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Research - What's New? 2009

Articles from the medical literature for 2009.

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)

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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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J Neurol Neurosurg Psychiatry. 2009 Dec;80(12):1344-9. Epub 2009 May 25.
Proinflammatory cell stress in sporadic inclusion body myositis muscle: overexpression of alphaB-crystallin is associated with amyloid precursor protein and accumulation of beta-amyloid.
Muth IE, Barthel K, Bähr M, Dalakas MC, Schmidt J.
Department of Neurology and Department of Experimental and Clinical Neuroimmunology, University Medicine Göttingen, Waldweg 33, 37073 Göttingen, Germany.
(see below)
BACKGROUND: In the pathology of sporadic inclusion body myositis (sIBM), the relevance of cell stress molecules such as the heat shock protein alphaB-crystallin, particularly in healthy appearing muscle fibres, has remained elusive. METHODS: 10 muscle biopsies from sIBM patients were serially stained for haematoxylin-eosin, trichrome and multi-immunohistochemistry for neural cell adhesion molecule (NCAM), alphaB-crystallin, amyloid precursor protein (APP), desmin, major histocompatibility complex I, beta-amyloid and ubiquitin. Corresponding areas of all biopsies were quantitatively analysed for all markers. Primary myotube cultures were exposed to the proinflammatory cytokines interleukin (IL)-1beta and interferon (IFN)-gamma.
RESULTS: In human myotubes exposed to IL-1beta+IFN-gamma, overexpression of APP was accompanied by upregulation of alphaB-crystallin. In sIBM muscle biopsies, over 20% of all fibres displayed accumulation of beta-amyloid or vacuoles/inclusions. A clearly larger fraction of the fibres were positive for alphaB-crystallin or APP. In contrast with the accumulation of beta-amyloid in atrophic fibres, a major part of fibres positive for APP or alphaB-crystallin showed no morphological abnormalities. Expression of APP and alphaB-crystallin significantly correlated with each other and most double positive fibres displayed accumulation of beta-amyloid, vacuoles or an atrophic morphology. In almost all of these fibres, other markers of degeneration/regeneration such as NCAM and desmin were evident as additional indicators of a cell stress response. Some fibres double positive for APP and alphaB-crystallin displayed infiltration by inflammatory cells.
CONCLUSION: Our results suggest that alphaB-crystallin is associated with overexpression of APP in sIBM muscle and that upregulation of alphaB-crystallin precedes accumulation of beta-amyloid. The data help to better understand early pathological changes and underscore the fact that a network of cell stress, inflammation and degeneration is relevant to sIBM. PMID: 19470495
Taken together, our data shed light on the recently described 'X fibres' in sIBM muscle and solidify evidence that aBcrystallin is part of an early cell stress response in skeletal muscle fibres. A significant association between APP/beta-amyloid and alphaB-crystallin was demonstrated in sIBM muscle fibres, including those that appeared normal by morphological criteria. The co-localisation of an inflammatory response and alphaB-crystallin together with induction of in vitro overexpression of alphaB-crystallin on proinflammatory cell stress underscores the relevance of inflammation in sIBM muscle, which may trigger or aggravate accumulation of beta-amyloid and vacuolar degeneration. The results further our understanding of sIBM pathology and may help to identify novel treatment strategies.

PubMed Link

Editorial commentaries
Sporadic inclusion body myositis: evidence of a link between inflammation, cell stress and beta-amyloid deposition
Frank Mastaglia
J Neurol Neurosurg Psychiatry 2009;80:1301 doi:10.1136/jnnp.2009.178889
The study by Muth et al (see above) has provided the most convincing evidence yet linking the amyloid deposition and vacuolar degeneration of myofibres to the inflammatory milieu in the muscle and a state of cell stress.
Their findings therefore support the view that the primary process in sIBM is inflammatory and are in keeping with various other lines of evidence which point to sIBM being a primary autoimmune disease of muscle.

PubMed Link

Muscle Nerve. 2009 Oct;40(4):520-8.
Nature of "Tau" immunoreactivity in normal myonuclei and inclusion body myositis.
Salajegheh M, Pinkus JL, Nazareno R, Amato AA, Parker KC, Greenberg SA.
Department of Neurology, Division of Neuromuscular Disease, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Sarcoplasmic accumulation of phosphorylated-tau has been widely stated to occur in and contribute to the pathogenesis of muscle disease in inclusion body myositis. Twenty inflammatory myopathy and 10 normal muscle samples along with a range of other tissues were stained with anti-'tau'antibodies (tau-5, pS422, and SMI-31). Myonuclear and sarcoplasmic fractions were prepared using differential solubilization and laser-capture microdissection, and immunoblots were performed using pS422 and SMI-31 antibodies. All three antibodies demonstrated anti-tau immunoreactivity in myonuclei from normal and diseased muscle, but not in nuclei from other tissues. Western blots showed pS422 and SMI-31 immunoreactivity against nuclear proteins outside the region expected for phosphorylated-tau. Antibodies previously reported to indicate abnormal accumulation of phosphorylated-tau in IBM myofibers react to normal myonuclei and recognize proteins other than tau. Normal myonuclei contain neurofilament H or other unidentified 200 kDa proteins with similar phosphorylated motifs accounting for SMI-31 immunoreactivity. PMID: 19626672

PubMed Link

J Med Dent Sci. 2008 Mar;55(1):181-7.
UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase in nuclei and rimmed vacuoles of muscle fibers in DMRV (distal myopathy with rimmed vacuoles).
Ishihara S, Tomimitsu H, Fujigasaki H, Saito F, Mizusawa H.
Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
BACKGROUND: UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) is a key molecule in the pathogenesis of distal myopathy with rimmed vacuoles (DMRV) and hereditary inclusion body myopathy (HIBM) and almost all such patients have some mutations in GNE. However, subcellular localization of GNE and the mechanism of muscular damage have not been clarified. METHODS: A rabbit polyclonal antibody for GNE was prepared. Immunohistochemistry was performed using anti-GNE and anti-nuclear protein antibodies. Western blotting with subcellular fractionated proteins was performed to determine subcellular localization of GNE. The sizes of myonuclei were quantified in muscle biopsies from patients with DMRV and amyotrophic lateral sclerosis (ALS). RESULTS: In DMRV muscles, immunohistochemistry identified GNE in sarcoplasm and specifically in myonuclei and rimmed vacuoles (RV). Nuclear proteins were also found in RVs. Immunohistochemistry showed colocalization of GNE and emerin in C2C12 cells. Western blotting revealed the presence of GNE in nuclear fractions of human embryonic kidney (HEK) 293T cells. The mean size of myonuclei of DMRV was significantly larger than that of ALS. CONCLUSION: GNE is present in myonuclei near nuclear membrane. Our results suggest that myonuclei are involved in RV formation in DMRV, and that mutant GNE in myonuclei seems to play some role in this process. PMID: 19845164

PubMed Link

J Neurochem. 2009 Oct 29. [Epub ahead of print]
In AbetaPP-overexpressing cultured human muscle fibers proteasome inhibition enhances phosphorylation of AbetaPP751 and GSK3beta activation; effects mitigated by lithium and apparently relevant to sporadic inclusion-body myositis.
Terracciano C, Nogalska A, King Engel W, Askanas V.
Department of Neurology, USC Neuromuscular Center, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA 90017.
Abstract Muscle fiber degeneration in sporadic inclusion-body myositis (s-IBM) is characterized by accumulation of multiprotein aggregates, including aggregated amyloid-beta-precursor protein 751 (AbetaPP(751)), amyloid-beta (Abeta), phosphorylated tau (p-tau), and other "Alzheimer-characteristic" proteins. Proteasome inhibition is an important component of the s-IBM pathogenesis. In brains of Alzheimer disease (AD) patients and AD transgenic mouse models, phosphorylation of neuronal AbetaPP(695) (p-AbetaPP) on Threonine(668) (T(668)) (equivalent to T(724) of AbetaPP(751)) is considered detrimental because it increases generation of cytotoxic Abeta and induces tau phosphorylation. Activated glycogen synthase kinase3beta (GSK3beta) is involved in phosphorylation of both AbetaPP and tau. Lithium, an inhibitor of GSK3beta, was reported to reduce levels of both the total AbetaPP and p-AbetaPP in AD animal models.
In relation to s-IBM, we now show for the first time that: 1. In AbetaPP-overexpressing cultured human muscle fibers (human muscle culture IBM model: a) proteasome inhibition significantly increases GSK3beta activity and AbetaPP phosphorylation; b) treatment with lithium decreases i) phosphorylated-AbetaPP; ii) total amount of AbetaPP, iii) Abeta oligomers, and iv) GSK3beta activity; and c) lithium improves proteasome function. 2. In biopsied s-IBM muscle fibers, GSK3beta is significantly activated and AbetaPP is phosphorylated on Thr(724). Accordingly, treatment with lithium, or other GSK3beta inhibitors, might benefit s-IBM patients. PMID: 19878439

PubMed Link

J Neurol Neurosurg Psychiatry. 2009 Nov;80(11):1186-93.
Inclusion body myositis: old and new concepts.
Amato AA, Barohn RJ.
Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115, USA. aamato@partners.org
Inclusion body myositis (IBM) is the most common idiopathic inflammatory myopathy occurring in patients over the age of 50 years and probably accounts for about 30% of all inflammatory myopathies. Muscle biopsy characteristically reveals endomysial inflammation, small groups of atrophic fibres, eosinophilic cytoplasmic inclusions and muscle fibres with one or more rimmed vacuoles. However, any given biopsy may lack these histopathological abnormalities; the clinical examination is often the key to diagnosis. Early and often asymmetrical weakness and atrophy of the quadriceps and flexor forearm muscles (ie, wrist and finger flexors) are the clinical hallmarks of IBM. The pathogenesis of IBM is unknown. It may be autoimmune inflammatory myopathy or a primary degenerative myopathy with a secondary inflammatory. A prevailing theory is that there is an overproduction of beta-amyloid precursor protein in muscle fibres that is somehow cleaved into abnormal beta-amyloid, and the accumulation of the latter is somehow toxic to muscle fibres. However, there are many problems with this theory and more work needs to be done. Unfortunately, IBM is generally refractory to therapy. Further research into the pathogenesis, along with both preliminary small pilot trials and larger double blind, placebo controlled efficacy trials, are needed to make progress in our understanding and therapeutic approach for this disorder. PMID: 19864656

PubMed Link

Ann N Y Acad Sci. 2009 Sep;1173:463-9.
A dual role for HSP90 and HSP70 in the inflammatory myopathies: from muscle fiber protection to active invasion by macrophages.
De Paepe B, Creus KK, Martin JJ, Weis J, De Bleecker JL.
Department of Neurology, Ghent University Hospital, Ghent, Belgium. boel.depaepe@ugent.be
Chaperones assist the metamorphosis of polypeptides to fully functional proteins. The family of heat shock proteins 70 (HSP70) bind at an early stage, while the HSP90 bind to proteins near their active conformation. We studied HSP90 and HSP70 in muscle biopsies from controls and patients diagnosed with the three main idiopathic inflammatory myopathies (IIM), namely dermatomyositis (DM), sporadic inclusion body myositis (IBM), and polymyositis (PM). Human skeletal muscle displayed constitutive levels of protein, but in IIM both HSP90 and HSP70 were upregulated. Regenerating muscle fibers of IIM and muscular dystrophy patients showed increased expression of HSP90 and HSP70, as did atrophic perifascicular muscle fibers of DM and vacuolated fibers of IBM. The infiltrates of IIM displayed weak homogeneous HSP70 staining. HSP90 were specifically upregulated in the CD68(+) cells, actively invading non-necrotic muscle fibers of IBM/PM and co-localized with inducible NO synthase. HSP90:HSP70 ratios were increased in IBM and PM tissues displaying high inflammation grade. Our results point to a multifaceted role for chaperones in muscle tissue: a general protective role for both HSP90 and HSP70 families in damaged muscle fibers, and a specific cytotoxic role for HSP90 in muscle fiber invasion typically associated with IBM and PM. PMID: 19758187

PubMed Link

Ann N Y Acad Sci. 2009 Sep;1173:370-7.
Distribution of the NF-kappaB complex in the inflammatory exudates characterizing the idiopathic inflammatory myopathies.
Creus KK, De Paepe B, Werbrouck BF, Vervaet V, Weis J, De Bleecker JL.
Department of Neurology, Ghent University Hospital, Belgium.
The transcription factor nuclear factor-kappaB (NF-kappaB) is a ubiquitously expressed protein family that is considered crucial in autoimmunity. We describe NF-kappaB p50 and p65, and the inhibitor I-kappaB alpha in the inflammatory exudates characteristic for the different idiopathic inflammatory myopathies (IIM), that is, endomysial CD8(+) cytotoxic T cells invading non-necrotic fibers in polymyositis (PM) and sporadic inclusion body myositis (sIBM), and the perimysial/perivascular CD20(+) B cells and CD4(+) T cells in dermatomyositis (DM). We also analyzed other inflammatory cells in the vicinity of active inflammation sites. Strikingly, actively invading CD4(+) cells in PM and sIBM contained both p65 and p50, whereas I-kappaB alpha was absent. This could point to a high activation state in which these cells are capable of expressing a variety of inflammatory mediators, contributing to the degradation of non-necrotic fibers. Secondly, CD68(+) macrophages in the infiltrates in all three IIM subtypes showed strong nuclear p50 and I-kappaB alpha staining. This may point to a role for p50 in counteracting inflammation, a reaction that could be enhanced by an upregulation of I-kappaB alpha as we observed with immunofluorescence. These results shed further light on the immunopathology of PM, sIBM and DM. CD4(+) and CD68(+) mononuclear cells may play a more prominent role than previously assumed. PMID: 19758175

PubMed Link

Gene Regul Syst Bio. 2009 May 8;3:89-101.
Safety and in vivo Expression of a GNE-Transgene: A Novel Treatment Approach for Hereditary Inclusion Body Myopathy-2.
Phadke AP, Jay C, Chen SJ, Haddock C, Wang Z, Yu Y, Nemunaitis D, Nemunaitis G, Templeton NS, Senzer N, Maples PB, Tong AW, Nemunaitis J.
Gradalis, Inc., Dallas, TX.
Hereditary inclusion body myopathy-2 (HIBM2) is an adult-onset, muscular disease caused by mutations in the GNE gene. HIBM2-associated GNE mutations causing hyposialyation have been proposed to contribute to reduced muscle function in patients with HIBM2, though the exact cause of this disease is unknown. In the current studies we examined pre-clinical in vivo toxicity, and expression of the plasmid-based, CMV driven wild-type GNE plasmid vector. The plasmid vector was injected intramuscularly (IM) or systemically (IV) into BALB/c mice, following encapsulation in a cationic liposome (DOTAP:Cholesterol). Single IM injections of the GNE-lipoplex at 40 mug did not produce overt toxicity or deaths, indicating that the no observable adverse effect level (NOAEL) dose for IM injection was greater than/=40 mug. Single intravenous (IV) infusion of GNE-lipoplex was lethal in 33% of animals at 100 mug dose, with a small proportion of animals in the 40 mug cohort demonstrating transient toxicity. Thus the NOAEL dose by the IV route was greater than 10 mug and less than or equal to 40 mug. Real-time RT-qPCR analysis demonstrated recombinant human GNE mRNA expression in 100% of muscle tissues that received IM injection of 40 mug GNE-lipoplex, at 2 weeks. These results indicate that GNE-lipoplex gene transfer is safe and can produce durable transgene expression in treated muscles. Our findings support future exploration of the clinical efficacy of GNE-lipoplex for experimental gene therapy of HIBM2. PMID: 19838336

PubMed Link

J Neurol Neurosurg Psychiatry. 2009 Oct;80(10):1060-8.
Evaluation and treatment of inflammatory myopathies.
Amato AA, Barohn RJ.
Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA. aamato@partners.org
The major types of idiopathic inflammatory myopathy include dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) and immune mediated necrotising myopathy (NM). These myositides appear clinically, histologically and pathogenically distinct. DM, PM and immune mediated NM are responsive to immunosuppressive therapy, in contrast with IBM which is generally refractory to therapy. Greater understanding of the pathogenic bases of these disorders should hopefully lead to better treatment. We need well designed, prospective, double blind, placebo controlled trials in order to determine the best therapeutic options for these different disorders. PMID: 19762898

PubMed Link

Muscle Nerve. 2009 Oct 7. [Epub ahead of print]
Immune-mediated necrotizing myopathy associated with statins.
Grable-Esposito P, Katzberg HD, Greenberg SA, Srinivasan J, Katz J, Amato AA.
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
We report patients from two neuromuscular centers who were evaluated between the years 2000 and 2008 and met the following criteria: (1) proximal muscle weakness occurring during or after treatment with statins; (2) elevated serum creatine kinase (CK); (3) persistence of weakness and elevated CK despite discontinuation of the statin; (4) improvement with immunosuppressive agents; and (5) muscle biopsy showing necrotizing myopathy without significant inflammation. Twenty-five patients fulfilled our inclusion criteria. Twenty-four patients required multiple immunosuppressive agents. Fifteen patients relapsed after being tapered off immunosuppressive therapy. Exposure to statins prior to onset was significantly higher in patients with necrotizing myopathy (82%) as compared to those with dermatomyositis (18%), polymyositis (24%), and inclusion-body myositis (38%) seen in the same time period. The lack of improvement following discontinuation of statins, the need for immunosuppressive therapy, and frequent relapse when treatment was tapered suggest an immune-mediated etiology for this rare, statin-associated necrotizing myopathy. Muscle Nerve, 2009. PMID: 19813188

PubMed Link

J Neurol. 2009 Oct 8. [Epub ahead of print]
The heart in sporadic inclusion body myositis: a study in 51 patients.
Cox FM, Delgado V, Verschuuren JJ, Ballieux BE, Bax JJ, Wintzen AR, Badrising UA.
Department of Neurology, Leiden University Medical Centre, P.O. Box 9600, 2300 RC, Leiden, The Netherlands, f.cox@lumc.nl.
The purpose of this study was to explore the prevalence and nature of cardiac abnormalities in sporadic inclusion body myositis (sIBM). Fifty-one sIBM patients were cross-sectionally studied using history-taking, physical examination, measurements of serum creatine kinase activity, the MB fraction (CK-MB), cardiac troponin T (cTnT) and I (cTnI), a 12-lead electrocardiogram (ECG) and 2-dimensional echocardiography. Present cardiac history was abnormal in 12 (24%) out of 51 patients, 12 (24%) patients had abnormalities on ECG, mostly aspecific, and in 12 (24%) patients the echocardiograph showed abnormalities. Elevated CK-MB was present in 42 (82%) patients and 40 (78%) had an elevated cTnT in the absence of acute cardiac pathology. In contrast, in one patient (2%) cTnI was elevated. There was no apparent association between elevated biomarkers, ECG or echocardiographic abnormalities. The prevalence of cardiac abnormalities in sIBM does not seem to be higher than would be expected in these elderly patients. Elevated CK-MB and cTnT levels are common, in contrast to cTnI, but do not reflect cardiac pathology. PMID: 19813068

PubMed Link

Muscle Nerve. 2009 Sep 18. [Epub ahead of print]
Consensus statement: The use of intravenous immunoglobulin in the treatment of neuromuscular conditions report of the aanem AD HOC committee.
Donofrio PD, Berger A, Brannagan TH 3rd, Bromberg MB, Howard JF, Latov N, Quick A, Tandan R.
American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM), 2621 Superior Drive NW Rochester, MN 55901.
Intravenous immunoglobulin (IVIG) is a therapeutic biologic agent that has been prescribed for over two decades to treat various neuromuscular conditions. Most of the treatments are given off-label, as little evidence from large randomized trials exists to support its use. Recently, IGIV-C has received an indication for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP). Because of the lack of evidence, an ad hoc committee of the AANEM was convened to draft a consensus statement on the rational use of IVIG for neuromuscular disorders. Recommendations were categorized as Class I-IV based on the strength of the medical literature. Class I evidence exists to support the prescription of IVIG to treat patients with Guillain-Barré syndrome (GBS), CIDP, multifocal motor neuropathy, refractory exacerbations of myasthenia gravis, Lambert-Eaton syndrome, dermatomyositis, and stiff person syndrome. Treatment of Fisher syndrome, polymyositis, and certain presumed autoimmune neuromuscular disorders is supported only by Class IV studies, whereas there is no convincing data to substantiate the treatment of inclusion body myopathy (IBM), idiopathic neuropathies, brachial plexopathy, or diabetic amyotrophy using IVIG. Treatment with IVIG must be administered in the context of its known adverse effects. There is little evidence to advise the clinician on the proper dosing of IVIG and duration of therapy. Muscle Nerve, 2009. PMID: 19768755

PubMed Link

J Neurol Neurosurg Psychiatry. 2009 Oct;80(10):1060-8.
Evaluation and treatment of inflammatory myopathies.
Amato AA, Barohn RJ.
Department of Neurology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115; aamato@partners.org.
The major types of idiopathic inflammatory myopathy include dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) and immune mediated necrotising myopathy (NM). These myositides appear clinically, histologically and pathogenically distinct. DM, PM and immune mediated NM are responsive to immunosuppressive therapy, in contrast with IBM which is generally refractory to therapy. Greater understanding of the pathogenic bases of these disorders should hopefully lead to better treatment. We need well designed, prospective, double blind, placebo controlled trials in order to determine the best therapeutic options for these different disorders. PMID: 19762898

PubMed Link

Ann N Y Acad Sci. 2009 Sep;1173:370-7.
Distribution of the NF-kappaB complex in the inflammatory exudates characterizing the idiopathic inflammatory myopathies.
Creus KK, De Paepe B, Werbrouck BF, Vervaet V, Weis J, De Bleecker JL.
Department of Neurology, Ghent University Hospital, Belgium.
The transcription factor nuclear factor-kappaB (NF-kappaB) is a ubiquitously expressed protein family that is considered crucial in autoimmunity. We describe NF-kappaB p50 and p65, and the inhibitor I-kappaB alpha in the inflammatory exudates characteristic for the different idiopathic inflammatory myopathies (IIM), that is, endomysial CD8(+) cytotoxic T cells invading non-necrotic fibers in polymyositis (PM) and sporadic inclusion body myositis (sIBM), and the perimysial/perivascular CD20(+) B cells and CD4(+) T cells in dermatomyositis (DM). We also analyzed other inflammatory cells in the vicinity of active inflammation sites. Strikingly, actively invading CD4(+) cells in PM and sIBM contained both p65 and p50, whereas I-kappaB alpha was absent. This could point to a high activation state in which these cells are capable of expressing a variety of inflammatory mediators, contributing to the degradation of non-necrotic fibers. Secondly, CD68(+) macrophages in the infiltrates in all three IIM subtypes showed strong nuclear p50 and I-kappaB alpha staining. This may point to a role for p50 in counteracting inflammation, a reaction that could be enhanced by an upregulation of I-kappaB alpha as we observed with immunofluorescence. These results shed further light on the immunopathology of PM, sIBM and DM. CD4(+) and CD68(+) mononuclear cells may play a more prominent role than previously assumed. PMID: 19758175

PubMed Link

Ann N Y Acad Sci. 2009 Sep;1173:463-9.
A dual role for HSP90 and HSP70 in the inflammatory myopathies: from muscle fiber protection to active invasion by macrophages.
De Paepe B, Creus KK, Martin JJ, Weis J, De Bleecker JL.
Department of Neurology, Ghent University Hospital, Ghent, Belgium. boel.depaepe@ugent.be
Chaperones assist the metamorphosis of polypeptides to fully functional proteins. The family of heat shock proteins 70 (HSP70) bind at an early stage, while the HSP90 bind to proteins near their active conformation. We studied HSP90 and HSP70 in muscle biopsies from controls and patients diagnosed with the three main idiopathic inflammatory myopathies (IIM), namely dermatomyositis (DM), sporadic inclusion body myositis (IBM), and polymyositis (PM). Human skeletal muscle displayed constitutive levels of protein, but in IIM both HSP90 and HSP70 were upregulated. Regenerating muscle fibers of IIM and muscular dystrophy patients showed increased expression of HSP90 and HSP70, as did atrophic perifascicular muscle fibers of DM and vacuolated fibers of IBM. The infiltrates of IIM displayed weak homogeneous HSP70 staining. HSP90 were specifically upregulated in the CD68(+) cells, actively invading non-necrotic muscle fibers of IBM/PM and co-localized with inducible NO synthase. HSP90:HSP70 ratios were increased in IBM and PM tissues displaying high inflammation grade. Our results point to a multifaceted role for chaperones in muscle tissue: a general protective role for both HSP90 and HSP70 families in damaged muscle fibers, and a specific cytotoxic role for HSP90 in muscle fiber invasion typically associated with IBM and PM. PMID: 19758187

PubMed Link

Curr Opin Rheumatol. 2009 Aug 28. [Epub ahead of print]
An update on the immunogenetics of idiopathic inflammatory myopathies: major histocompatibility complex and beyond.
Chinoy H, Lamb JA, Ollier WE, Cooper RG.
aThe University of Manchester Rheumatic Diseases Centre, Salford Royal NHS Foundation Trust, Salford, UK bCentre for Integrated Genomic Medical Research, The University of Manchester, Manchester, UK.
PURPOSE OF REVIEW: To update the reader on immunogenetic advances in idiopathic inflammatory myopathy (IIM) over the past 18 months. RECENT FINDINGS: In Caucasian IIM, despite a shared association with the human leukocyte antigen (HLA) 8.1 ancestral haplotype (HLA-DRB1*03-DQA1*05-DQB1*02), anti-Jo-1 and anti-PM-Scl antibody-positive cases have differing IIM clinical phenotypes. A study of the HLA-DPB1 region has shown that DPB1*0101 is associated with anti-Jo-1 positivity but not with anti-PM-Scl. IIM single nucleotide polymorphism studies have demonstrated associations in the protein tyrosine phosphatase, nonreceptor type 22, tumour necrosis factor alpha and interleukin-1 genes. The GM 13 allotype has been confirmed as a risk factor in Caucasian IIM. In inclusion body myositis, the HLA 8.1 ancestral haplotype may not only influence disease susceptibility but also disease expression. A follow-up study including a meta-analysis of the apolipoprotein E gene in inclusion body myositis suggests that this gene does not confer risk of disease. SUMMARY: Although a substantial part of the genetic risk for developing adult and juvenile IIM lies within the major histocompatibility complex, recent research suggests that genetic regions outside of the major histocompatibility complex are also potentially involved in conferring IIM disease susceptibility, although with more modest effect sizes. An ongoing and internationally coordinated IIM genome-wide association scan may provide further insights into IIM immunogenetics. PMID: 19730377

--In comparison to the recent acceleration of immunogenetic work being undertaken in polymyositis, dermatomyositis and JDM, there has been a relative paucity of substantive candidate gene work in IBM. Sporadic IBM is the most common IIM, particularly in individuals older than 50 years, so this situation may reflect a previous lack of coordinated efforts to recruit IBM patients for DNA collection. As IBM patients respond poorly to immunosuppressive treatments and some IBM phenotypes may be harder to diagnose than other IIM subtypes, it could be argued that greater resources should be utilized in the study of IBM immunogenetics. Indeed, within Europe and the United States, efforts are now underway to address this specific deficit. An Australian genetic study [31] has recently reported on 57 biopsy-proven cases of sporadic IBM. Alleles forming a part of the HLA 8.1 and 35.2 ancestral haplotypes were found to be increased compared with a control population, thus confirming the findings from previous smaller IBM HLA studies [32]. A trend towards lower quadriceps muscle strength, and a tendency of average muscle strength to decline over time, rather than plateau, was also noted in HLA-DR3- positive compared with HLA-DR3-negative cases [31]. Such a result may suggest that the HLA 8.1 ancestral haplotype influences not only disease susceptibility in IBM but also disease expression. Similarities have previously been noted in accumulated proteins from sporadic IBM muscle biopsies and brain tissue plaques from Alzheimer's disease cases, including amyloid-b precursor protein, amyloid-b and apolipoprotein E (apoE) [33]. The APOE gene has previously been investigated in sporadic IBM, in which one study's [34] results suggested that the APOE e4 allele was a risk factor for sporadic IBM. However, subsequent studies [35] have failed to reproduce this finding (Fig. 2). The same research group that described the original APOE e4 association conducted a follow-up study in the same cohort of sporadic IBM cases described above in [31]. Neither the follow-up study (P=0.9) nor a meta-analysis of all previous IBM APOE genetic studies (P=0.18) demonstrated a significant increase of the APOE e4 allele compared with control populations (Fig. 2). Thus, although the apoE protein may be involved in the pathogenesis of sporadic IBM, the current evidence suggests that the APOE genotype does not influence the risk of developing disease. These problems highlight the difficulties of conducting candidate gene studies in rare populations, that is, in which lack of statistical power may influence the null hypothesis.

chart1


PubMed Link

Curr Opin Rheumatol. 2009 Sep 1. [Epub ahead of print]
Role of cytokines and chemokines in idiopathic inflammatory myopathies.
De Paepe B, Creus KK, De Bleecker JL.
Department of Neurology and Neuromuscular Reference Center, Laboratory for Myopathology, Ghent University Hospital, Ghent, Belgium.
PURPOSE OF REVIEW: Cytokines and chemokines are essential players in the initiation and progression of the idiopathic inflammatory myopathies (IIMs). This review focuses on the most recent data and the new insight they provide for the disease mechanisms of dermatomyositis, polymyositis and sporadic inclusion body myositis. RECENT FINDINGS: Interferon-alpha and beta are implicated in the innate immune responses underlying dermatomyositis, whereas interferon-gamma stands forward as a more general regulator of the IIMs, reflected by the induction of many interferon-gamma-inducible genes in patients. Interleukin-1beta and interleukin-18 are localized to the inflammatory cells present in IIM muscle, where they may focally induce further recruitment of immune cells. Lymphotoxins are implicated in the cytotoxic activities toward polymyositis and inclusion body myositis muscle fibers, and in the organization and antibody production by B-cells in dermatomyositis. The alpha-chemokines CXCL9, CXCL10 and the beta-chemokines CCL2, CCL3, CCL4, CCL19 and CCL21 are expressed in IIM muscle. The B-cell activator CXCL13 is particularly prominent in the larger perimysial infiltrates of dermatomyositis. SUMMARY: The cytokine-chemokine patterns described in recent studies provide further evidence for predominance of Th1-mediated reactions in the different IIMs, inflammation-induced degenerative phenomena in inclusion body myositis, and a possible role for lymphoneogenesis in the sustained inflammatory response in dermatomyositis. PMID: 19726994

b-Amyloid-associated degeneration in inclusion body myositis It is an ongoing discussion whether or not IBM should be considered essentially a degenerative disorder of muscle presenting with secondary inflammation. The vacuolar degeneration of muscle fibers and the accumulation and aggregation of proteins, including b-amyloid, occur specifically in IBM and are not present in the other IIMs. The results of a recent study by Schmidt et al. provide arguments for a direct association between bamyloid accumulation and inflammation. In contrast to polymyositis and dermatomyositis, MHC-I, CXCL9, IL1-b, amyloid precursor protein (APP) and b-amyloid are jointly found in some abnormal muscle fibers in IBM. Also, in human skeletal muscle cell cultures, APP expression can be induced by pro-inflammatory cytokines. An earlier study has shown that in-vitro stimulation of myoblasts with pro-inflammatory cytokines, including IL-1b and TNF-a, leads to enhanced tau phosphorylation. These observations suggest that pro-inflammatory mediators could be upstream events that lead to the formation of protein aggregates in the affected fibers of IBM. The debate that sprung from publication of these results [32,33] illustrates that views on this issue differ considerably and that further studies are needed for scientific consensus to be firmly established in this regard.


.

Pryse-Phillips, W. (2009). Companion to clinical neurology (3rd ed.), pp. 517 - 518. New York: Oxford University Press.

inclusion body myopathy (vacuolar myopathy sparing the quadriceps, myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles) A (usually) dominantly inherited proximal syndrome with these features, the contractures normalizing in later childhood.1452

Suggested diagnostic criteria are
(1) A primary skeletal muscle disease presenting usually with distal muscle weakness in the legs.
(2) Sustained quadriceps sparing, despite marked weakness of all other hip muscles.
(3) Onset in late teenage years or early adult life.
(4). The presence of at least two affected family members.
(5) Modest elevation of serum CK levels.
(6) Numerous rimmed vacuoles with few other pathologic changes in muscle fibers.
(7) Detection of numerous filamentous inclusions without inflammation on muscle biopsy.2581, 237
Variants are IBM1 (dominant); IBM2 (recessive; 9p12, GNE); IBM3 (17p13, MyHC-IIa, dominant) and IBM with Paget disease (9p13, dominant).

inclusion body myositis (sporadic) (sIBM) A benign, usually slowly progressive inflammatory myopathy resembling chronic polymyositis, most common in males over the age of 50 years. The condition presents with painless asymmetrical proximal and distal weakness especially of the flexor digitorum profundus (more than sublimis) and finger extensors, quadriceps and glutei, with foot-drop from affection of the tibialis anterior, and loss of the knee jerks. Occasionally dysphagia, skin or ocular, facial or respiratory muscle involvement, fatigue or arthralgias are noted. The weakness does not respond to steroid therapy.3258, 5312 The condition is slowly progressive to a state of marked disability. Serum CK levels are normal or slightly raised.2292 This is the most common inflammatory myopathy in older adults.

Three distinct subsets of IBM have been recognized
(a) sporadic IBM An inflammatory vacuolar myositis with the distinct clinical phenotype described above
(b) familial inflammatory IBM An inflammatory vacuolar myositis occurring in several family members of the same generation with clinical and histological phenotype identical with the sporadic form
(c) hereditary inclusion body myopathy A group of noninflammatory vacuolar myopathies of recessive or dominant inheritance.
The recessive disease is usually characterized by quadriceps sparing and is linked to chromosome 9p. The dominant form comprises a heterogeneous group of vacuolar myopathies not all of which have been genetically identified yet1410 and includes Finnish and Swedish forms, oculopharyngeal muscular dystrophy, and Welander distal myopathy.1882

Confirmation of the diagnosis is pathological; biopsy specimens show the presence of ragged red fibers, rimmed vacuoles, and intranuclear filaments, as well as many of the usual changes of myositis.3310 Both myopathic and neurogenic EMG patterns may be found. The condition is unresponsive to current treatments. Adenovirus has been isolated from a few cases.
The entity has been reviewed1882 and diagnostic criteria have been proposed.2581 For a full examination of the disorder, visit the following Web site: http://www.ninds.nih.gov/disorders/ inclusion_body_myositis/inclusion_body_ myositis.htm.

Variant forms include familial inclusion body myositis, a dominantly inherited form of the disease;4637 a form presenting with dysphagia;5308 late juvenile sIBM; and sIBM features in association with HTLV1 infection, post-polio syndrome or neuropathy.

One set of diagnostic criteria for inclusion body myositis proposed is given in Chart I-6.

chart1

Inclusion Body Myositis Functional Rating Scale An assessment tool designed for this condition that rates swallowing, handwriting (with dominant hand prior to IBM onset), cutting food and handling utensils, fine motor tasks (such as opening doors, using keys and picking up small objects), dressing, hygiene (bathing and toileting), turning in bed and adjusting covers, sit-to-stand capability, and walking and climbing stairs, each on a five-point scale.3122

237. Argov Z, Eisenberg I, Grabov-Nardini G et al. Hereditary inclusion body myopathy. Neurology 2003;60:1519-23
1410. Dalakas M. Progress in inflammatory myopathies: Good but not good enough. J Neurol Neurosurg Psychiatry 2001;70:569-73.
1882. Engel W, Askanas V. Inclusion body myositis. Neurology 2006;66:S20-S29.
2292. Garlepp MJ, Mastaglia FL. Inclusion body myositis. J Neurol Neurosurg Psychiatry 1996;60:251-5.
2581. Griggs RC, Askanas V, DiMauro S et al. Inclusion body myositis and myopathies. Ann Neurol 1995;38:705-15.
3122. Jackson CE, Barohn RJ, Gronseth G et al. Inclusion body myositis functional rating scale: A reliable and valid measure of disease severity. Muscle Nerve 2008;37:473-6.
3258. Julien J, Vital C, Vallant J et al. Inclusion body myositis. J Neurol Sci 1982;55: 15-24.
3310. Karpati G, Carpenter S. Idiopathic inflammatory myopathies. Curr Opin Neurol Neurosurg 1988;1: 806-14.
4637. Neville HE, Baumbach LL, Ringel SP et al. Familial inclusion body myositis. Neurology 1992;42:897-902.
5308. Riminton DS, Chambers ST, Parkin PJ et al. Inclusion body myositis presenting solely as dysphagia. Neurology 1993;43:1241-3
5312. Ringel SP, Kenny CE, Neville HE et al. Spectrum of inclusion body myositis. Arch Neurol 1987;44:1154-7.


PubMed Link

Neuromuscul Disord. 2009 Aug 29. [Epub ahead of print] doi:10.1016/j.nmd.2009.07.015
Sporadic inclusion body myositis: HLA-DRB1 allele interactions influence disease risk and clinical phenotype.
Mastaglia FL, Needham M, Scott A, James I, Zilko P, Day T, Kiers L, Corbett A, Witt CS, Allcock R, Laing N, Garlepp M, Christiansen FT.
Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australian Neuromuscular Research Institute (ANRI), Queen Elizabeth II Medical Centre, Nedlands, Perth, WA 6009, Australia.
Susceptibility to sIBM is strongly associated with the HLA-DRB1*03 allele and the 8.1 MHC ancestral haplotype (HLA-A1, B8, DRB1*03) but little is known about the effects of allelic interactions at the DRB1 locus or disease-modifying effects of HLA alleles. HLA-A, B and DRB1 genotyping was performed in 80 Australian sIBM cases and the frequencies of different alleles and allele combinations were compared with those in a group of 190 healthy controls. Genotype-phenotype correlations were also investigated. Amongst carriers of the HLA-DRB1*03 allele, DRB1*03/*01 heterozygotes were over-represented in the sIBM group (p less than 0.003) while. DRB1*03/*04 heterozygotes were under-represented (p less than 0.008). The mean age-at-onset (AAO) was 6.5years earlier in DRB1*03/*01 heterozygotes who also had more severe quadriceps muscle weakness than the rest of the cohort. The findings indicate that interactions between the HLA-DRB1*03 allele and other alleles at the DRB1 locus can influence disease susceptibility and the clinical phenotype in sIBM. PMID: 19720533

In summary, our findings indicate that HLA alleles are determinants not only of disease risk in sIBM but may also have modifying effects on the disease phenotype, and that certain HLA-DRB1 allele combinations can influence the age-at-onset and severity of the disease. Further studies are needed to determine whether such effects are also present in other populations. In addition, as this was a cross-sectional study, a longitudinal study is now required to confirm the association between HLA genotype and severity of muscle weakness.


PubMed Link

Acta Neuropathol. 2009 Aug 29. [Epub ahead of print]
Vacuolar myopathy in a dog resembling human sporadic inclusion body myositis.
King J, Lecouteur RA, Aleman M, Williams DC, Moore PF, Guo LT, Mizisin AP, Shelton GD.
Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA.
Sporadic inclusion body myositis (sIBM) is the most common myopathy in people over the age of 50 years. While immune-mediated inflammatory myopathies are well documented in dogs, sIBM has not been described. An 11-year-old dog with chronic and progressive neuromuscular dysfunction was evaluated for evidence of sIBM using current pathologic, immunohistochemical and electron microscopic diagnostic criteria. Vacuoles and congophilic intracellular inclusions were identified in cryostat sections of multiple muscle biopsies and immunostained with antibodies against amyloid-beta peptide, amyloid-beta precursor protein, and proteosome 20S of the ubiquitin-proteosome system. Cellular infiltration and increased expression of MHC Class I antigen were observed. Cytoplasmic filamentous inclusions, membranous structures, and myeloid bodies were identified ultrastructurally. These observations constitute the first evidence that both the inflammatory and degenerative features of human sIBM can occur in a non-human species. PMID: 19718499

Thursday 9 July 2009 Researchers uncover potential treatment for inclusion body myositis


Doubts about Tau: New evidence casts doubt on the role of tau protein in inclusion-body myositis.


PubMed Link

Neuromuscul Disord. 2009 Jun;19(6):406-11. Epub 2009 May 26.
Basement membrane remodelling and segmental fibrosis in sporadic inclusion body myositis.
Doppler K, Mittelbronn M, Lindner A, Bornemann A.
Institute of Brain Research, University of Tubingen, Calwerstr. 3, D-72076 Tubingen, Germany.
Sporadic inclusion body myositis (sIBM) is a debilitating idiopathic inflammatory myopathy. Little is known about the pathogenetic mechanisms that lead to myofiber degeneration. In the present study, we evaluated the integrity of the myofiber basement membrane in non-necrotic myofibers invaded by inflammatory infiltrates. We used 100 ten mum thick serial sections obtained from biopsies of 5 patients suffering from sIBM. Biopsies from 5 patients suffering from polymyositis served as controls. We performed sequential HE staining and immunolabeling using anti-CD68, -CD8, -merosin, -laminin alpha4 chain, and -collagen IV antibodies. In sIBM, we detected a total of 89 non-necrotic myofibers that were invaded by inflammatory cells. The invasive process and its sequelae were segmental in nature and included destruction of the myofiber basement membrane, and eventually, partial replacement by fibrosis of the invaded myofiber. In polymyositis, we found only two myofibers that were affected in this way. In sIBM, basement membrane remodelling and irreversible replacement by fibrosis of myofibers appear to represent the end result of a process in which the balance between injury and repair are disrupted. PMID: 19473842

It is unclear what mechanisms are involved in myofiber degeneration and necrosis in inflammatory myopathies, and how cytotoxic cells gain access to myofibers.

We have demonstrated that invasion of myofibers by autoinvasive cells is accompanied by disruption of the BM and partial replacement of the myofiber by fibrosis. The resulting myofiber fragments are separated from the connective tissue by newly synthesized BM material.

[this research] lends support to the notion that new BM is synthesized after inflammatory cells have destroyed the BM of the invaded myofiber.

[this research shows that] new BM material is synthesized to seal off the lesion against the endomysial space, and that part of the destroyed myofiber is replaced by a connective tissue scar.


PubMed Link

Acta Neuropathol. 2009 Sep;118(3):407-13. Epub 2009 Jun 26.
p62/SQSTM1 is overexpressed and prominently accumulated in inclusions of sporadic inclusion-body myositis muscle fibers, and can help differentiating it from polymyositis and dermatomyositis.
Nogalska A, Terracciano C, D'Agostino C, King Engel W, Askanas V.
Department of Neurology, USC Neuromuscular Center, Good Samaritan Hospital, University of Southern California Keck School of Medicine, Los Angeles, CA 90017-1912, USA.
p62, also known as sequestosome1, is a shuttle protein transporting polyubiquitinated proteins for both the proteasomal and lysosomal degradation. p62 is an integral component of inclusions in brains of various neurodegenerative disorders, including Alzheimer disease (AD) neurofibrillary tangles (NFTs) and Lewy bodies in Parkinson disease. In AD brain, the p62 localized in NFTs is associated with phosphorylated tau (p-tau). Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle disease associated with aging, and its muscle tissue has several phenotypic similarities to AD brain. Abnormal accumulation of intracellular multiprotein inclusions, containing p-tau in the form of paired helical filaments, amyloid-beta, and several other "Alzheimer-characteristic proteins", is a characteristic feature of the s-IBM muscle fiber phenotype. Diminished proteasomal and lysosomal protein degradation appear to play an important role in the formation of intra-muscle-fiber inclusions. We now report that: (1) in s-IBM muscle fibers, p62 protein is increased on both the protein and the mRNA levels, and it is strongly accumulated within, and as a dense peripheral shell surrounding, p-tau containing inclusions, by both the light- and electron-microscopy. Accordingly, our studies provide a new, reliable, and simple molecular marker of p-tau inclusions in s-IBM muscle fibers. The prominent p62 immunohistochemical positivity and pattern diagnostically distinguish s-IBM from polymyositis and dermatomyositis. (2) In normal cultured human muscle fibers, experimental inhibition of either proteasomal or lysosomal protein degradation caused substantial increase of p62, suggesting that similar in vivo mechanisms might contribute to the p62 increase in s-IBM muscle fibers. PMID: 19557423
--We now report our novel findings that in s-IBM muscle fibers, p62 is: (a) accumulated in muscle fiber inclusions, where it co-localizes with p-tau by both light- and electronmicroscopic immunohistochemistry; and (b) increased both on the protein and mRNA levels.
--In conclusion, our studies demonstrate that p62 is an integral part of s-IBM PHF inclusions. Because (a) the p62 immunoreactivity is very specific and strong, possibly due to its being concentrated as a peripheral 'enclosure'of the PHFs bundles, and (b) its apparent specificity for s-IBM, HRP/DAB staining of p62 using easily available commercial antibodies seems to provide a new diagnostic pathologic marker of s-IBM to enable its distinction from polymyositis and dermatomyositis.

PubMed Link

Arq Neuropsiquiatr. 2008 Jun;66(2B):428-30.
Links Inclusion body myositis and HIV infection.
Freitas MR, Neves MA, Nascimento OJ, de Mello MP, Botelho JP, Chimelli L.
Neurology Department, Fluminense Federal University, Niteroi, RJ, Brazil. mgdefreitas@hotmail.com
PMID: 18641890
We report a case of a male patient, who presented with signs and symptoms of IBM in association with HIV infection.

PubMed Link

Curr Opin Neurol. 2009 Aug 12. [Epub ahead of print]
Inflammatory myopathies: disease mechanisms.
Greenberg SA.
Children's Hospital Informatics Program, Department of Neurology, Division of Neuromuscular Disease, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
PURPOSE OF REVIEW: Recent developments pertaining to disease mechanisms in the inflammatory myopathies are discussed, emphasizing those areas that are of particular interest to me. RECENT FINDINGS: The identification and further characterization of the type 1 interferon pathway in dermatomyositis is leading down a path of genomic medicine. Myonuclear structural abnormalities and the presence of nucleic acid-binding proteins, including the TAR DNA binding protein TDP-43, in sporadic inclusion body myositis (sIBM) sarcoplasm are important recent observations. This is an area likely to provide deep understanding of the mechanism of myofiber injury in sIBM. Proteomic characterization of proteins in sIBM muscle, muscle functioning as a lymphoid tissue, and the nature of belief systems, particularly one pertaining to beta-amyloid and sIBM, are other areas of interest. SUMMARY: Clarification of disease mechanisms is providing a basis for rational drug development for some patients with myositis. PMID: 19680126
--[early] investigators formulated a hypothesis that rimmed vacuoles, a feature that distinguishes sIBM from polymyositis on hematoxylin and eosin (H and E) and trichrome- stained muscle sections, derived from the breakdown of myonuclei. Between 1996 and 2007, few published papers mentioned these data.
--it is my opinion that research in this area will lead to fundamental understanding of sIBM disease mechanisms, for several reasons.
--First, rimmed vacuoles are likely derived from myonuclei. Their linings are blue on H and E and red on trichrome-stained sections, as are myonuclei. In quantitative studies of paired adjacent sections, 73% of H and E-identified rimmed vacuoles were found lined with the nuclear membrane proteins lamin A/C and emerin (Fig. 3a) [29]. Nonquantitative studies have also reported emerin and a nuclear histone protein lining these vacuoles [30], and two other proteins visible in normal muscle only in myonuclei, valosincontaining protein (VCP) [31] and TAR DNA binding protein (TDP)-43 [32].
--Second, investigators using electron microscopy to study sIBM have emphasized the distinct myonuclear morphological changes present [23,24,29].
-- Third, 15 years ago, experiments attempting (and failing) to confirm claims of specific beta-amyloid precursor protein (bAPP) transcript abundance in sIBM muscle instead found an unidentified nucleic acid-binding protein lining vacuoles of some sIBMmyofibers [26].
--Recently, the nucleic acid-binding protein TDP-43 was identified by Dr Conrad Weihl and colleagues in non-nuclear sarcoplasm in sIBM and hereditary inclusion body myopathy (hIBM) due to VCP mutations [32].
-- sarcoplasmic accumulations of TDP-43 were found in a mean of 23% of sIBM myofibers across 23 patients. The presence of more than 1% of such affected myofibers in a muscle biopsy specimen was 91% sensitive and 100% specific for sIBM among 50 patients with inflammatory myopathies. sIBM sarcoplasmic TDP-43 was accompanied by myonuclear depletion, present in 12% of myonuclei of such fibers compared to 99% of myonuclei in fibers lacking sarcoplasmic accumulation (Fig. 3c) [34].
-- studies have suggested substantial depletion in fast-twitch sarcomeric and glycolytic enzyme proteins in sIBM samples compared to other inflammatory myopathy and normal muscle.
--The mechanisms and consequences of TDP-43 redistribution from myonuclei to sarcoplasm in a high percentage of sIBM myofibers are uncertain.
-- Inclusion body myositis: what's missing? Pronounced atrophy of muscle, particularly forearm flexors and quadriceps, is a long recognized feature of sIBM. The simple question of what specific proteins are missing from these atrophied sIBM muscles is only recently beginning to be addressed.
-- it appears that this protein loss may be due to failure of translation not transcription. Whether this hypothesis is correct and whether these findings have mechanistic value to sIBM are uncertain.
-- paraphrased -- it has been widely accepted that beta-amyloid plays a central, important role in IBM etiology. It appears that this consensus is not based upon a scholarly application of citation but rather a distorted pattern based upon using citation as a persuasive tool. When such methods are used in medical studies involving clinical trials this has a direct impact on patients and also has implications when government funding is applied for. Widespread belief in a claim is not evidence of it validity.

PubMed Link

Toxic Levels Of Alzheimer's Clusters In Brain Determined
ScienceDaily (Aug. 13, 2009)
- Scientists have long suspected that Alzheimer's disease (AD) is caused by a small protein called the amyloid beta-protein (A-beta). This protein clumps or binds to itself, eventually changing chemically to create brain protein deposits (plaques) that are characteristic of AD. However, recent studies have suggested that it is not the plaques that cause AD but rather these small, grape-like clusters of A-beta. These clusters vary in size, and the relationship between cluster size and their ability to kill nerve cells (toxicity) has never been determined accurately.
Until now. By creating various sizes of A-beta clusters in the lab that exactly match what forms in brains of those afflicted with AD, neurologists at UCLA have determined that toxicity increases dramatically as clusters increase in size from two to three to four A-betas. The researchers also report that although the larger clusters are more toxic than smaller ones, the larger formations are relatively rare; smaller versions are numerous and thus are an inviting target for the development of new therapeutic drugs.
In addition, said David Teplow, senior author and a professor of neurology, developing the ability to make A-beta clusters in a very pure and precise way that duplicates what forms in AD brains will enable scientists to make detailed studies of their structures. This too will make development of future therapeutic drugs much easier and likely more successful. The research appears in the early on line edition of the Proceedings of the National Academy of Sciences (PNAS).
Alzheimer's disease is the most common form of late-life dementia. More then five million Americans have been diagnosed with the disease, 24 million worldwide, and the numbers are expected to reach 81 million by the year 2040.
"We now have the best understanding yet of what types of toxic A-beta structures we should target with new classes of therapeutic drugs," said senior author David Teplow, a professor of neurology at UCLA.
The researchers looked at the A-beta molecule, which is the chemical building block for structures that cause Alzheimer's. The molecule binds together, forming clusters of various sizes. The researchers found that the larger the cluster, the greater the toxicity, but they also found that the increase in toxicity with these clusters is not linear.
"Clusters that contain two A-beta molecules are more toxic than a single A-beta molecule, and those with three molecules are more toxic that those with two," said Teplow. But clusters of the A-beta molecule composed of dimers (two A-beta molecules forming a cluster) are three-fold more toxic than the simple monomer compound, but trimers (with three A-beta molecules) and tetramers (four molecules) are more than 10-fold more toxic than are monomers, he said.
This suggests that the larger, more toxic clusters should be the target for scientists trying to stop Alzheimer's. But Teplow notes that the relative amounts of the smaller clusters are far greater than that of the bigger clusters and are, in total, more toxic.
So in an Alzheimer's brain, the larger clusters are relatively rare, he said. "Think of the molecules being wrapped in very weak Velcro. So a number of molecules can bind together to form large clusters, but they break apart very easily."
Having developed a process in the lab to be able to make pure forms of these A-beta clusters of specific size will enable detailed study of their structures to show where every atom is. "This will make development of drugs much easier and likely more successful," he said.

PNAS published online before print August 12, 2009, doi:10.1073/pnas.0905127106
Structure-neurotoxicity relationships of amyloid beta-protein oligomers
Kenjiro Ono, Margaret M. Condron, and David B. Teplow
[Insights and Implications
Our results provide significant insights into the biophysical and pathobiological behavior of A-beta, and importantly, into strategies for developing therapeutics for AD. The 'specific activity' of A-beta assemblies depends nonlinearly on oligomer order. In fact, dimers were app. 3-fold more toxic than monomers, and tetramers were app. 13-fold more toxic. Are tetramers the 'most toxic' assembly? We do not know. Determination of a complete toxicity/order correlation is not possible because of the progressive decrease in occurrence frequency of higher-order oligomers, which precludes their isolation and study.]


PubMed Link

Clin Rheumatol. 2009 Jun;28 Suppl 1:S21-2. Epub 2008 Dec 6.
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.
---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.
---The patient was commenced on prednisolone and mycophenolate mofetil and started to show clinical improvement in her swallowing and mobility. Since discharge, she has continued to improve and her steroid dose is being reduced. Two months later, she was able to eat normally, power in the upper limbs was full, and she was mobilizing independently.
---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]. PMID: 19067104

PubMed Link

Muscle Nerve. 2009 Aug 7. [Epub ahead of print]


This paper has been retracted: no explanation has been given as to why.

Effects of recombinant type I interferon therapy on human muscle diseases.
Stubgen JP.
Department of Neurology and Neuroscience, Weill Medical College of Cornell University/New York Presbyterian Hospital, 525 East 68th Street, New York, New York 10065-4885, USA.
Interferons (IFNs) are potent extracellular protein mediators of host defense and homeostasis. Type I IFNs have well-established direct antiviral, antiproliferative, and immunomodulatory properties. The worldwide, increasing and long-term use of INFalpha, particularly for the treatment of chronic hepatitis C virus infection, has drawn attention to the development or exacerbation of numerous autoimmune phenomena, including a spectrum of myopathies. Management entailed withdrawal of INFalpha with supportive, immunomodulatory, and symptomatic treatment as deemed clinically indicated. However, IFNbeta therapy for relapsing-remitting multiple sclerosis rarely triggered clinically manifest autoimmunity. The mechanisms through which type I IFNs induce autoimmunity are incompletely understood, and they likely vary depending on the inherent differences in the pathogenesis of the immune disorder on a background of patient genetic susceptibility. INFalpha therapy had unpredictable effects on hepatitis C-associated myopathies. The immunomodulating effects of IFNbeta therapy showed no clinically significant benefit during prospective controlled treatment trials of inclusion body myositis. Type I IFNs have the theoretical potential to either cause or treat autoimmune muscular disorders by altering the complicated and delicate balances within immune system networks. Muscle Nerve, 2009. PMID: 19670318
---Meanwhile, IFNb has not fulfilled its promise as an alternative immunomodulatory drug for treatmentresistant autoimmune neuromuscular diseases, such as IBM. However, treatment protocols have not been optimized so that longer treatment duration may be necessary to realize the full potential of IFNb for chronic inflammatory immune mediated disorders.
---Inflammatory myopathies are a rare complication of INFa treatment.

STUBGEN figure 2


PubMed Link

Muscle Nerve. 2009 Jul 22. [Epub ahead of print] [Muscle Nerve. 2009 Jul;40(1):19-31.]
Nature of 'Tau' immunoreactivity in normal myonuclei and inclusion body myositis.
Salajegheh M, Pinkus JL, Nazareno R, Amato AA, Parker KC, Greenberg SA.
Department of Neurology, Division of Neuromuscular Disease, Brigham and Women's Hospital, 75 Francis Street, and Harvard Medical School, Boston, Massachusetts 02115, USA.
Sarcoplasmic accumulation of phosphorylated-tau has been widely stated to occur in and contribute to the pathogenesis of muscle disease in inclusion body myositis. Twenty inflammatory myopathy and 10 normal muscle samples along with a range of other tissues were stained with anti-'tau' antibodies (tau-5, pS422, and SMI-31). Myonuclear and sarcoplasmic fractions were prepared using differential solubilization and laser-capture microdissection, and immunoblots were performed using pS422 and SMI-31 antibodies. All three antibodies demonstrated anti-tau immunoreactivity in myonuclei from normal and diseased muscle, but not in nuclei from other tissues. Western blots showed pS422 and SMI-31 immunoreactivity against nuclear proteins outside the region expected for phosphorylated-tau. Antibodies previously reported to indicate abnormal accumulation of phosphorylated-tau in IBM myofibers react to normal myonuclei and recognize proteins other than tau. Normal myonuclei contain neurofilament H or other unidentified 200 kDa proteins with similar phosphorylated motifs accounting for SMI-31 immunoreactivity. Muscle Nerve, 2009. PMID: 19626672

DISCUSSION An important role for phosphorylated tau in inclusion body myositis has been claimed based on the belief that this protein is in some way abnormally present in IBM myofibers, a view that appears to be widely accepted (Suppl. Table 1). This belief has provided support for mechanistic claims regarding IBM myofiber injury and for claims that 'tau pathology' in a mouse model is a therapeutic biomarker applicable to IBM drug development.3 We were therefore surprised to find that three well known anti-'tau' antibodies showed immunoreactivity to most myonuclei in all normal and diseased specimens we examined.

Our studies have several implications with regard to IBM. First, we have concern regarding the validity of the interpretation of anti-"tau" immunoreactivity in IBM muscle sections as indicating the presence of tau.1-3 Second, since such immunoreactivity is already present in IBM myonuclei, interpreting it as present in the sarcoplasm of a myofiber requires a method that allows for concurrent visualization of nuclei, such as methyl green counterstaining or DAPI in fluorescent studies, as we have done here. No previous studies reporting anti-'tau' aggregates in IBM myofibers have excluded such 'aggregates' from myonuclei. Even when confirmed as sarcoplasmic, the most natural interpretation of the significance of such anti-'tau' immunoreactivity is simply that it reflects prior nuclear degeneration.20-23 Third, we have concern regarding the rationale for therapeutic development of compounds that target tau metabolism in patients with IBM, 3 given the above considerations, and the paucity of visible myofiber cross-sections containing anti-'tau' immunoreactivity in all published studies that provide quantitative data. Fourth, although electron microscopy has shown accumulation of tubulofilaments in a small number of myonuclei and extranuclear regions of IBM myofibers, the identities of the molecules constituting these filaments are unknown.


PubMed Link

Acta Reumatol Port. 2009 Apr-Jun;34(2A):161-82.
Sporadic inclusion body myositis: an unsolved mystery.
Machado P, Miller A, Holton J, Hanna M.
Department of Rheumatology, Coimbra University Hospital, Praceta Mota Pinto, 3000-075 Coimbra, Portugal. pedrommcmachado@gmail.com
Sporadic inclusion body myositis (sIBM) is considered to be the most common acquired muscle disease associated with aging. It is a disabling disorder still without effective treatment. sIBM causes weakness and atrophy of the distal and proximal muscles. Involvement of quadriceps and deep finger flexors are clues to early diagnosis. Dysphagia in the course of the disease is common. Muscle biopsy shows chronic myopathic features, lymphocytic infiltration invading non-necrotic fibbers, rimmed vacuoles and accumulation of amyloid-related proteins. It remains uncertain whether sIBM is primarily an immune-mediated inflammatory myopathy or a degenerative myopathy with an associated inflammatory component. This review describes the epidemiology and clinical features of the disease as well as the current genetic and pathogenic concepts and therapeutic approaches. Despite recent clues, in many respects sIBM remains an unsolved mystery. PMID: 19474772

Read this associated editorial first: Inappropriate referencing in research: Has serious consequences, and the research community needs to act

PubMed Link

BMJ. 2009 Jul 20;339:b2680. doi: 10.1136/bmj.b2680.
Comment in: BMJ. 2009;339:b2049.
How citation distortions create unfounded authority: analysis of a citation network.
Greenberg SA.
Children's Hospital Informatics Program and Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. sagreenberg@partners.org
OBJECTIVE: To understand belief in a specific scientific claim by studying the pattern of citations among papers stating it. DESIGN: A complete citation network was constructed from all PubMed indexed English literature papers addressing the belief that beta amyloid, a protein accumulated in the brain in Alzheimer's disease, is produced by and injures skeletal muscle of patients with inclusion body myositis. Social network theory and graph theory were used to analyse this network. MAIN OUTCOME MEASURES: Citation bias, amplification, and invention, and their effects on determining authority. RESULTS: The network contained 242 papers and 675 citations addressing the belief, with 220,553 citation paths supporting it. Unfounded authority was established by citation bias against papers that refuted or weakened the belief; amplification, the marked expansion of the belief system by papers presenting no data addressing it; and forms of invention such as the conversion of hypothesis into fact through citation alone. Extension of this network into text within grants funded by the National Institutes of Health and obtained through the Freedom of Information Act showed the same phenomena present and sometimes used to justify requests for funding. CONCLUSION: Citation is both an impartial scholarly method and a powerful form of social communication. Through distortions in its social use that include bias, amplification, and invention, citation can be used to generate information cascades resulting in unfounded authority of claims. Construction and analysis of a claim specific citation network may clarify the nature of a published belief system and expose distorted methods of social citation. PMID: 19622839


PubMed Link

Nat Med. 2009 Jun;15(6):690-5.
Prophylactic treatment with sialic acid metabolites precludes the development of the myopathic phenotype in the DMRV-hIBM mouse model.
Malicdan MC, Noguchi S, Hayashi YK, Nonaka I, Nishino I.
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
Distal myopathy with rimmed vacuoles (DMRV)-hereditary inclusion body myopathy (hIBM) is an adult-onset, moderately progressive autosomal recessive myopathy; eventually, affected individuals become wheelchair bound1. It is characterized clinically by skeletal muscle atrophy and weakness, and pathologically by rimmed vacuoles, which are actually accumulations of autophagic vacuoles2, 3, 4, scattered angular fibers and intracellular accumulation of amyloid and other proteins5. To date, no therapy is available for this debilitating myopathy, primarily because the disease pathomechanism has been enigmatic. It is known that the disease gene underlying DMRV-hIBM is GNE, encoding glucosamine (UDP-N-acetyl)-2-epimerase and N-acetylmannosamine kinase6, 7, 8--two essential enzymes in sialic acid biosynthesis9. It is still unclear, however, whether decreased sialic acid production causes muscle degeneration, as GNE has been proposed to have roles other than for sialic acid biosynthesis10, 11, 12. By showing that muscle atrophy and weakness are completely prevented in a mouse model of DMRV-hIBM after treatment with sialic acid metabolites orally, we provide evidence that hyposialylation is indeed one of the key factors in the pathomechanism of DMRV-hIBM. These results support the notion that DMRV-hIBM can potentially be treated simply by giving sialic acids, a strategy that could be applied in clinical trials in the near future. PMID: 19448634

PubMed Link

Muscle Nerve. 2009 Jul 17. [Epub ahead of print]
Hereditary inclusion-body myopathy: Clues on pathogenesis and possible therapy.
Broccolini A, Gidaro T, Morosetti R, Mirabella M.
Department of Neuroscience, Catholic University, L.go A. Gemelli 8, 00168 Rome, Italy.
Hereditary inclusion-body myopathy (h-IBM), or distal myopathy with rimmed vacuoles (DMRV), is an autosomal recessive disorder with onset in early adult life and a progressive course leading to severe disability. h-IBM/DMRV is due to mutations of a gene (GNE) that codes for a rate-limiting enzyme in the sialic acid biosynthetic pathway. Despite the identification of the causative gene defect, it has not been unambiguously clarified how GNE gene mutations impair muscle metabolism. Although numerous studies have indicated a key role of hyposialylation of glycoproteins in h-IBM/DMRV pathogenesis, others have demonstrated new and unpredicted functions of the GNE gene, outside the sialic acid biosynthetic pathway, that may also be relevant. This review illustrates the clinical and pathologic characteristics of h-IBM/DMRV and the main clues available to date concerning the possible pathogenic mechanisms and therapeutic perspectives of this disorder. Muscle Nerve, 2009. PMID: 19618441

sialic acid


PubMed Link

J Neurol Sci. 2009 Apr 15;279(1-2):47-52. Epub 2009 Jan 25.
CCR7+ myeloid dendritic cells together with CCR7+ T cells and CCR7+ macrophages invade CCL19+ nonnecrotic muscle fibers in inclusion body myositis.
Tateyama M, Fujihara K, Misu T, Itoyama Y.
Department of Neurology, Tohoku University School of Medicine, Sendai, Japan. mtateyama@em.neurol.med.tohoku.ac.jp
CCR7 and its ligands CCL19 and CCL21 are a key chemokine system in T cell priming in secondary lymphoid organs, and are rarely expressed in normal muscle tissue. We immunohistochemically investigated the expression of this chemokine system in the muscles of seven patients with inclusion body myositis (IBM). In all cases, CCR7+ mononuclear cells infiltrated in the endomysium, preferentially surrounded and invaded nonnecrotic muscle fibers. Double immunostaining revealed that such CCR7+ mononuclear cells included BDCA-1+ myeloid dendritic cells as well as CD8+ cells, CD4+ cells and CD68+ macrophages. On the other hand, CCL19 was widely expressed on muscle fibers including those invaded by mononuclear cells. CCL19 was also expressed diffusely on endomysial mononuclear cells and endothelium of vessels. Immunoreactivities of CCL21 were detected on some muscle fibers and mononuclear cells. By RT-PCR analyses, mRNA of CCR7 was detected in all the patients and that of CCL19 and CCL21 was detected in six. These findings showed that the CCL19, CCL21/CCR7 chemokine system is expressed in muscles of IBM. The chemokine mediated attraction in dendritic and other immune cells and muscle cells may be crucial in sustained antigen presentation, T cell activation and immune attack to muscles in the pathogenesis of IBM. PMID: 19171354

PubMed Link

Mol Biol Cell. 2009 Mar;20(5):1533-44. Epub 2009 Jan 14.
The insulin/Akt signaling pathway is targeted by intracellular beta-amyloid.
Lee HK, Kumar P, Fu Q, Rosen KM, Querfurth HW.
Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA.
Intraneuronal beta-amyloid (Abeta(i)) accumulates early in Alzheimer's disease (AD) and inclusion body myositis. Several organelles, receptor molecules, homeostatic processes, and signal transduction components have been identified as sensitive to Abeta. Although prior studies implicate the insulin-PI3K-Akt signaling cascade, a specific step within this or any essential metabolic or survival pathway has not emerged as a molecular target. We tested the effect of Abeta42 on each component of this cascade. In AD brain, the association between PDK and Akt, phospho-Akt levels and its activity were all decreased relative to control. In cell culture, Abeta(i) expression inhibited both insulin-induced Akt phosphorylation and activity. In vitro experiments identified that beta-amyloid (Abeta), especially oligomer preparations, specifically interrupted the PDK-dependent activation of Akt. Abeta(i) also blocked the association between PDK and Akt in cell-based and in vitro experiments. Importantly, Abeta did not interrupt Akt or PI3K activities (once stimulated) nor did it affect more proximal signal events. These results offer a novel therapeutic strategy to neutralize Abeta-induced energy failure and neuronal death. PMID: 19144826

PubMed Link

J Neurol. 2009 Jul 15. [Epub ahead of print]
Detecting dysphagia in inclusion body myositis.
Cox FM, Verschuuren JJ, Verbist BM, Niks EH, Wintzen AR, Badrising UA.
Department of Neurology, Leiden University Medical Centre, P.O. Box 9600, 2300 RC, Leiden, The Netherlands, f.cox@lumc.nl.
Dysphagia is an important yet inconsistently recognized symptom of inclusion body myositis (IBM). It can be disabling and potentially life-threatening. We studied the prevalence and symptom-sign correlation of dysphagia. Fifty-seven IBM patients were interviewed using a standard questionnaire for dysphagia and 43 of these underwent swallowing videofluoroscopy (VFS). Symptoms of dysphagia were present in 37 of 57 patients (65%). Nevertheless, only 17 of these patients (46%) had previously and spontaneously complained about swallowing to their physicians. Both symptoms of impaired propulsion (IP) (59%) and aspiration-related symptoms (52%) were frequently mentioned. Swallowing abnormalities on VFS were present in 34 of 43 patients (79%) with IP of the bolus in 77% of this group. The reported feeling of IP was confirmed by VFS in 92% of these patients. Dysphagia in IBM is common but underreported by the vast majority of patients if not specifically asked for. In practice, two questions reliably predict the presence of IP on VFS: 'Does food get stuck in your throat' and 'Do you have to swallow repeatedly in order to get rid of food'. These questions are an appropriate means in selecting IBM patients for further investigation through VFS and eventual treatment. PMID: 19603245

PubMed Link

Biochim Biophys Acta. 2009 Jul 10. [Epub ahead of print]
Hereditary Inclusion Body Myopathy: A Decade of Progress.
Huizing M, Krasnewich DM.
Cell Biology of Metabolic Disorders Unit.
Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive, quadriceps sparing type commonly referred to as HIBM but also termed h-IBM or Inclusion Body Myopathy 2 (IBM2). The clinical manifestations begin with muscle weakness progressing over the next 10-20 years uniquely sparing the quadriceps until the most advanced stage of the disease. Histopathology of an HIBM muscle biopsy shows rimmed vacuoles on Gomori's trichrome stain, small fibers in groups and tubulofilaments without evidence of inflammation. In affected individuals distinct mutations have been identified in the GNE gene, which encodes the bifunctional enzyme uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase/N-acetyl-mannosamine (ManNAc) kinase (GNE/MNK). GNE/MNK catalyzes the first two committed steps in the biosynthesis of acetylneuraminic acid (Neu5Ac), an abundant and functionally important sugar. The generation of HIBM animal models has led to novel insights into both the disease and the role of GNE/MNK in pathophysiology. Recent advances in therapeutic approaches for HIBM, including administration of N-acetyl mannosamine (ManNAc), a precursor of Neu5Ac will be discussed. PMID: 19596068

PubMed Link

Acta Neuropathol. 2009 Jul 14. [Epub ahead of print]
The ubiquitin proteasome system in neuropathology.
Lehman NL.
Department of Pathology and Laboratory Medicine, Hermelin Brain Tumor Center, Henry Ford Health System, 2799 West Grand Boulevard, Detroit, MI, 48202, USA, nllehman@yahoo.com.
The ubiquitin proteasome system (UPS) orchestrates the turnover of innumerable cellular proteins. In the process of ubiquitination the small protein ubiquitin is attached to a target protein by a peptide bond. The ubiquitinated target protein is subsequently shuttled to a protease complex known as the 26S proteasome and subjected to degradative proteolysis. The UPS facilitates the turnover of proteins in several settings. It targets oxidized, mutant or misfolded proteins for general proteolytic destruction, and allows for the tightly controlled and specific destruction of proteins involved in development and differentiation, cell cycle progression, circadian rhythms, apoptosis, and other biological processes. In neuropathology, alteration of the UPS, or mutations in UPS target proteins may result in signaling abnormalities leading to the initiation or progression of tumors such as astrocytomas, hemangioblastomas, craniopharyngiomas, pituitary adenomas, and medulloblastomas. Dysregulation of the UPS may also contribute to tumor progression by perturbation of DNA replication and mitotic control mechanisms, leading to genomic instability. In neurodegenerative diseases caused by the expression of mutant proteins, the cellular accumulation of these proteins may overload the UPS, indirectly contributing to the disease process, e.g., sporadic Parkinsonism and prion diseases. In other cases, mutation of UPS components may directly cause pathological accumulation of proteins, e.g., autosomal recessive Parkinsonism and spinocerebellar ataxias. Defects or dysfunction of the UPS may also underlie cognitive disorders such as Angelman syndrome, Rett syndrome and autism, and muscle and nerve diseases, e.g., inclusion body myopathy and giant axon neuropathy. This paper describes the basic biochemical mechanisms comprising the UPS and reviews both its theoretical and proven involvement in neuropathological diseases. The potential for the UPS as a target of pharmacological therapy is also discussed. PMID: 19597829

PubMed Link

Brain Pathol. 2009 Jul;19(3):493-506.
Inclusion body myositis: a degenerative muscle disease associated with intra-muscle fiber multi-protein aggregates, proteasome inhibition, endoplasmic reticulum stress and decreased lysosomal degradation.
Askanas V, Engel WK, Nogalska A.
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, 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 there is no enduring treatment. Abnormal accumulation of intracellular multi-protein inclusions is a characteristic feature of the s-IBM phenotype, and as such s-IBM can be considered a "conformational disorder," caused by protein unfolding/misfolding combined with the formation of inclusion bodies. Abnormal intracellular accumulation of unfolded proteins may lead to their aggregation and inclusion body formation. The present article is focusing on the multiple proteins that are accumulated in the form of aggregates within s-IBM muscle fibers, and it explores the most recent research advances directed toward a better understanding of mechanisms causing their impaired degradation and abnormal aggregation. We illustrate that, among other factors, abnormal misfolding, accumulation and aggregation of proteins are associated with their inadequate disposal-and these factors are combined with, and perhaps provoked by, an aging intracellular milieu. Other concurrent and possibly provocative phenomena known within s-IBM muscle fibers are: endoplasmic reticulum stress and unfolded protein response, mitochondrial abnormalities, proteasome inhibition, lysosome abnormality and endodissolution. Together, these appear to lead to the s-IBM-specific vacuolar degeneration, and muscle fiber atrophy, concluding with muscle fiber death. PMID: 19563541

Askanas09

Figure 1. Intracellular abnormalities present in sporadic inclusion body myositis (s-IBM) muscle fibers. We propose that predisposing genes and an aging muscle fiber milieu contribute to the muscle fiber abnormalities typical of s-IBM (details in the text). Decreased SIRT1 activity might play a central, age-related role in the s-IBM pathogenic cascade.


PubMed Link

Acta Neuropathol. 2009 Jun 26. [Epub ahead of print]
p62/SQSTM1 is overexpressed and prominently accumulated in inclusions of sporadic inclusion-body myositis muscle fibers, and can help differentiating it from polymyositis and dermatomyositis.
Nogalska A, Terracciano C, D'Agostino C, King Engel W, Askanas V.
Department of Neurology, USC Neuromuscular Center, Good Samaritan Hospital, University of Southern California Keck School of Medicine, 637 S. Lucas Ave, Los Angeles, CA, 90017-1912, USA.
p62, also known as sequestosome1, is a shuttle protein transporting polyubiquitinated proteins for both the proteasomal and lysosomal degradation. p62 is an integral component of inclusions in brains of various neurodegenerative disorders, including Alzheimer disease (AD) neurofibrillary tangles (NFTs) and Lewy bodies in Parkinson disease. In AD brain, the p62 localized in NFTs is associated with phosphorylated tau (p-tau). Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle disease associated with aging, and its muscle tissue has several phenotypic similarities to AD brain. Abnormal accumulation of intracellular multiprotein inclusions, containing p-tau in the form of paired helical filaments, amyloid-beta, and several other 'Alzheimer-characteristic proteins', is a characteristic feature of the s-IBM muscle fiber phenotype. Diminished proteasomal and lysosomal protein degradation appear to play an important role in the formation of intra-muscle-fiber inclusions. We now report that: (1) in s-IBM muscle fibers, p62 protein is increased on both the protein and the mRNA levels, and it is strongly accumulated within, and as a dense peripheral shell surrounding, p-tau containing inclusions, by both the light- and electron-microscopy. Accordingly, our studies provide a new, reliable, and simple molecular marker of p-tau inclusions in s-IBM muscle fibers. The prominent p62 immunohistochemical positivity and pattern diagnostically distinguish s-IBM from polymyositis and dermatomyositis. (2) In normal cultured human muscle fibers, experimental inhibition of either proteasomal or lysosomal protein degradation caused substantial increase of p62, suggesting that similar in vivo mechanisms might contribute to the p62 increase in s-IBM muscle fibers. PMID: 19557423

PubMed Link

Proc Natl Acad Sci U S A. 2009 Jun 19. [Epub ahead of print]
Secretion of amyloidogenic gelsolin progressively compromises protein homeostasis leading to the intracellular aggregation of proteins.
Page LJ, Suk JY, Bazhenova L, Fleming SM, Wood M, Jiang Y, Guo LT, Mizisin AP, Kisilevsky R, Shelton GD, Balch WE, Kelly JW.
Department of Cell Biology.
Familial amyloidosis of Finnish type (FAF) is a systemic amyloid disease associated with the deposition of proteolytic fragments of mutant (D187N/Y) plasma gelsolin. We report a mouse model of FAF featuring a muscle-specific promoter to drive D187N gelsolin synthesis. This model recapitulates the aberrant endoproteolytic cascade and the aging-associated extracellular amyloid deposition of FAF. Amyloidogenesis is observed only in tissues synthesizing human D187N gelsolin, despite the presence of full-length D187N gelsolin and its 68-kDa cleavage product in blood-demonstrating the importance of local synthesis in FAF. Loss of muscle strength was progressive in homozygous D187N gelsolin mice. The presence of misfolding-prone D187N gelsolin appears to exacerbate the age-associated decline in cellular protein homeostasis (proteostasis), reflected by the intracellular deposition of numerous proteins, a characteristic of the most common degenerative muscle disease of aging humans, sporadic inclusion body myositis. PMID: 19549824

TDP Webpage

PubMed Link

Muscle Nerve. 2009 Jun 16;40(1):8-9. [Epub ahead of print]
Editorial: TDP-43: A reliable immunohistochemistry marker for inclusion body myositis?
Verma A, Tandan R.
Department of Neurology, University of Miami Miller School of Medicine, Clinical Research Building, 1120 NW 14 Street, Suite 1317 Miami, FL 33136.
PMID: 19533631
-see article below
-TDP-43 is a 414 amino acid protein encoded by the transactive response (TAR) DNA binding protein gene on chromosome 1p36.
-TDP-43 is chiefly involved in well characterized transcription function and RNA splicing regulation. Recent studies suggest that TDP-43 may be involved in other cellular processes, such as microRNA biogenesis, apoptosis, cell division, mRNA stabilization and regulation of neuronal plasticity.
-Over the past year, TDP-43 immunoreactive UBIs have been reported in sIBM and in familial myopathies with or without vacuolar change.
-TDP-43 is so far the most sensitive and specific diagnostic immunohistochemistry marker for IBM.
-to date, no TDP-43 mutation has been associated with sIBM patients.
-It is unknown if protein aggregates are a cause or consequence of the disease process.
Reference: Muscle Nerve. 2009 Jun 16;40(1):19-31. [Epub ahead of print]
Sarcoplasmic redistribution of nuclear TDP-43 in inclusion body myositis.
Salajegheh M, Pinkus JL, Taylor JP, Amato AA, Nazareno R, Baloh RH, Greenberg SA.

TDP Webpage

PubMed Link

Muscle Nerve. 2009 Jun 16;40(1):19-31. [Epub ahead of print]
Sarcoplasmic redistribution of nuclear TDP-43 in inclusion body myositis.
Salajegheh M, Pinkus JL, Taylor JP, Amato AA, Nazareno R, Baloh RH, Greenberg SA.
Department of Neurology, Division of Neuromuscular Disease, Brigham and Women's Hospital, and Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
-see article above
The nucleic acid binding protein TDP-43 was recently identified in normal myonuclei and in the sarcoplasm of inclusion body myositis (IBM) muscle. Here we found TDP-43 sarcoplasmic immunoreactivity in 23% of IBM myofibers, while other reported IBM biomarkers were less frequent, with rimmed vacuoles in 2.8%, fluorescent Congo red material in 0.57%, SMI-31 immunoreactivity in 0.83%, and focal R1282 beta-amyloid immunoreactivity in 0.00% of myofibers. The presence of as little as greater than 1% of myofibers with nonnuclear sarcoplasmic TDP-43 was highly sensitive (91%) and specific (100%) to IBM among 50 inflammatory myopathy patient samples, although some patients with hereditary inclusion body myopathies and myofibrillar myopathy also had sarcoplasmic TDP-43. TDP-43 mutations were sought, and none were identified. TDP-43 could be one of many nucleic acid binding proteins that are abnormally present in IBM sarcoplasm. They could potentially interfere with the normal function of extranuclear RNAs that maintain myofiber protein production. Muscle Nerve 40: 19-31, 2009. PMID: 19533646

Kagen, L. J. (Editor), (2009). The Inflammatory Myopathies. New York: Humana Press. This book presents a comprehensive review of the inflammatory myopathies, including dermatomyositis, polymyositis, and inclusion body myositis. Representing the most up-to-date knowledge on this family of diseases, The Inflammatory Myopathies covers clinical presentation, methods of diagnosis, ongoing assessment of clinical course, treatment, and the latest information on pathogenesis. Physical, laboratory, imaging, and serological findings are discussed in the context of chronic disease, complications, and co-morbidities. The role and mechanism of inflammatory response is also explored with reference to emerging humoral and cellular targets for therapeutic intervention. The Inflammatory Myopathies is the gold-standard in the field and a must have resource for rheumatologists, neurologists and all healthcare professionals who treat afflicted patients.

Chapter on IBM


PubMed Link

Acta Neuropathol. 2009 Jun 6.
Increased plasma amyloid-beta(42) protein in sporadic inclusion body myositis.
Abdo WF, van Mierlo T, Hengstman GJ, Schelhaas HJ, van Engelen BG, Verbeek MM.
Institute of Neurology, Neuromuscular Centre Nijmegen, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands, f.abdo@neuro.umcn.nl. PMID: 19504113
The median plasma Ab42 levels were significantly increased in the s-IBM group versus controls and PM group. When we divided the s-IBM patients into two groups, with concentrations either above or below the median levels of Ab42, we neither found any differences in demographic data nor in disease severity.

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

Mastaglia09


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

J Clin Neuromuscul Dis. 2009 Jun;10(4):178-184.
Improvement in Aerobic Capacity After an Exercise Program in Sporadic Inclusion Body Myositis.
Johnson LG, Collier KE, Edwards DJ, Philippe DL, Eastwood PR, Walters SE, Thickbroom GW, Mastaglia FL.
From the *Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Western Australia; daggerSchool of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, Western Australia; double daggerDepartment of Pulmonary Physiology, Sir Charles Gairdner Hospital, Perth, Western Australia; section signSchool of Anatomy and Human Biology, University of Western Australia, Nedlands, Western Australia; and paragraph signSchool of Physiotherapy, Curtin University of Technology, Bentley, Western Australia.
OBJECTIVES:: The study aimed to investigate the effects of a combined functional and aerobic exercise program on aerobic capacity, muscle strength, and functional mobility in a group of patients with sporadic inclusion body myositis (IBM). METHODS:: Aerobic capacity, muscle strength, and functional capacity assessments were conducted on 7 participants with sporadic IBM before and after a 12-week exercise program, which included resistance exercises and aerobic stationary cycling 3 times per week on alternative days. RESULTS:: Aerobic capacity of the group increased significantly by 38%, and significant strength improvements were observed in 4 of the muscle groups tested (P less than 0.05). The exercise program was well tolerated, and there was no significant change in the serum creatine kinase level after the exercise period. CONCLUSIONS:: An aerobic exercise program can be safely tolerated by patients with sporadic IBM and can improve aerobic capacity and muscle strength when combined with resistance training. These findings indicate that aerobic and functional muscle strengthening exercise should be considered in the management of patients with IBM. PMID: 19494728
quote: We have previously shown that strength and flexibility training can be safely administered in IBM and can improve function. In the present study, we hypothesized that the addition of aerobic exercise to a program of strength and flexibility training would be safe, well tolerated, and improve aerobic capacity and functional mobility in these patients.
quote: In summary, this study has shown that significant improvements in aerobic capacity can be attained through a home-based, patient-specific functional and aerobic exercise program. Furthermore, in the absence of muscle damage, functional improvements can be made and significant strength gains can be attained in nondiseased muscles when trained. The results of this study indicate that patients with IBM can improve their aerobic capacity with training; however, the selective nature of this disease may restrict the potential strength gains in muscles involved in IBM, and it remains to be seen if exercise can produce long term disease-modifying benefits. Importantly, the training program was safe and tolerable. The findings from this study suggest that aerobic and functional muscle strengthening exercises are complementary and should be considered in the management of patients with IBM.

PubMed Link

Neuromuscul Disord. 2009 May 25. [Epub ahead of print]
Basement membrane remodelling and segmental fibrosis in sporadic inclusion body myositis.
Doppler K, Mittelbronn M, Lindner A, Bornemann A.
Institute of Brain Research, University of Tubingen, Calwerstr. 3, D-72076 Tubingen, Germany.
Sporadic inclusion body myositis (sIBM) is a debilitating idiopathic inflammatory myopathy. Little is known about the pathogenetic mechanisms that lead to myofiber degeneration. In the present study, we evaluated the integrity of the myofiber basement membrane in non-necrotic myofibers invaded by inflammatory infiltrates. We used 100 ten mum thick serial sections obtained from biopsies of 5 patients suffering from sIBM. Biopsies from 5 patients suffering from polymyositis served as controls. We performed sequential HE staining and immunolabeling using anti-CD68, -CD8, -merosin, -laminin alpha4 chain, and -collagen IV antibodies. In sIBM, we detected a total of 89 non-necrotic myofibers that were invaded by inflammatory cells. The invasive process and its sequelae were segmental in nature and included destruction of the myofiber basement membrane, and eventually, partial replacement by fibrosis of the invaded myofiber. In polymyositis, we found only two myofibers that were affected in this way. In sIBM, basement membrane remodelling and irreversible replacement by fibrosis of myofibers appear to represent the end result of a process in which the balance between injury and repair are disrupted. PMID: 19473842

PubMed Link

Neuromuscul Disord. 2009 Jan;19(1):66-8. Epub 2008 Dec 11.
A case of asymptomatic cytoplasmic body myopathy revealed by sinvastatin.
Evangelista T, Ferro J, Pereira P, de Carvalho M.
Department of Neurology, Hospital de Santa Maria, Lisbon, Portugal. tmevangelista@fm.ul.pt
There are only a few reports on the effect of statins over diseased muscle and none in cytoplasmic body myopathy. This is a heterogeneous entity that can be asymptomatic until late in life and is characterized by the presence of numerous cytoplasmic bodies in muscle biopsy. A 74-years-old male received statin treatment on two separate occasions, first with sinvastatin and afterwards with rosuvastatin. In both cases, he experienced diffuse myalgia, lower limbs weakness and respiratory fatigue and improved after interruption of each treatment course. Electromyography has shown signs of muscle necrosis, serum creatine kinase (CK) concentration was increased and muscle biopsy revealed numerous cytoplasmic bodies. To our knowledge this is the first report of statin-related muscle necrosis in a patient with CBM. According to the literature neuropathological features of statin myopathy do not include the presence of cytoplasmic bodies so we assume that cytoplasmic body myopathy was asymptomatically present before statin treatment. This case supports the role of muscle biopsy in patients that develop muscular necrosis while on statin treatment. PMID: 19084404

PubMed Link

Brain. 2009 May 19. [Epub ahead of print]
Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis.
Dalakas MC, Rakocevic G, Schmidt J, Salajegheh M, McElroy B, Harris-Love MO, Shrader JA, Levy EW, Dambrosia J, Kampen RL, Bruno DA, Kirk AD.
1 Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, Bethesda, USA.
Sporadic inclusion-body myositis (sIBM) is the most common disabling, adult-onset, inflammatory myopathy histologically characterized by intense inflammation and vacuolar degeneration. In spite of T cell-mediated cytotoxicity and persistent, clonally expanded and antigen-driven endomysial T cells, the disease is resistant to immunotherapies. Alemtuzumab is a humanized monoclonal antibody that causes an immediate depletion or severe reduction of peripheral blood lymphocytes, lasting at least 6 months. We designed a proof-of-principle study to examine if one series of Alemtuzumab infusions in sIBM patients depletes not only peripheral blood lymphocytes but also endomysial T cells and alters the natural course of the disease. Thirteen sIBM patients with established 12-month natural history data received 0.3 mg/kg/day Alemtuzumab for 4 days. The study was powered to capture greater than/=10% increase strength 6 months after treatment. The primary end-point was disease stabilization compared to natural history, assessed by bi-monthly Quantitative Muscle Strength Testing and Medical Research Council strength measurements. Lymphocytes and T cell subsets were monitored concurrently in the blood and the repeated muscle biopsies. Alterations in the mRNA expression of inflammatory, stressor and degeneration-associated molecules were examined in the repeated biopsies. During a 12-month observation period, the patients' total strength had declined by a mean of 14.9% based on Quantitative Muscle Strength Testing. Six months after therapy, the overall decline was only 1.9% (P less than 0.002), corresponding to a 13% differential gain. Among those patients, four improved by a mean of 10% and six reported improved performance of daily activities. The benefit was more evident by the Medical Research Council scales, which demonstrated a decline in the total scores by 13.8% during the observation period but an improvement by 11.4% (P less than 0.001) after 6 months, reaching the level of strength recorded 12 months earlier. Depletion of peripheral blood lymphocytes, including the naive and memory CD8+ cells, was noted 2 weeks after treatment and persisted up to 6 months. The effector CD45RA(+)CD62L(-) cells, however, started to increase 2 months after therapy and peaked by the 4th month. Repeated muscle biopsies showed reduction of CD3 lymphocytes by a mean of 50% (P less than 0.008), most prominent in the improved patients, and reduced mRNA expression of stressor molecules Fas, Mip-1a and alphaB-crystallin; the mRNA of desmin, a regeneration-associated molecule, increased. This proof-of-principle study provides insights into the pathogenesis of inclusion-body myositis and concludes that in sIBM one series of Alemtuzumab infusions can slow down disease progression up to 6 months, improve the strength of some patients, and reduce endomysial inflammation and stressor molecules. These encouraging results, the first in sIBM, warrant a future study with repeated infusions (Clinical Trials. Gov NCT00079768). PMID: 19454532

The drug, as given, was well tolerated without any immediate or long-term side-effects, such as thyroiditis or ITP, as reported in other trials (the CAMMS233 Trial, 2008). Although the sample was small, it was powered to capture changes in muscle strength even in a 6-month period owing to the availability of natural history data in the same patients. Even if the improvement was arguably modest, no other agent has shown any similar effect in the decline of the disease course. Some benefits noted with IVIg or with anti-thymocyte globulin were marginal and short-lived (Dalakas et al., 1997; Lindberg et al., 2003). Because IBM is predictably disabling and notoriously resistant to therapies, the encouraging results from this pilot study and the good tolerance of the drug, provide the impetus to consider a large placebocontrolled trial with repeated infusions to assess the long-term benefits keeping in mind the safety concerns raised in the recent multiple sclerosis trial (the CAMMS233 Trial, 2008).

Article Here

More Information.

Wait a minute. This article needs to be read carefully. There are some issues with the statistics. For example, although these numbers are reported as being very significant, it's hard to see how this conclusion is supported by such a low sample size. In addition, about half of the cases showed improvement and about half did not. Further, we need to differentiate statistical significance from clinical. The threshold for success of this study was only a 10% improvement so even if there was a significant improvement based on this criteria, it is questionable whether this would produce a clinical or practical improvement in one's function. While one could argue that any improvement is important it is also important not to be misled by the way this research is presented.

[The generic name for Campath is alemtuzumab. Campath is a monoclonal antibody designed to latch onto cells expressing CD52 thereby killing them. CD52 is a type of protein known as a leukocyte antigen, expressed on the surface of several types of white blood cells (leukocytes) including lymphocytes (which include T cells), macrophages, monocytes and thymocytes (immature lymphocytes). Campath has been shown to be very effective at destroying T-cells. After one infusion with Campath, the body's T cell population may take years fully to regenerate.]


PubMed Link

Nat Med. 2009 May 17. [Epub ahead of print]
Prophylactic treatment with sialic acid metabolites precludes the development of the myopathic phenotype in the DMRV-hIBM mouse model.
Malicdan MC, Noguchi S, Hayashi YK, Nonaka I, Nishino I.
[1] Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan. [2] Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Distal myopathy with rimmed vacuoles (DMRV)-hereditary inclusion body myopathy (hIBM) is an adult-onset, moderately progressive autosomal recessive myopathy; eventually, affected individuals become wheelchair bound. It is characterized clinically by skeletal muscle atrophy and weakness, and pathologically by rimmed vacuoles, which are actually accumulations of autophagic vacuoles, scattered angular fibers and intracellular accumulation of amyloid and other proteins. To date, no therapy is available for this debilitating myopathy, primarily because the disease pathomechanism has been enigmatic. It is known that the disease gene underlying DMRV-hIBM is GNE, encoding glucosamine (UDP-N-acetyl)-2-epimerase and N-acetylmannosamine kinase-two essential enzymes in sialic acid biosynthesis. It is still unclear, however, whether decreased sialic acid production causes muscle degeneration, as GNE has been proposed to have roles other than for sialic acid biosynthesis. By showing that muscle atrophy and weakness are completely prevented in a mouse model of DMRV-hIBM after treatment with sialic acid metabolites orally, we provide evidence that hyposialylation is indeed one of the key factors in the pathomechanism of DMRV-hIBM. These results support the notion that DMRV-hIBM can potentially be treated simply by giving sialic acids, a strategy that could be applied in clinical trials in the near future. PMID: 19448634

PubMed Link

J Neurosci. 2009 May 13;29(19):6132-41.
Immunization with amyloid-beta attenuates inclusion body myositis-like myopathology and motor impairment in a transgenic mouse model.
Kitazawa M, Vasilevko V, Cribbs DH, LaFerla FM.
Department of Neurobiology and Behavior and Neurology, University of California, Irvine, California 92697-4545, USA.
Inclusion body myositis (IBM), the most common muscle disease to afflict the elderly, causes slow but progressive degeneration of skeletal muscle and ultimately paralysis. Hallmark pathological features include T-cell mediated inflammatory infiltrates and aberrant accumulations of proteins, including amyloid-beta (Abeta), tau, ubiquitinated-proteins, apolipoprotein E, and alpha-synuclein in skeletal muscle. A large body of work indicates that aberrant Abeta accumulation contributes to the myodegeneration. Here, we investigated whether active immunization to promote clearance of Abeta from affected skeletal muscle fibers mitigates the IBM-like myopathological features as well as motor impairment in a transgenic mouse model. We report that active immunization markedly reduces intracellular Abeta deposits and attenuates the motor impairment compared with untreated mice. Results from our current study indicate that Abeta oligomers contribute to the myopathy process as they were significantly reduced in the affected skeletal muscle from immunized mice. In addition, the anti-Abeta antibodies produced in the immunized mice blocked the toxicity of the Abeta oligomers in vitro, providing a possible key mechanism for the functional recovery. These findings provide support for the hypothesis that Abeta is one of the key pathogenic components in IBM pathology and subsequent skeletal muscle degeneration. PMID: 19439591 ARTICLE HERE

"The motor performance of the immunized mice was markedly better as determined by the constant speed and accelerating rotarod tests. These results provide strong evidence that reducing Abeta levels in muscle can mitigate the motor impairments."

Although numerous in vitro, in vivo, and clinical studies point to a toxic role for Abeta in muscle, its role in the pathogenesis of IBM remains poorly understood. Some investigators argue that IBM is a combined proteinopathy and inflammatory disease, and these two processes can interact and influence each other (Dalakas, 2006b; Needham and Mastaglia, 2008). Recent findings showing that inflammation mediates Abeta or tau pathology in skeletal muscle supports this view (Kitazawa et al., 2008; Schmidt et al., 2008). However, others suggest Abeta accumulation is a downstream event, because all known genetic mutations for the hereditary form of IBM are not associated with APP processing or degradation. Interestingly, recent mouse models of hereditary IBM harboring GNE or VCP mutations exhibit intracellular Abeta-like deposits in the skeletal muscle (Malicdan et al., 2007; Weihl et al., 2007), indicating that although these mutations do not have a direct relationship with APP, they modulate APP processing or Abeta degradation, causing the accumulation of Abeta in affected skeletal muscle fibers.

Currently, more than 10 new approaches to active and passive immunotherapy are in various stages of clinical trials with the goal of improving the safety and efficacy of anti-Abeta immunotherapy approaches (Wisniewski and Konietzko, 2008). As a consequence of this continued improvement in anti-Abeta therapeutic strategies, there may be real opportunities to safely pursue a clinical trial in IBM patients.


PubMed Link

Curr Opin Rheumatol. 2009 Mar;21(2):158-63.
Exercise effects in patients with adult idiopathic inflammatory myopathies.
Alexanderson H.
Department of Physical Therapy, Karolinska University Hospital, Stockholm, Sweden. helene.alexanderson@karolinska.se
PURPOSE OF REVIEW: To give an update on recent findings on effects of exercise in patients with adult inflammatory myopathies. RECENT FINDINGS: Although responding to treatment, a majority of patients with polymyositis and dermatomyositis develop sustained disability. The reason for this is not clear. However, a recent study further supports the hypothesis of hypoxia in muscle tissue as a contributor to muscle weakness. The percentage of type I oxygen-dependent muscle fibers increased after a 12-week submaximal home exercise program along with improved muscle endurance in patients with chronic polymyositis or dermatomyositis. Creatine supplements in addition to the same home exercise program are more beneficial than exercise alone in patients with chronic polymyositis or dermatomyositis. Patients with chronic disease tolerate intensive resistance training resulting in improved muscle strength and muscle endurance. This 7-week exercise study also reported reduced disease activity and possibly even reduced muscle inflammation. SUMMARY: These recent studies are in line with earlier ones further supporting safety and efficacy of exercise in patients with polymyositis or dermatomyositis. There is an urgent need for larger randomized controlled trials also including patients with inclusion body myositis to further increase knowledge of disease mechanisms causing disability, exercise effects, and what exercise program is most efficient in patients with different entities of idiopathic inflammatory myopathies. PMID: 19339927

PubMed Link

Biol Chem. 2009 May 9. [Epub ahead of print]
Regulation and pathophysiological implications of UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) as the key enzyme of sialic acid biosynthesis.
Reinke SO, Lehmer G, Hinderlich S, Reutter W.
Beuth Hochschule fur Technik Berlin, Fachbereich Life Sciences and Technology, Labor fur Biochemie, Seestrasse 64, D-13347 Berlin, Germany.
Abstract The key enzyme for the biosynthesis of N-acetylneuraminic acid, from which all other sialic acids are formed, is the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). GNE is a highly conserved protein found throughout the animal kingdom. Its highest expression is seen in the liver and placenta. GNE is regulated by a variety of biochemical means, including tetramerisation promoted by the substrate UDP-GlcNAc, phosphorylation by protein kinase C and feedback inhibition by CMP-Neu5Ac, which is defect in the human disease sialuria. GNE knock-out in mice leads to embryonic lethality, emphasizing the crucial role of this key enzyme for sialic acid biosynthesis. The metabolic capacity to synthesize sialic acid and CMP-sialic acid upon ManNAc loads is amazingly high. An additional characteristic of GNE is its interaction with proteins involved in the regulation of development, which might play a crucial role in the hereditary inclusion body myopathy. Due to the importance of increased concentrations of tumor-surface sialic acid, first attempts to find inhibitors of GNE have been successful. PMID: 19426133

PubMed Link

J Neurol Sci. 2009 Mar 15;278(1-2):25-9. Epub 2008 Dec 20.
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

Expert Opin Pharmacother. 2009 May;10(7):1183-90.
Treatment of the inflammatory myopathies: update and practical recommendations.
Hengstman GJ, van den Hoogen FH, van Engelen BG.
Department of Neurology, Catharina Hospital, PO Box 1350, 5602 ZA Eindhoven, The Netherlands. gerald.hengstman@catharina-ziekenhuis.nl
BACKGROUND: The inflammatory myopathies are a heterogeneous group of diseases including dermatomyositis, polymyositis, and inclusion body myositis. Clinical trials in myositis are rare, making it difficult to make clear recommendations on the treatment of these rare disorders. OBJECTIVE: To give an overview of treatment options and strategies and to provide the clinician with a framework that can be used in treating patients with myositis. METHODS: Results of clinical trials in myositis, case series and important case reports are presented and discussed. RESULTS/CONCLUSION: Most patients with dermatomyositis or polymyositis require treatment with oral high-dose prednisone combined with azathioprine or methotrexate to facilitate early tapering of prednisone. In case of treatment failure, intravenous immunoglobulin can be tried, followed by rituximab, mycophenolate mofetil, or tacrolimus depending on the specific clinical situation. A treatment trial with oral prednisone combined with methotrexate is advised in a subgroup of patients with inclusion body myositis. PMID: 19405792

TDP Webpage

PubMed Link

J Neuropathol Exp Neurol. 2009 Mar;68(3):262-73.
TAR DNA-Binding protein 43 accumulation in protein aggregate myopathies.
Olive M, Janue A, Moreno D, Gamez J, Torrejon-Escribano B, Ferrer I.
Institut de Neuropatologia, Servei Anatomia Patologica, IDIBELL-Hospital Universitari de Bellvitge, Spain.
Protein aggregate myopathies, including myofibrillar myopathies and sporadic inclusion body myositis (sIBM), are characterized by abnormal protein aggregates composed of various muscular and ectopic proteins. Previous studies have shown the crucial role ofdysregulated transcription factors such as neuron-restrictive silencerfactor in the expression of aberrant proteins in myotilinopathies. Here, we assessed possible aberrant expression of TAR DNA-bindingprotein 43 (TDP-43), another factor involved in transcription regulation. TDP-43-immunoreactive intracytoplasmic inclusions were seen in all cases examined of myotilinopathy, desminopathy, and sIBM, and in 1 case of inclusion body myositis with Paget disease of bone and frontotemporal degeneration (IBMPFD). TAR DNA-binding protein 43 colocalized with myotilin and valosin in myotilinopathies and IBMPFD, respectively, but only occasionally colocalized with ubiquitin in myotilinopathies, desminopathies, sIBM, and IBMPFD; this indicates that accumulated TDP-43 is largely not ubiquitinated. Moreover, phosphorylated TDP-43 at Ser403/404 and Ser409/410 accumulated in the cytoplasm of vulnerable fibers but did not always colocalize with nonphosphorylated TDP-43. Cytoplasmic deposition was accompanied by decreased TDP-43 localization in the nuclei of affected fibers. These findings indicate that TDP-43 not only is another protein accumulated in myofibrillar myopathies, sIBM, and IBMPFD but also likely has a role through altered microRNA processing in the abnormal protein production, modification, and accumulation in protein aggregate myopathies. PMID: 19225410

Alzheimer's Findings Resolve Dispute Over How Disease Kills Brain Cells
April 15th, 2009 in Medicine and Health / Neuroscience
(PhysOrg.com) -- For a decade, Alzheimer's disease researchers have been entrenched in debate about one of the mechanisms believed to be responsible for brain cell death and memory loss in the illness. Now researchers at the University of Michigan and the University of California, San Diego have settled the dispute. Resolving this controversy improves understanding of the disease and could one day lead to better treatments.
Michael Mayer, an assistant professor in the U-M departments of Biomedical Engineering and Chemical Engineering, and Jerry Yang, an assistant professor in the Department of Chemistry and Biochemistry at UCSD, and their colleagues found a flaw in earlier studies supporting one side of the debate. Their findings are published online in the Journal of Neurotoxicity Research. They will appear in the May print edition.
Their results clarify how small proteins called amyloid-beta peptides damage brain cell membranes, allowing extra calcium ions to enter the neurons. An ion is an electrically-charged particle. An ion imbalance in a cell can trigger its suicide.
Amyloid-beta peptides are the prime suspects for causing cell death in Alzheimer's, although other mechanisms could also be to blame. The disease is not well understood.
The researchers confirmed evidence found by others that amyloid-beta peptides prick pores into brain cell membranes, opening channels where calcium ions can rush in. This was one mechanism the field had contemplated, but other evidence suggested a different scenario. Some researchers believed that the peptide caused a general thinning of the cell membranes and these thinned membranes lost their ability to keep calcium ions out of brain cells. Mayer and Yang disproved this latter theory.
"When you understand these mechanisms better, you have a better chance of being able to pharmaceutically counteract them as a possible treatment. For instance, if amyloid-beta thins membranes, this general effect might be difficult to treat. On the other hand, if it forms pores, this effect might be treatable with pore blockers. Ion channel blockers are medications sold today to treat a variety of diseases," Mayer said. He cautions that much research is needed before it is known whether such medications are effective and safe to treat Alzheimer's.
Mayer and Yang were able to explain the other experimental results that blamed cell membrane thinning for uncontrolled calcium ion fluctuations. It turns out that in these studies, trace amounts of residual solvent used to prepare the peptide had a dramatic effect. The Michigan- and UCSD-led team reproduced these experimental results using only the solvent, without the peptide. The solvent is called Hexafluoroisopropanol, or HFIP.
"HFIP is a good solvent used to break up clumps of the peptide to prepare for experiments, but it's toxic and membrane-active. What we found was that the reported preparation procedure did not remove the solvent effectively," Mayer said. "Our findings are watertight since we could reproduce the thinning effect in the absence of amyloid-beta peptides by this solvent alone."
Yang and Mayer carried out these experiments by examining how the electric current fluctuates across artificial membranes and live human cancer cell membranes in the presence of the amyloid-beta peptide. (Cancer cells are often used in biological experiments because they reproduce rapidly.) They also measured the fluctuation of ions in mouse brain cells and in genetically-modified mouse brain cells that produce human amyloid-beta peptide.
In all these trials, the electrodes measuring across the cell membrane registered spikes in electric current consistent with what researchers would expect from the formation of pores in the cell membrane and not from thinning of membranes.
"This ongoing controversy has slowed our own progress in Alzheimer's research as well as progress in other labs," Mayer said. "It is our hope that putting this disagreement to rest by showing that amyloid beta peptides do not thin membranes but instead form discrete pores in membrane can help the field move forward at a more rapid pace."
The paper is called "Amyloid-beta-induced ion flux in artificial lipid bilayers and neuronal cells: Resolving a controversy." Members of Mayer's and Yang's research groups contributed to this study, as did the research group of R. Scott Turner, an associate professor of neurology at the U-M Medical School. The research is funded by the Wallace H. Coulter Foundation, the National Science Foundation, the Alzheimer's Disease Research Center and the Alzheimer's Association. U-M has filed for patent protection on this research, and it is seeking licensing partners to help bring the technology to market. Provided by University of Michigan http://www.physorg.com/news159031657.html


Obituary: George Karpati


PubMed Link

J Clin Neuromuscul Dis. 2008 Dec;10(2):79-82.
Neuromuscular pathology case.
Lacomis D.
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. lacomisd@upmc.edu
No Abstract.
CASE REPORT A 56 year-old man was evaluated for progressive weakness and an elevated serum creatine kinase. He has had human immunodeficiency virus-1 (HIV-1) infection/AIDS for 23 years. He had been on triple antiviral therapy (efavirenz, tenofovir disoproxil fumarate, and lamivudine) with only 1 opportunistic infection, namely pneumocystis carinii pneumonia, 8 years earlier. There was remote use of zidovudine without resultant myopathy. HIV-1 viral load had been undetectable. Proximal leg weakness began 1 year earlier; thigh atrophy and proximal armweakness were noted 6 months earlier. He had difficulty in getting up from a chair and climbing stairs. He denied rash, myalgia, or constitutional symptoms. He recently discontinued the antiviral agents because he felt they could be causing weakness.

PubMed Link

Ann Neurol. 2009 Jan;65(1):7-11.
Sporadic inclusion body myositis: pathogenic considerations.
Karpati G, O'Ferrall EK.
Department of Neurology, McGill University, Montreal Neurological Institute, Montreal, Quebec, Canada. george.karpati@mcgill.ca
Sporadic inclusion body myositis is the commonest acquired disease of skeletal muscles after 50 years of age, and as such it has commanded a great deal of attention of investigators over the past 25 years. As a result, a large amount of information has accumulated concerning its clinical profile, myopathology, and immunopathology. In the myopathology and immunopathology, there is general agreement that the characteristic features could be divided into a degenerative and an inflammatory group. However, there has been controversy about the possible role of these changes in the pathogenesis of muscle fiber damage. In particular, there is no agreement whether a cause-and-effect relationship exists between these two groups of changes, and if so, which is the primary one. In this brief overview, we examine the validity of the various controversial observations and critically review the justification for the two major hypotheses for the primary role of inflammation versus degeneration. PMID: 19194875

lee09

Rubin, M. (2009, May). Inclusion Body Myositis: A Final Word. Neurology Alert, 27(9), 68-69.SPORADIC INCLUSION BODY MYOSITIS (IBM) IS THE most common acquired myopathy with onset over the age of 50 years. Unresponsive to therapy, its etiology remains a puzzle. In this paper, the last published in his lifetime, George Karpati, who in 1978 first described IBM as a distinct clinical and pathological entity, offers a final word on its pathogenesis. Categorized as an inflammatory myopathy, both degenerative and inflammatory changes are seen pathologically. Myonuclear abnormalities, including the presence of 18-nm tubular filaments, rimmed vacuoles, small-caliber muscle fibers, increased endomysial connective tissue, muscle fiber hypertrophy, and ragged red fibers suggesting mitochondrial abnormalities, comprise the degenerative changes reported. Cytoplasmic--amyloid accumulation, reputedly myotoxic, has been described by some, but not found by others. None of these findings are diagnostic in isolation but the constellation of these features is characteristic. Endomysial CD8+ lymphocyte and macrophage collections with partial invasion of these cells into nonnecrotic muscle fibers, as well as endomysial dendritic and CD138+ plasma cells, encompass the inflammatory features of IBM. Proposed pathogenic paradigms ascribe either a primary role to inflammation with degenerative changes the resulting byproduct, or the reverse, with degenerative changes believed to be primary, and inflammation a secondary phenomenon. The firm skeptic (George Karpati) accepts neither scenario. Inflammation-first advocates suggest that an antigenic trigger, perhaps a virus, provokes a process, including clonal expansion of CD8+ lymphocytes and release of proinflammatory cytokines and chemokines, which results in cell injury and death. Arguing against this scenario is the lack of therapeutic benefit with immunosuppression, the paucity of necrosis and regeneration in sporadic IBM, and the absence of inflammatory changes in the inherited form. Degeneration-first advocates offer that, well before clinical symptoms begin, alterations of the myonuclear matrix putatively develops, resulting in transcriptional or RNA-handling dysregulation and nuclear membrane dissolution, with rimmed vacuole and tubular filament formation. Subsequent inflammatory changes may be immune mediated. Hereditary IBM lacks these inflammatory changes, arguing against this theory as well. Most plausibly, inflammatory and degenerative changes occur independently, the consequence of hitherto undiscovered agents, and it is to these agent(s) provocateurs that future research should best be directed to resolve the controversy and ultimately offer efficacious treatment.


PubMed Link

Curr Opin Rheumatol. 2009 Mar;21(2):158-63.
Exercise effects in patients with adult idiopathic inflammatory myopathies.
Alexanderson H.
Department of Physical Therapy, Karolinska University Hospital, Stockholm, Sweden. helene.alexanderson@karolinska.se
PURPOSE OF REVIEW: To give an update on recent findings on effects of exercise in patients with adult inflammatory myopathies. RECENT FINDINGS: Although responding to treatment, a majority of patients with polymyositis and dermatomyositis develop sustained disability. The reason for this is not clear. However, a recent study further supports the hypothesis of hypoxia in muscle tissue as a contributor to muscle weakness. The percentage of type I oxygen-dependent muscle fibers increased after a 12-week submaximal home exercise program along with improved muscle endurance in patients with chronic polymyositis or dermatomyositis. Creatine supplements in addition to the same home exercise program are more beneficial than exercise alone in patients with chronic polymyositis or dermatomyositis. Patients with chronic disease tolerate intensive resistance training resulting in improved muscle strength and muscle endurance. This 7-week exercise study also reported reduced disease activity and possibly even reduced muscle inflammation. SUMMARY: These recent studies are in line with earlier ones further supporting safety and efficacy of exercise in patients with polymyositis or dermatomyositis. There is an urgent need for larger randomized controlled trials also including patients with inclusion body myositis to further increase knowledge of disease mechanisms causing disability, exercise effects, and what exercise program is most efficient in patients with different entities of idiopathic inflammatory myopathies. PMID: 19339927

PubMed Link

Muscle Nerve. 2009 Mar 16. [Epub ahead of print]
Fast-twitch sarcomeric and glycolytic enzyme protein loss in inclusion body myositis.
Parker KC, Kong SW, Walsh RJ; Bch, Salajegheh M, Moghadaszadeh B, Amato AA, Nazareno R, Lin YY, Krastins B, Sarracino DA, Beggs AH, Pinkus JL, Greenberg SA.
Harvard-Partners Center for Genetics and Genomics, Proteomics Core, Harvard Medical School, Boston, Massachusetts USA.
Inclusion body myositis (IBM) is an inflammatory disease of skeletal muscle of unknown cause. To further understand the nature of the tissue injury in this disease, we developed methods for large-scale detection and quantitation of proteins in muscle biopsy samples and analyzed proteomic data produced by these methods together with histochemical, immunohistochemical, and microarray data. Twenty muscle biopsy samples from patients with inflammatory myopathies (n = 17) or elderly subjects without neuromuscular disease (n = 3) were profiled by proteomic studies using liquid chromatographic separation of peptides followed by mass spectrometry. Thirteen of the diseased samples additionally underwent microarray studies. Seventy muscle specimens from patients with a range of neuromuscular disorders were examined by ATPase histochemical methods. Smaller numbers of samples underwent immunohistochemical and immunoblot studies. Mass spectrometric studies identified and quantified approximately 300 total distinct proteins in each muscle sample. In IBM and to a lesser extent in polymyositis, proteomic studies confirmed by histochemical, immunohistochemical, and immunoblot studies showed loss of many fast-twitch specific structural proteins and glycolytic enzymes despite relative preservation of transcript levels. Increased abundance of a nuclear membrane protein, immunoglobulins, and two calpain-3 substrates were present. The atrophy present in IBM muscle is accompanied by preferential loss of fast-twitch structural proteins and glycolytic enzymes, particularly glycogen debranching enzyme, with relative preservation of the abundance of their respective transcripts. Although muscle atrophy has long been recognized in IBM, these studies are the first to report specific proteins which are reduced in quantity in IBM muscle. Muscle Nerve, 2008. PMID: 19291799

PubMed Link

Acta Neuropathol. 2009 Mar 12. [Epub ahead of print]
Amyloid-beta42 is preferentially accumulated in muscle fibers of patients with sporadic inclusion-body myositis.
Vattemi G, Nogalska A, King Engel W, D'Agostino C, Checler F, Askanas V.
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA, 90017, USA.
Sporadic inclusion-body myositis (s-IBM) is the only muscle disease in which accumulation of amyloid-beta (Abeta) in abnormal muscle fibers appears to play a key pathogenic role. Increased amyloid-beta precursor protein (AbetaPP) and Abeta accumulation have been reported to be upstream steps in the development of the s-IBM pathologic phenotype, based on cellular and animal models. Abeta is released from AbetaPP as a 40 or 42 aminoacid peptide. Abeta42 is considered more cytotoxic than Abeta40, and it has a higher propensity to aggregate and form amyloid fibrils. Using highly specific antibodies, we evaluated in s-IBM muscle biopsies intra-muscle fiber accumulation of Abeta40 and Abeta42-immunoreactive aggregates by light- and electron-microscopic immunocytochemistry, and quantified their amounts by ELISA. In s-IBM, 80-90% of the vacuolated muscle fibers and 5-20% of the non-vacuolated muscle fibers contained plaque-like Abeta42-immunoreactive inclusions, while only 69% of those fibers also contained Abeta40 deposits. By immuno-electronmicroscopy, Abeta42 was associated with 6-10 nm amyloid-like fibrils, small electron-dense floccular clumps and larger masses of amorphous material. Abeta40 was present only on small patches of floccular clumps and amorphous material; it was not associated with 6-10 nm amyloid fibrils. By ELISA, in s-IBM muscle biopsies Abeta42 was present in values 8.53-44.7 pg/ml, while Abeta40 was not detectable; normal age-matched control biopsies did not have any detectable Abeta42 or Abeta40. Thus, in s-IBM muscle fibers, Abeta42 is accumulated more than Abeta40. We suggest that Abeta42 oligomers and their cytotoxicity may play an important role in the s-IBM pathogenesis. PMID: 19280202

Published online 25 February 2009 | Nature | doi:10.1038/news.2009.121
News 'Harmless' prion protein linked to Alzheimer's disease
Non-infectious form of prion protein could cause brain degeneration.
Heidi Ledford

Prion proteins may react with amyloid-β peptides inside the brain cells of Alzheimer's patients.

Non-infectious prion proteins found in the brain may contribute to Alzheimer's disease, researchers have found.

The surprising new results, reported this week in Nature 1, show that normal prion proteins produced naturally in the brain interact with the amyloid-β peptides that are hallmarks of Alzheimer's disease. Blocking this interaction in preparations made from mouse brains halted some neurological defects caused by the accumulation of amyloidβ peptide. It was previously thought that only infectious prion proteins, rather than their normal, non-infectious counterparts, played a role in brain degeneration.

The results have yet to be confirmed in humans, but suggest that targeting the non-infectious prion protein (PrPc) could provide an alternative route to treating Alzheimer's disease. "The need is huge," says Paul Aisen, an Alzheimer's researcher based at the neurosciences department of the University of California, San Diego. "And it's great news for the field when a new idea is brought forth with strong evidence that can lead to new therapeutic strategies."

Proteins misbehaving

Alzheimer's disease has long been linked to the build-up of amyloid-β peptides, first into relatively short chains known as oligomers, and then eventually into the long, sticky fibrils that form plaques in the brain. The oligomeric form of the peptide is thought to be toxic, but exactly how it acts in the brain is unknown.

Stephen Strittmatter and his colleagues at Yale University in New Haven, Connecticut searched for brain cell proteins that interact with amyloid-β oligomers. To their surprise, they found PrPc, the normal, non-infectious prion protein.

Normal prion proteins are produced naturally in the brain, but can cause disease when they come into contact with an infectious form of the protein (PrPSc) that folds into an unusual conformation. These infectious prions convert innocuous prion proteins into the infectious form, which forms clumps and leads to neurodegenerative diseases, such as variant Creutzfeldt-Jakob disease, the human form of mad cow disease.

Strittmatter's team found that in brain slices taken from mice that were engineered to lack the prion protein, amyloid-? did not cause defects in a process called long-term potentiation, which is important for long-term memory formation. Similarly, using an antibody to block the prion protein also prevented damage caused by the errant amyloid-β peptides.

Therapeutic potential

Researchers have struggled to determine what prion proteins normally do in the brain. Mice that lack the protein appear largely normal, with possible minor deficits in the generation of new neurons and responses to stress. A recent study found evidence that the prion protein may also be necessary for mice to have a normal sense of smell 2.

Nevertheless, the results in mice suggest that blocking the protein may have unwanted side-effects, says Lennart Mucke, a neurologist at the Gladstone Institute of Neurological Disease in San Francisco, California. Although some are already at work to develop drugs that target the prion protein, these programmes target the infectious form of the protein and may not be useful in warding off Alzheimer's disease.

But Strittmatter and his colleagues mapped the region of the prion protein that interacts with amyloid-β, giving researchers a clear target in the search for inhibitors of this interaction. Mucke, meanwhile, points out that an enzyme called ?-secretase can cleave the prion protein at a site that would prevent it from binding to amyloid-β. This same enzyme can also cleave amyloid-β itself, meaning that enhancing that enzyme's activity could yield two strikes against Alzheimer's disease.

Although more work needs to be done to confirm the results in animal and human studies, Aisen says Alzheimer's disease researchers will welcome a new target in the fight against the frustrating disease. Clinical trials are underway to test drugs that aim to reduce the levels of amyloid-β in the brain, but researchers are pessimistic about ever driving amyloid-β levels down to zero. Meanwhile, treatments already on the market target symptoms of the disease, and not it's underlying cause.

"The treatments we have for Alzheimer's disease today are symptomatic and entirely inadequate," says Aisen. "There's no question that we need treatments that target the mechanisms behind neurodegeneration in Alzheimer's disease."

References
1. Lauren, J. et al. Nature 457, 1128-1132 (2009).
2. Le Pichon, C. E. et al. Nature Neuroscience 12, 60-69 (2008).


PubMed Link

J Agric Food Chem. 2009 Jan 28;57(2):503-8.
Amyloid-degrading ability of nattokinase from Bacillus subtilis natto.
Hsu RL, Lee KT, Wang JH, Lee LY, Chen RP.
Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
More than 20 unrelated proteins can form amyloid fibrils in vivo which are related to various diseases, such as Alzheimer's disease, prion disease, and systematic amyloidosis. Amyloid fibrils are an ordered protein aggregate with a lamellar cross-beta structure. Enhancing amyloid clearance is one of the targets of the therapy of these amyloid-related diseases. Although there is debate on whether the toxicity is due to amyloids or their precursors, research on the degradation of amyloids may help prevent or alleviate these diseases. In this study, we explored the amyloid-degrading ability of nattokinase, a fibrinolytic subtilisin-like serine protease, and determined the optimal conditions for amyloid hydrolysis. This ability is shared by proteinase K and subtilis in Carlsberg, but not by trypsin or plasmin. PMID: 19117402

PubMed Link

Muscle Nerve. 2009 Feb 10;39(3):283-296. [Epub ahead of print]
Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease.
Rodino-Klapac LR, Haidet AM, Kota J, Handy C, Kaspar BK, Mendell JR.
Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, Ohio 43205 USA.
In most cases, pharmacologic strategies to treat genetic muscle disorders and certain acquired disorders, such as sporadic inclusion body myositis, have produced modest clinical benefits. In these conditions, inhibition of the myostatin pathway represents an alternative strategy to improve functional outcomes. Preclinical data that support this approach clearly demonstrate the potential for blocking the myostatin pathway. Follistatin has emerged as a powerful antagonist of myostatin that can increase muscle mass and strength. Follistatin was first isolated from the ovary and is known to suppress follicle-stimulating hormone. This raises concerns for potential adverse effects on the hypothalamic-pituitary-gonadal axis and possible reproductive capabilities. In this review we demonstrate a strategy to bypass off-target effects using an alternatively spliced cDNA of follistatin (FS344) delivered by adeno-associated virus (AAV) to muscle. The transgene product is a peptide of 315 amino acids that is secreted from the muscle and circulates in the serum, thus avoiding cell-surface binding sites. Using this approach our translational studies show increased muscle size and strength in species ranging from mice to monkeys. Adverse effects are avoided, and no organ system pathology or change in reproductive capabilities has been seen. These findings provide the impetus to move toward gene therapy clinical trials with delivery of AAV-FS344 to increase size and function of muscle in patients with neuromuscular disease. Muscle Nerve 39: 283-296, 2009. PMID: 19208403

In conclusion, gene therapy using follistatin to inhibit myostatin holds promise for the treatment of muscle disease. Our findings that demonstrate increased muscle size and strength with reduced fibrosis in the mdx mouse, as well as our success in translating the findings to nonhuman primates, sets the stage for human clinical trials. We have encountered no adverse effects, no effect on reproductive capacity, and no immunogenicity of the follistatin transgene or its product. Therefore, the antiinflammatory effects of follistatin will facilitate efforts in a variety of diseases, particularly those like sporadic inclusion body myositis, where medical management has left many patients disabled and without treatment options.


Amyloid-beta and tau in Alzheimer's disease Frank M. LaFerla


PubMed Link

Muscle Nerve. 2009 Feb;39(2):144-9.
Obstructive sleep apnea in patients with inflammatory myopathies.
Selva-O'Callaghan A, Sampol G, Romero O, Lloberes P, Trallero-Araguas E, Vilardell-Tarrés M.
Internal Medicine Department, Vall D'Hebron General Hospital, Universitat Autonoma Barcelona, C/Siracusa No. 12 Bis "A," Barcelona, Spain.
The purpose of this study was to determine the frequency of obstructive sleep apnea in patients with inflammatory myopathy. An observational and prospective study was performed on a cohort of adult patients with inflammatory myopathy followed at a specialized outpatient clinic. Sixteen consecutive adult patients were evaluated by the Epworth Sleepiness Scale (ESS) and by complete polysomnography study. Disease activity and severity were assessed using the Myositis Disease Activity Assessment Tool (MDAAT) and Myositis Damage Index (MDI), respectively. Associations between sleep parameters and other factors were calculated using the chi-square test, Fisher's exact test, Mann-Whitney U-test, and Wilcoxon's test. A serum autoantibody profile was determined for all patients. The mean apnea-hypopnea index was 28.7 (23.8), and 14 patients (87%) had an apnea-hypopnea index >5. The mean frequency of respiratory arousals was 20.1 (12.5). Eleven (68%) patients reported frequently-always snoring, and 3 (19%) had excessive daytime sleepiness (ESS >10). Seven patients were offered continuous positive airway pressure (CPAP) therapy; 4 tolerated the procedure well and reported a clear improvement in daytime sleepiness and/or sleep quality. No significant association was observed between the apnea-hypopnea index and clinical or immunological groups. Dysphagia, disease activity, and disease severity were not significantly associated with any sleep parameters. The frequency of obstructive sleep apnea in adult patients with inflammatory myopathy is high. The possibility that these alterations play a role in persistent fatigue in these patients cannot be ruled out. Muscle Nerve 39: 144-149, 2009. PMID: 19145652

In conclusion, we found a high frequency of obstructive sleep apnea (OSA) in patients with inflammatory myopathies. Weakness of the oropharyngeal muscles could explain this finding. The possibility that these alterations play a role in the persistence of fatigue in patients with inflammatory myopathies cannot be ruled out.


PubMed Link

J Neurol Sci. 2009 Jan 24. [Epub ahead of print]
CCR7+ myeloid dendritic cells together with CCR7+ T cells and CCR7+ macrophages invade CCL19+ nonnecrotic muscle fibers in inclusion body myositis.
Tateyama M, Fujihara K, Misu T, Itoyama Y.
Department of Neurology, Tohoku University School of Medicine, Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
CCR7 and its ligands CCL19 and CCL21 are a key chemokine system in T cell priming in secondary lymphoid organs, and are rarely expressed in normal muscle tissue. We immunohistochemically investigated the expression of this chemokine system in the muscles of seven patients with inclusion body myositis (IBM). In all cases, CCR7+ mononuclear cells infiltrated in the endomysium, preferentially surrounded and invaded nonnecrotic muscle fibers. Double immunostaining revealed that such CCR7+ mononuclear cells included BDCA-1+ myeloid dendritic cells as well as CD8+ cells, CD4+ cells and CD68+ macrophages. On the other hand, CCL19 was widely expressed on muscle fibers including those invaded by mononuclear cells. CCL19 was also expressed diffusely on endomysial mononuclear cells and endothelium of vessels. Immunoreactivities of CCL21 were detected on some muscle fibers and mononuclear cells. By RT-PCR analyses, mRNA of CCR7 was detected in all the patients and that of CCL19 and CCL21 was detected in six. These findings showed that the CCL19, CCL21/CCR7 chemokine system is expressed in muscles of IBM. The chemokine mediated attraction in dendritic and other immune cells and muscle cells may be crucial in sustained antigen presentation, T cell activation and immune attack to muscles in the pathogenesis of IBM. PMID: 19171354

We previously reported CCR7+ mononuclear cells in the endomysium of IBM as well as polymyositis [13]. In the present study, we also found that CCR7+ mononuclear cells included dendritic cells in both diseases. Thus, the CCR7 expression patterns were similar in IBM and polymyositis, although mononuclear cells invading nonnecrotic muscle fibers tended to be more frequent in IBM than in polymyositis in our study as shown in a previous report [35]. Even so,we still do not know why the current immunosuppressive therapies are not effective in IBM. To further investigate whether CCR7 and its ligands play differential roles in the pathogenesis of IBM and polymyositis, we may have to compare the reactivities of this chemokine system to the immunological treatments in the two disorders.


PubMed Link

Mol Biol Cell. 2009 Jan 14. [Epub ahead of print]
The Insulin/Akt Signaling Pathway Is Targeted by Intracellular {beta}-Amyloid.
Lee HK, Kumar P, Fu Q, Rosen KM, Querfurth HW.
Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135.
Monitoring Editor: M. Bishr Omary
Intraneuronal beta-amyloid (Abeta) accumulates early in Alzheimer's disease (AD) and Inclusion Body Myositis. Several organelles, receptor molecules, homeostatic processes and signal transduction components have been identified as sensitive to Abeta. While prior studies implicate the insulin-PI3K-Akt signaling cascade, a specific step within this or any essential metabolic or survival pathway has not emerged as a molecular target. We tested the effect of Abeta42 on each component of this cascade. In AD brain, the association between PDK and Akt, phospho-Akt levels and its activity were all decreased relative to control. In cell culture, Abetai expression inhibited both insulin-induced Akt phosphorylation and activity. In vitro experiments identified that Abeta, especially oligomer preparations, specifically interrupted the PDK-dependent activation of Akt. Abetai also blocked the association between PDK and Akt in cell-based and in vitro experiments. Importantly, Abeta did not interrupt Akt or PI3K activities (once stimulated) nor did it affect more proximal signal events. These results offer a novel therapeutic strategy to neutralize beta-amyloid-induced energy failure and neuronal death. PMID: 19144826

Figure 8 Model of Insulin-PI3K-Akt signaling in Alzheimer's Disease. Intracellular Beta-amyloid is depicted to interfere with Akt activation by PDK-1 via two possible mechanisms. This may occur at a possible hydrophobic interaction site between Akt and PDK or directly through inhibition of the ATP-dependent kinase's ability to phosphorylate T308 of Akt.

lee09


PubMed Link

Mol Neurodegener. 2009 Jan 6;4(1):2. [Epub ahead of print]
Intracellular amyloid formation in muscle cells of Abeta-transgenic Caenorhabditis elegans: determinants and physiological role in copper detoxification.
Minniti AN, Rebolledo DL, Grez PM, Fadic R, Aldunate R, Volitakis I, Cherny RA, Opazo C, Masters C, Bush AI, Inestrosa NC.
ABSTRACT: BACKGROUND: The amyloid beta-peptide is a ubiquitous peptide, which is prone to aggregate forming soluble toxic oligomers and insoluble less-toxic aggregates. The intrinsic and external/environmental factors that determine Abeta aggregation in vivo are poorly understood, as well as the cellular meaning of this process itself. Genetic data as well as cell biological and biochemical evidence strongly support the hypothesis that Abeta is a major player in the onset and development of Alzheimer's disease. In addition, it is also known that Abeta is involved in Inclusion Body Myositis, a common myopathy of the elderly in which the peptide accumulates intracellularly. RESULTS: In the present work, we found that intracellular Abeta aggregation in muscle cells of Caenorhabditis elegans overexpressing Abeta peptide is affected by two single amino acid substitutions, E22G (Arctic) and V18A (NIC). Both variations show decrease intracellular amyloidogenesis compared to wild type Abeta. We show that intracellular amyloid aggregation of wild type Abeta is accelerated by Cu2+ and diminished by copper chelators. Moreover, we demonstrate through toxicity and behavioral assays that Abeta-transgenic worms display a higher tolerance to Cu2+ toxic effects and that this resistance may be linked to the formation of amyloid aggregates. CONCLUSIONS: Our data show that intracellular Abeta amyloid aggregates may trap excess of free Cu2+ buffering its cytotoxic effects and that accelerated intracellular Abeta aggregation may be part of a cell protective mechanism. PMID: 19126228

Therefore, the present evidence suggests, for the first time, that intracellular amyloid deposits are dynamically structured by the presence of metals in muscle cells, and that the formation of intracellular Aβ aggregates could be a part of the homeostatic mechanism responsible for protecting cells against abrupt changes in Cu2+ levels.


PubMed Link

Muscle Nerve. 2009 Jan;39(1):3-9.
Single muscle fiber contractile properties in adults with muscular dystrophy treated with MYO-029.
Krivickas LS, Walsh R, Amato AA.
Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital and Harvard Medical School, 125 Nashua Street, Boston, Massachusetts 02114, USA.
Myostatin inhibitors are being investigated as treatments for myopathies. We assessed single muscle fiber contractile properties before and after 6 months of study drug in 6 patients with facioscapulohumeral, Becker, and limb-girdle muscular dystrophy. Five of the patients received MYO-029, a myostatin inhibitor, and 1 received placebo. The chemically skinned single muscle fiber preparation was used to measure single fiber force, specific force, maximum unloaded shortening velocity, power, and specific power in type I and IIa fibers from each subject. In 4 of 5 patients who received MYO-029, improvement was seen in single muscle fiber contractile properties; thus, there may be a beneficial effect of myostatin inhibition on muscle physiology at the cellular level. No improvement was seen in the patient who received placebo. This finding may be clinically relevant in spite of the fact that quantitative muscle strength measurements in our patients did not improve. Further studies of myostatin inhibition as a treatment for muscular dystrophy are warranted, and single muscle fiber contractile studies are a useful assay for muscle function at the cellular level. Muscle Nerve 39: 3-9, 2009. PMID: 19086063
Here are several excerpts taken from the article.
The key finding of this study is that MYO-029, a neutralizing antibody to myostatin, improved the single muscle fiber contractile properties in 4 of 5 patients with muscular dystrophy who received MYO- 029.
The efficacy of myostatin inhibition is most likely disease-specific and may also be dependent upon the stage of the disease during which therapy is provided.
The results of this small case series of patients treated with a myostatin inhibitor are promising. Although the larger study of MYO-02932 did not demonstrate improvement in whole muscle size, strength, or function, there appears to be some beneficial effect of the drug at the cellular level, and it may be dose-dependent. Four of the 5 patients receiving drug received the lowest dose given in the larger study,32 so it is impressive that improvement in specific force and power was seen even at these low doses. The patients enrolled in this study were adults with chronic disease; greater benefits might be achieved by inhibiting myostatin at a younger age, and thus at an earlier stage in the disease process. Further study of myostatin inhibition in patients with muscular dystrophy is warranted, and single muscle fiber contractile studies provide a useful assay for the effect of treatment on physiology at the cellular level.

PubMed Link

Curr Neurol Neurosci Rep. 2009 Jan;9(1):83-9.
Inclusion body myositis: review of recent literature.
Greenberg SA.
Department of Neurology, Brigham and Women's Hospital,75 Francis Street, Boston, MA 02115, USA. sagreenberg@partners.org.
Inclusion body myositis (IBM) is a progressive inflammatory skeletal muscle disease of unknown cause and without effective treatment. This article discusses existing literature, emphasizing disease mechanisms and models. In particular, it addresses limitations in the beta-amyloid-mediated theory of IBM myofiber injury, flawed rationales of animal models of this disease, and recent reports regarding treatment. PMID: 19080758 This is an important article that should be read in its entirety-- available here.


Mail Bill: btillier@shaw.ca

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