscle wasting, muscle degeneration and extensive fiber regeneration. Prolonged expression of RNF5 in the muscle also results in the formation of fibers containing congophilic material, blue-rimmed vacuoles and inclusion bodies. These phenotypes were associated with altered expression and activity of ER chaperones, characteristic of myodegenerative diseases such as s-IBM. Conversely, muscle regeneration and induction of ER stress markers were delayed in RNF5 KO mice subjected to cardiotoxin treatment. While supporting a role for RNF5 Tg mice as model for s-IBM, our study also establishes the importance of RNF5 in muscle physiology and its deregulation in ER stress associated muscular disorders.
J Neurol Neurosurg Psychiatry. 2008 Feb 12 [Epub ahead of print]
Oculopharyngeal myopathy with inflammation and calcinosis: an unusual phenotype.
Jenkins T, Al-Sarraj S, Rose M.
Kings College Hospital, London, United Kingdom.
We report a patient with progressive proximal and distal weakness, dysphagia, respiratory weakness, subcutaneous calcifications, ptosis and ophthalmoparesis with inflammation, rimmed vacuoles and positive amyloid and ubiquitin on muscle biopsy. The histopathological features fit best with inclusion body myositis but ophthalmoparesis and ptosis have not been described in that disorder. The clinical phenotype fits best with hereditary inclusion body myopathy or distal-oculopharyngeal muscular dystrophy but the degree of inflammation seen is unusual. None of these are associated with calcinosis. We present this as an unusual phenotype for any vacuolar myopathy and as a challenge to the current diagnostic criteria for sporadic inclusion body myositis.
J Neurol Neurosurg Psychiatry. 2008 Feb 7 [Epub ahead of print]
Sporadic inclusion body myositis: Phenotypic variability and influence of HLA-DR3 in a cohort of 57 Australian cases.
Needham M, James I, Corbett A, Day T, Christiansen F, Phillips B, Mastaglia FL.
Centre for Neuromuscular and Neurological disorders, Australian Neuromuscular Research Institute (AN, Australia.
BACKGROUND AND AIMS: There have been few studies of the variability in the clinical phenotype in sporadic inclusion body myositis (sIBM) and it is not known whether the human leucocyte antigen (HLA) haplotype influences the phenotype and course of the disease. We studied a large cohort of sIBM patients in order to determine the degree of phenotypic variability and different modes of presentation, as well as the influence of HLA haplotypes. METHOD: A cross-sectional study of 57 biopsy-proven sIBM cases from three Australian centres was performed. Patients were interviewed and examined by a single investigator, and had HLA typing and autoantibody studies. RESULTS: Whilst the initial symptoms in the majority of cases were attributable to quadriceps weakness (79%), a proportion of patients presented because of finger weakness (12%), foot drop (7%) or dysphagia (1.8%). Although the majority had the classic combination of quadriceps and forearm muscle involvement, some patients had predominantly forearm weakness with sparing of the quadriceps, or severe involvement of the anterior tibial muscles Asymmetric involvement was common (82%), particularly of the forearm muscles, with the non-dominant side being more severely affected in most cases. Carriage of the HLA-DRB1*0301 (DR3) allele was associated with lower quadriceps muscle strength and a more rapid decline in strength. CONCLUSIONS: The findings emphasise the variability in the mode of presentation, patterns of muscle involvement and clinical course of sIBM in this population, and indicate that the HLA-DRB1*0301 (DR3) allele may influence the rate of progression as well as susceptibility to the disease.
Am J Med Genet A. 2008 Feb 7 [Epub ahead of print]
Clinical studies in familial VCP myopathy associated with Paget disease of bone and frontotemporal dementia.
Kimonis VE, Mehta SG, Fulchiero EC, Thomasova D, Pasquali M, Boycott K, Neilan EG, Kartashov A, Forman MS, Tucker S, Kimonis K, Mumm S, Whyte MP, Smith CD, Watts GD.
division of Genetics and Metabolism, Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Inclusion body myopathy with Paget disease of the bone (PDB) and/or frontotemporal dementia (IBMPFD, OMIM 167320), is a progressive autosomal dominant disorder caused by mutations in the Valousin-containing protein (VCP, p97 or CDC48) gene. IBMPFD can be difficult to diagnose. We assembled data on a large set of families to illustrate the number and type of misdiagnoses that occurred. Clinical analysis of 49 affected individuals in nine families indicated that 42 (87%) of individuals had muscle disease. The majority were erroneously diagnosed with limb girdle muscular dystrophy (LGMD), facioscapular muscular dystrophy, peroneal muscular dystrophy, late adult onset distal myopathy, spinal muscular atrophy, scapuloperoneal muscular dystrophy, or amyotrophic lateral sclerosis (ALS) among others. Muscle biopsies showed rimmed vacuoles characteristic of an inclusion body myopathy in 7 of 18 patients (39%), however, inclusion body myopathy was correctly diagnosed among individuals in only families 5 and 15. Frontotemporal dementia (FTD) was diagnosed in 13 individuals (27%) at a mean age of 57 years (range 48.9-60.2 years); however, several individuals had been diagnosed with Alzheimer disease. Histopathological examination of brains of three affected individuals revealed a pattern of ubiquitin positive neuronal intranuclear inclusions and dystrophic neurites. These families expand the clinical phenotype in IBMPFD, a complex disorder caused by mutations in VCP. The presence of PDB in 28 (57%) individuals suggests that measuring serum alkaline phosphatase (ALP) activity may be a useful screen for IBMPFD in patients with myopathy. (c) 2008 Wiley-Liss, Inc.
J Clin Neurosci. 2008 Feb 5 [Epub ahead of print]
Two-dimensional gel electrophoresis in inclusion body myositis.
Hutchinson DO, Jongbloed B.
Department of Neurology, Auckland Hospital, PB 92024, Auckland, New Zealand.
Inclusion body myositis (IBM) is an acquired inflammatory myopathy in which a wide range of proteins is deposited within the cytoplasm of muscle fibres. To explore the possibility that this deposition occurs due to uncontrolled protein production arising from a defect at the nuclear level, we studied muscle samples from IBM and control subjects using two-dimensional gel electrophoresis. Twenty-seven gels from five controls and 24 gels from six patients with IBM were exhaustively compared using image analysis software and visual inspection. We found significant intra- and inter-subject variability in the number of protein spots on the gels. From 2272 to 4522 spots were found in different control gels, and from 2821 to 4153 spots in the IBM gels. No unique spots were identified in the IBM gels. When viewed with other work, the results of this study suggest that widespread, uncontrolled activation of genes is unlikely to be a component of the pathogenesis in IBM.
Web address: http://www.sciencedaily.com/releases/2008/01/ 080131121807.htm
Pathway To Turn Off Immune System Cells Discovered

ScienceDaily (Feb. 1, 2008) -
University of Minnesota researchers have discovered a new way to turn genes off in human T cells, a type of white blood cell that helps the immune system fight infections. Turning off genes, through a process known as mRNA decay, is important for regulating the body's immune response after fighting infection. This research could lead to development of new drugs that turn off the immune system in patients with autoimmune diseases -- such as rheumatoid arthritis and lupus. It could also prevent cancer cells from dividing. Researchers used a novel approach that combines molecular biology and computational analysis to identify mRNA sequence responsible for turning off T cells. "Although this study analyzed T cells, this pathway is present in all human cells," said Paul Bohjanen, M.D., Ph.D., co-director of the Center for Infectious Diseases and Microbiology Translational Research (CIDMTR) and principal investigator of the study. "Knowledge from this study can be applied to help researchers better understand other types of cells and how they function." During an infection, T cells turn on and divide to help clear the infection from the body. After the infection is cleared, the cells need to turn off so the body can return to a stable condition. If the cells do not turn off, however, they can cause damage to the body and can potentially develop into cancer cells. This research is important because to date, understanding the mechanisms that turn off cells has not been very well understood. Researchers measured the rate of mRNA decay for each of the approximately 6,000 genes in human T cells. That information was then analyzed by George Karypis, Ph.D., associate professor of computer science, and his colleagues at the Minnesota Supercomputing Institute, using complex computer programs to identify a sequence present in mRNA that was destroyed rapidly in the cell. Bohjanen and his colleagues performed molecular biology experiments to confirm that this sequence targets mRNA for destruction and was responsible for turning off genes in activated T cells. "This discovery would not have been possible without the interdisciplinary collaboration between molecular biologists and computer scientists," Bohjanen said. The collaboration between Bohjanen and Karypis was facilitated by Irina Vlasova, M.D., Ph.D., research associate in Bohjanen's molecular biology laboratory, who received training in computational biology through a Minnesota Supercomputing Institute fellowship. The research is published in the February 1 issue of Molecular Cell. The research was conducted by researchers at CIDMTR, Department of Microbiology, Department of Medicine, Department of Computer Science, and division of Biostatistics. The research was funded by grants from the National Institutes of Health, the Minnesota Medical Foundation, the Minnesota Supercomputing Institute, the Lymphoma Research Foundation, and the Swedish Research Council. Adapted from materials provided by University of Minnesota, via EurekAlert!, a service of AAAS.

Need to cite this story in your essay, paper, or report? University of Minnesota (2008, February 1). Pathway To Turn Off Immune System Cells Discovered. ScienceDaily.

Retrieved February 2, 2008, from http://www.sciencedaily.com­ /releases/2008/01/080131121807.htm


Neuromuscular Disorders Volume 18, Issue 1, January 2008, Pages 27-33

Histone H1 is released from myonuclei and present in rimmed vacuoles with DNA in inclusion body myositis

Satoshi Nakano, a, , Akiyo Shindea, Kengo Fujitaa, Hidefumi Itoa and Hirofumi Kusakaa
To investigate myonuclear alterations in sporadic inclusion body myositis (s-IBM), we immuno-localized histones in muscles in 11 patients. The examination showed that vacuolar rims were frequently positive for histone H1. In triple-color fluorescence study, the H1-positive products were found on the inner side of an emerin-positive circle with DNA. Moreover, H1-positive materials appeared to be released into the cytoplasm in some vacuoles and myonuclei. The localization of H1 was different from phosphorylated Elk-1, which is a nuclear protein, but abnormally accumulated in the cytoplasm in s-IBM. The results strongly support the hypothesis that rimmed vacuoles are derived from the nucleus. The cytoplasmic H1-release suggests dysfunction of nuclear membranes in an early phase of the nuclear disintegration. We hypothesize that, in s-IBM muscles, compromised nuclear envelope may permit release of some nuclear components such as histone H1 and cannot facilitate the incorporation of others to the nucleus as in pElk-1.


Muscle Nerve. 2008 Jan 30 [Epub ahead of print]
Inclusion body myositis functional rating scale: A reliable and valid measure of disease severity.
Jackson CE, Barohn RJ, Gronseth G, Pandya S, Herbelin L; The Muscle Study Group (MSG)Muscle Study Group Members: Investigators: Rabi Tawil, MD, Robert Griggs, MD, Charles Thornton, MD (Rochester, NY); John Kissel, MD, Jerry Mendell, MD (Columbus, OH); Angela Genge, MD, George Karpati, MD (Montreal, Quebec, Canada); Carlayne Jackson, MD (San Antonio, TX); Michael Rose, MD (London, UK); Anthony Amato, MD (Boston, MA); Richard Barohn, MD, David Saperstein, MD (Kansas City, KS); Biostatistician: Michael P McDermott, PhD; Clinical Evaluators: Shree Pandya, Deborah Wahlen, Wendy King, Adriana Venturini, Deborah Myers, Samantha Prisley, Michelle Tagerman, Meredith O'Brien, Laura Herbelin; Clinical Coordinators: Lynn Cos, Karen Downing, Roza Plesiak, Frieda Barefield, Catherine Morrison, Hannah Briemberg; Safety Monitoring Committee: Robert Holloway, MD, Derick Peterson, PhD, Joanne Janciuras; Data Management: William Martens; Research Administrator: Christine Blood.. University of Texas Health Science Center, 7703 Floyd Curl Drive, Mail Code 7883, San Antonio, Texas, USA.

We developed a disease-specific, 10-point functional rating scale for patients with inclusion body myositis (IBMFRS). The IBMFRS was utilized as a secondary outcome measure in a multicenter pilot trial of the clinical safety and tolerability of high-dose β(beta) interferon-1a. In this trial, 28 IBM patients completed the IBMFRS at baseline and monthly for 6 months. The IBMFRS showed statistically significant correlations (P < 0.001) with maximal voluntary isometric contraction, manual muscle testing, handgrip dynamometry, and the amyotrophic lateral sclerosis (ALS) functional rating scale (ALSPRS). Compared to these other outcome measures, the IBMFRS was also the most sensitive measure of change over the course of the study.


Muscle Nerve, 2008. euromuscul Disord. 2007 Dec 19 [Epub ahead of print]
Sporadic inclusion body myositis: a continuing puzzle. Article attached.
Needham M, Mastaglia FL.
Centre for Neuromuscular and Neurological disorders, Level 4, A Block, Australian Neuromuscular Research Institute, Queen Elizabeth II Medical Centre, University of Western Australia, Perth, WA 6009, Australia.
There is now compelling evidence that sporadic inclusion body myositis (sIBM) is a muscle-specific autoimmune disease in which both T and B-cells play a part and in which both cytotoxic muscle fibre necrosis and degeneration occur. However the factors responsible for breakdown of immune tolerance and the nature of the target antigens expressed by muscle fibres remain unknown. Genetic factors are known to contribute to susceptibility, in particular MHC haplotyes which may influence antigenic presentation, and could also operate through genetic variations in muscle fibre constituents or immune effector mechanisms. Viral infection may act as a trigger mechanism, as in cases of HIV-associated sIBM. Our understanding of the mechanisms leading to the degenerative changes in muscle fibres is still incomplete. Protein misfolding and proteasomal dysfunction rather than defective transcriptional control is likely to underlie the abnormal accumulation of multiple proteins in the muscle fibre inclusions. However, aberrant transcription is thought to be the basis for the accumulation of potentially toxic mutant protein forms (e.g. UBB(+1)). The origin of the multiple clonally expanded somatic mtDNA mutations in COX-negative segments of muscle fibres remains uncertain but may be linked to the effects of oxidative stress. It is proposed that the disproportionate involvement of certain muscles in sIBM may be due to the existence of muscle group-specific transcriptomes which are differentially affected by the disease process and that the male predominance of the disease may indicate the influence of genes preferentially expressed in males. There is a need to develop better animal models of sIBM in which the relationship between the inflammatory and degenerative components of the disease as well as the gender difference in susceptibility and differential vulnerability of different muscle groups can be more critically investigated.


Am J Physiol Regul Integr Comp Physiol. 2008 Jan 23
Rabbits fed cholesterol-enriched diets exhibit pathological features of inclusion body myositis.
Chen X, Ghribi O, Geiger JD.
Pharmacology, Physiology and Therapeutics, University of North Dakota, Grand Forks, North Dakota, United States.
Sporadic inclusion body myositis (IBM) is the most common age-related muscle disease in humans; however its etiology is unknown, there are few animal models for this disease, and effective treatments have not been identified. Similarities between pathological findings in Alzheimer's disease brain and IBM skeletal muscle include increased levels of amyloid precursor protein (APP) and amyloid β(beta)-protein (Aβ(beta)). Moreover, there have been suggestions that elevated levels of free cholesterol might participate in the pathogenesis of Alzheimer's disease and IBM due, in part, to its role in Aβ(beta) generation. Here, we tested the hypothesis that rabbits fed cholesterol-enriched diets might faithfully exhibit human-like IBM pathological features. In skeletal muscle of one-third of the female rabbits fed cholesterol-enriched diet but not control diet, we found features of IBM including vacuolated muscle fibers, increased numbers of mononuclear inflammatory cells, increased intramuscular deposition of Aβ(beta), hyperphosphorylated tau, and increased numbers of muscle fibers immunopositive for ubiquitin. The cholesterol-enriched diet increased mRNA and protein levels of APP, increased the protein levels of β(beta)APP cleaving enzyme, and shifted APP processing in favor of Aβ(beta) production. Our study has demonstrated that increased ingestion of high levels of dietary cholesterol can result in pathological features that resemble IBM closely and thus may serve as an important new model with which to study this debilitating disorder. Key words: Amyloid precursor protein, Amyloid beta, Alzheimer's disease, Skeletal muscle.

Biochem Soc Trans. 2008 Feb;36(Pt 1):105-8.
Roles of VCP in human neurodegenerative disorders.
Kakizuka A.
Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies, and SORST (Solution Oriented Research for Science and Technology), Japan Science Technology Agency. Kyoto 606-8501, Japan.
Abnormal protein aggregates are commonly observed in affected neurons in many neurodegenerative disorders. We have reported that VCP (valosin-containing protein) co-localizes with protein aggregates in neurons of patients and in cultured cells expressing diseased proteins. However, the significance of such co-localization remains to be elucidated. In the present paper, I discuss the involvement of VCP in the processes of both the formation and re-solubilization of abnormal protein aggregates. In the study, VCP recognized and accumulated on to pre-formed protein aggregates created by proteasome inhibition. VCP knockdown or expression of dominant-negative VCP both significantly delayed the elimination of ubiquitin-positive aggregates. VCP was also involved in the clearance of pre-formed polyglutamine aggregates. Paradoxically, VCP knockdown also diminished polyglutamine aggregate formation. Furthermore, its ATPase activity is required for the re-solubilization and reactivation of heat-denatured proteins, such as luciferase, from insoluble aggregates. We thus propose that VCP functions as a mediator for both aggregate formation and clearance, depending on the concentration of soluble aggregate-prone proteins, indicating that VCP has dual functions as an aggregate formase and an unfoldase. We then examined the potentially elevated aggregate formase activities of mutant VCPs, which have been found to cause IBMPFD (inclusion body myopathy, Paget disease of bone and front-temporal dementia). Indeed, all IBMPFD VCPs showed elevated aggregate formase activities on both polyglutamine and proteasome inhibitor-mediated aggregates. Biochemically, all IBMPFD VCPs showed elevated ATPase activities as well as elevated binding affinities not only for several VCP cofactors, but also for ubiquitinated proteins. Thus controlling the function of VCP, namely decreasing aggregate formase activities and/or increasing unfoldase activities, is expected to be of great benefit for the treatment of IBMPFD and also several neurodegenerative disorders with intracellular protein inclusions.


J Rheumatol. 2008 Jan 15 [Epub ahead of print]
Epidemiology of Sporadic Inclusion Body Myositis and Polymyositis in Olmsted County, Minnesota.
Wilson FC, Ytterberg SR, St Sauver JL, Reed AM.
From the divisions of Rheumatology, Pediatric Rheumatology, and Health Sciences Research, Mayo Clinic, College of Medicine, Rochester, Minnesota, USA.
OBJECTIVE: To determine the incidence and prevalence of sporadic inclusion body myositis (sIBM) and polymyositis (PM) in a population-based study. METHODS: Charts of patients with myositis in Olmsted County, Minnesota, USA, from 1981 to 2000 were reviewed. RESULTS: For sIBM, the age- and sex-adjusted incidence rates per 100,000 were 0.79 (95% confidence interval = 0.24-1.35), and for PM, 0.41 (95% CI 0.08-0.73). The age- and sex-adjusted prevalence rates per 100,000 were 7.06 (95% CI 0.87-13.24) for sIBM and 3.45 (95% CI 0.00-7.35) for PM. CONCLUSION: The incidence and prevalence rates for sIBM are higher than previously reported. PMID: 18203321 [PubMed - as supplied by publisher]

Related article
Anti-TNF-α (alpha) Therapy Produces Rapid Improvement in Alzheimer's Disease

Caroline Cassels Medscape Medical News 2008. 2008 Medscape
January 15, 2008 Perispinal etanercept (Enbrel, Amgen), an anticytokine therapy that targets excess tumor necrosis factor α (alpha) (TNF α (alpha)) in the brain, has been shown to produce almost immediate cognitive and behavioral improvement in a patient with moderate Alzheimer's disease (AD). If confirmed in larger studies, researchers say these findings may herald a major breakthrough in the treatment of the condition, which currently affects about 5 million Americans and 27 million individuals worldwide. "This rapid response within minutes and the more prolonged response that we've seen [in other patients], is largely, or entirely, unprecedented in Alzheimer's disease," principal investigator Edward Tobinick, MD, director of the Institute for Neurological Research, a private medical group in Los Angeles, told Medscape Neurology & Neurosurgery. Etanercept, which was approved for human use in 1998 for the initial indication of rheumatoid arthritis, is currently used to treat a wide variety of inflammatory disorders in which TNF-α is thought to play a role. Using a unique, patented method that may enable direct-to-the-central-nervous-system delivery of etanercept via injection with a fine-gauge needle into the cerebrospinal venous system, investigators administered the drug in an 81-year-old male who had moderate AD, with "remarkable" results. "Prior to treatment this patient was unable to tell us which state he lived in or what year it was and was unable to identify 9 out of 10 common everyday objects that are included in the Boston Naming Test," said Dr. Tobinick. However, the authors report that within 10 minutes of drug administration, there was a marked improvement and the patient was able to name the state he was in and was 1 year off in identifying the correct year. Furthermore, he was calmer and less agitated, and his responses to questions were less effortful and more rapid, with less latency. Two hours after treatment the patient's status continued to improve, and he could correctly name 9 of the first 10 pictures on the Boston Naming Test. The study is published online January 9 in the Journal of Neuroinflammation. In addition to this single case study, Dr. Tobinick and colleagues previously published the results of a 6-month proof-of-concept study in 2006 demonstrating the efficacy of perispinal etanercept in an open-label trial of 15 patients. Although the investigators noted a similar, immediate improvement in several of the subjects, who received once-per-week therapy, the study protocol allowed only for monthly evaluation, prompting the investigators to document the treatment's rapid response in the current, single case study. "When we initially designed the study we didn't expect such a rapid response, but once we started treatment we noticed that many patients responded very quickly, often within a few minutes. This was quite a surprise, but it has since been repeated and confirmed, and now we have seen positive clinical responses with maintenance therapy that, in some cases, has exceeded 3 years," said Dr. Tobinick. Not a Cure Despite these encouraging results, Dr. Tobinick was quick to point out that this therapy should not be considered curative. "This is not a cure. It doesn't bring patients back to normal, but all indications lead us to believe that it produces a significant effect that is noticeable and important to family members and to the patients themselves," he said. Neuroinflammation accompanied by overexpression of cytokines is a standard characteristic of brain pathology in AD, and scientists have long suspected the involvement of the proinflammatory TNF-a in AD pathogenesis - a hypothesis that is supported by a rapidly growing body of basic science and genetic evidence. More relevant than the proinflammatory effects associated with overexpression of TNF-a that ultimately may give rise to the development of amyloid plaques are recent findings by Irish researchers that β(beta) amyloid, and specifically β(beta) amyloid oligomer interference with memory mechanisms in AD, are mediated by TNF-a. "The current thinking among the Alzheimer's research community is that it is probably the small groups of dissolved amyloid plaques, known as amyloid oligomers, that circulate in the brain and the cerebrospinal fluid, rather than the plaques deposited in the brain, that are responsible for memory problems [in AD]. "The fact that the amyloid interference with memory seems to be mediated by TNF-a suggests that an anti-TNF-a approach might have the potential to ameliorate these memory deficits, and that is one of the things I think we're seeing in these patients," said Dr. Tobinick. Tremendous Promise Before beginning perispinal etanercept for the treatment of AD, Dr. Tobinick's facility had more than 5 years of clinical experience using it in thousands of patients with severe disk-related back and neck pain. In the course of this experience, he observed that some of these patients seemed to experience improved cognitive function as a "side effect" of treatment. This observation, coupled with increasing evidence that TNF may play a role in synaptic dysfunction, led him to test the therapy in suspected AD patients. Currently, he said, his team is available to partner with academic medical institutions to help design controlled clinical trials to test the therapy in larger numbers of AD patients. "We have enough information now to indicate that these larger trials really should go forward as quickly as possible," said Dr. Tobinick. In addition to AD, he believes this therapy holds "tremendous promise" for patients with other types of brain disorders, including frontotemporal dementia, primary progressive aphasia, and chronic traumatic brain injury. Other areas of possible future research for the therapy could also include treatment of spinal cord injury, brain tumors, and a variety of other neurodegenerative diseases. No Time to Waste In an accompanying editorial, Sue Griffin, PhD, director of research at the Donald W. Reynolds Institute on Aging at the University of Arkansas for Medical Sciences, in Little Rock, said the findings by Dr. Tobinick and colleagues are unprecedented and warrant immediate further investigation. Considered a pioneer in the field of neuroinflammation, Dr. Griffin was the first to describe the link between cytokine overexpression in the brain and AD in a landmark study published in 1989. "I hope the scientific community will look at this work and respond very quickly to investigate it. With 5 million Americans with Alzheimer's, we have no time to waste," Dr. Griffin told Medscape Neurology & Neurosurgery. Dr. Griffin said she personally witnessed perispinal etanercept therapy in several of Dr. Tobinick's patients and was "amazed." "I must admit I was skeptical at first. So I went down to watch the procedure and to speak with both the patients and their families before and after treatment. It was truly one of the most remarkable things I've ever seen," said Dr. Griffin. She is currently working to set up a research collaboration with Dr. Tobinick to bring the procedure to her institution for the purposes of clinical as well as basic scientific research. One potential downside of the therapy, said Dr. Griffin, may be its cost, which comes in at approximately $30,000 annually for once-weekly treatment. However, she said, if proven viable, the cost of therapy needs to be weighed against the cost of caring for millions of severely disabled patients. More information is available on the Institute for Neurological Research Web site. Dr. Tobinick can be reached at etmd@ucla.edu. Study coauthor Dr. Hyman Gross declares no competing interest related to the study. Dr. Tobinick owns stock in Amgen, the manufacturer of etanercept, and has multiple issued and pending patents, including US patents 6,982,089 and 7,214,658, which describe the parenteral and perispinal use of etanercept for the treatment of Alzheimer's disease and other neurological disorders. J Neuroinflammation. Published online January 9, 2008. Abstract

J Neuroinflammation. 2008 Jan 9;5(1):2 [Epub ahead of print]
Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration.

Tobinick EL, Gross H.

ABSTRACT: Substantial basic science and clinical evidence suggests that excess tumor necrosis factor- α (alpha) (TNF-α (alpha)) is centrally involved in the pathogenesis of Alzheimer's disease. In addition to its pro-inflammatory functions, TNF-α (alpha) has recently been recognized to be a gliotransmitter that regulates synaptic function in neural networks. TNF-α (alpha) has also recently been shown to mediate the disruption in synaptic memory mechanisms, which is caused by β(beta)-amyloid and β(beta)-amyloid oligomers. The efficacy of etanercept, a biologic antagonist of TNF-α (alpha), delivered by perispinal administration, for treatment of Alzheimer's disease over a period of six months has been previously reported in a pilot study. This report details rapid cognitive improvement, beginning within minutes, using this same anti-TNF treatment modality, in a patient with late-onset Alzheimer's disease. Rapid cognitive improvement following perispinal etanercept may be related to amelioration of the effects of excess TNF-α (alpha) on synaptic mechanisms in Alzheimer's disease and provides a promising area for additional investigation and therapeutic intervention.


Front Biosci. 2008 Jan 1;13:2548-77.
Chemokines in idiopathic inflammatory myopathies.
Paepe BD, Creus KK, Bleecker JL.
Department of Neurology, Ghent University Hospital, Ghent, Belgium.
The idiopathic inflammatory myopathies (IIM) represent a heterogeneous group of acquired muscle diseases. The three best-studied subgroups: dermatomyositis (DM), polymyositis (PM), and sporadic inclusion body myositis (IBM), differ considerably both clinically and pathophysiologically. DM is a chiefly humoral endotheliopathy often associated with characteristic skin manifestations. In PM and IBM nonnecrotic muscle fibers are invaded by auto-aggressive cytotoxic T-cells and macrophages. IBM presents with additional structural abnormalities of myofibers, including rimmed vacuoles and depositions of ectopic proteins. Data accumulates implicating the chemokines in the immunopathogenesis of the different IIM. This review bundles current knowledge of the chemokine and chemokine receptor expression in the skeletal muscle of DM, PM and IBM patients. The IIM are characterized by a general increase of specific chemokines, while the chemokine distribution reflects the two different immune responses represented within these muscle diseases: (I) The endotheliopathy of DM is characterized by increased levels of CXCL12 and CCL2 in the affected blood vessels, (II) In the myocytotoxic immune response of PM and IBM, active invasion of nonnecrotic myofibers by inflammatory cells is associated with CXCL10 and CCL2 upregulation. The ever accumulating data illustrates the important role of the chemokine system in IIM, indicating the therapeutic potential of interfering agents. This raises hopes for future treatments for DM and PM with fewer side effects, and the possible establishment of a therapy suited for IBM, a myopathy which has proven unresponsive to all available immuno-modulating interventions up till now.

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Mail Bill: btillier@shaw.ca

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