Inclusion Body Myositis Research - what's new? 2005

A sample of MAJOR, selected articles from the medical literature.

December 2005
Neurol Sci. 2005 Dec;26(5): 303-9.
Clinical and muscle magnetic resonance imaging study of an Italian family with autosomal dominant inclusion body myopathy not linked to known genetic loci.
Rodolico C, Toscano A, Patitucci A, Muglia M, Gaeta M, D'Arrigo G, Migliorato A, Messina S, Quattrone A, Messina C, Vita G.
Department of Neurosciences, Psychiatry and Anaesthesiology, University of Messina, A.O.U. "G. Martino", Via C. Valeria, I-98125, Messina, Italy, crodolico@unime.it.
The objective was to report a clinical, pathological and muscle magnetic resonance (MR) study of an Italian family with an autosomal dominant inclusion body myopathy (AD-IBM). Eight subjects (age range 20-56 years; 5 females and 3 males) belonging to four generations were studied. Onset of disturbances (distal weakness at lower limbs) ranged from 20 to 28 years. CK levels were increased to five times. Only in an early stage oedema of involved muscles has been demonstrated by muscle MR. Quadriceps femoris was characteristically spared; in the last phases a mild involvement of the vasti became evident with persistent sparing of the rectus femori. Rimmed vacuoles and hyperphosphorylated tau filaments were evident at muscle biopsy. Linkage analysis excluded the association of the disease to chromosome loci 14q11, 17p13.1, 2p13, 19p13. The study suggests that quadriceps sparing is a characteristic feature also of AD-IBM. This finding could represent a muscle-image hallmark helpful in diagnosis of autosomal dominant muscular disorders.
December 2005
Twenty two articles resulted from a conference held on inclusion body myositis (s-IBM) - Inclusion-body myositis: Clinical and pathologic aspects, and basic research potentially relevant to treatment. January 26-28, 2005 in Santa Monica. The TMA funded the Conference and the Muscular Dystrophy Association assisted by funding the printing and distribution of the Conference report. The 22 articles were published in electronic format as an Expedited E-Pub at www.neurology.org on December 16, 2005. They appear in print in Neurology Volume 66(2) Supplement 1 January 24, 2006. See this special section.
December 2005
NEUROLOGY 2005;65:1782-1787
Plasma cells in muscle in inclusion body myositis and polymyositis
S.A. Greenberg, MD; E.M. Bradshaw, PhD; J.L. Pinkus, PhD; G.S. Pinkus, MD; T. Burleson; B. Due; L.S. Bregoli, Dott.ssa; K.C. O'Connor, PhD; and A.A. Amato, MD
Abstract Background: Previous immunohistochemical studies of muscle from patients with inclusion body myositis and polymyositis found many more T cells than B cells, suggesting a role for intramuscular cell-mediated immune mechanisms rather than humoral mechanisms. Methods: Microarray studies were performed on muscle biopsy specimens from 40 patients with inclusion body myositis (IBM; n = 23), polymyositis (PM; n = 6), and without neuromuscular disease (n = 11). Reverse transcription PCR of selected immunoglobulin gene transcripts was performed on two patient samples. Qualitative immunohistochemical studies for B-cell lineage cell surface markers were performed on 28 muscle specimens and quantitative studies performed on a subset of 19 untreated patients with IBM or PM. CD138+ cells were isolated from muscle using laser capture microdissection, and immunoglobulin transcripts were PCR amplified to determine the presence or absence of immunoglobulin gene rearrangements unique to the B-cell lineage. Results: Immunoglobulin gene transcripts accounted for 59% in IBM and 33% in PM of the most stringently defined highest differentially expressed muscle transcripts compared with normal. Plasma cells, terminally differentiated B cells expressing CD138 but not CD19 or CD20, are present in IBM and PM muscle in numbers several times higher than B cells. Conclusions: There are differentiated B cells in the form of CD138+ plasma cells within the muscle of patients with inclusion body myositis and polymyositis. The principle of linked recognition of B-cell activation predicts several strategies for autoantigen discovery that could not otherwise be pursued through the study of the infiltrating T-cell population alone.
From the discussion: The functional role of plasma cells in muscle in IBM and PM is unclear. Although B and plasma cells have a variety of roles other than antibody secretion that have been defined in other settings, such as antigen-presenting functions and stimulatory cells for other immune system cells, we know of no data that address these later functions in IBM and PM. Our data indicate at least an antibody transcriptional response but do not provide any evidence as to whether plasma cell antibody production in muscle is a primary effector mechanism for tissue damage, what the degree of antigen specificity of this response is, and where the maturation of B cells into plasma cells takes place. However, if there is antigen specificity to the plasma cell response, the methodology we have used can be extended to the construction of recombinant antibodies of identical specificity for screening of muscle tissue for these antigens. Because of the principle of linked recognition,23 antigens recognized by these antibodies may be the same as those recognized by the T cells generally believed to directly mediate myofiber injury in IBM and PM. For example, in myasthenia gravis, T- and B-cell specificities are directed against the same protein structures.24 The method used here for determining the identity of cells in a tissue is an important adjunct to immunohistochemistry, and a similar approach has previously been used for the study of T cells in PM.25 Immunohistochemical definition of cell types has significant limitations. For example, cells expressing CD4 in muscle have been widely assumed to be T helper cells, though other cell types also express and show immunoreactivity to CD4, including human peripheral blood monocytes and tissue macrophages26,27 and blood and tissue myeloid and plasmacytoid dendritic cells.28-31 Singlecell molecular phenotyping of immune system cells in muscle offers the potential for additional cellular and more precise molecular characterization of the inflammatory process.

November 2005
Medicine (Baltimore). 2005 Nov;84(6):338-349.
Immunogenetic Risk and Protective Factors for the Idiopathic Inflammatory Myopathies: Distinct HLA-A, -B, -Cw, -DRB1 and -DQA1 Allelic Profiles and Motifs Define Clinicopathologic Groups in Caucasians.
O'hanlon TP, Carrick DM, Arnett FC, Reveille JD, Carrington M, Gao X, Oddis CV, Morel PA, Malley JD, Malley K, Dreyfuss J, Shamim EA, Rider LG, Chanock SJ, Foster CB, Bunch T, Plotz PH, Love LA, Miller FW.
From National Institute of Environmental Health Sciences (TPO, DMC, EAS, LGR, FWM), Center for Information Technology (JDM, JD), National Cancer Institute (SJC, CBF), and National Institute of Arthritis and Musculoskeletal Disease (PHP), National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland; University of Texas-Houston Health Science Center (FCA, JDR), Houston, Texas; Basic Research Program (MC, XG), SAIC Frederick National Cancer Institute, Frederick, Maryland; University of Pittsburgh School of Medicine (CVO, PAM), Pittsburgh, Pennsylvania; Malley Research Programming Inc (KM), Rockville, Maryland; Mayo Clinic (TB), Rochester, Minnesota; and United States Food and Drug Administration (LAL), Rockville, Maryland.
ABSTRACT:: The idiopathic inflammatory myopathies (IIM) are systemic connective tissue diseases in which autoimmune pathology is suspected to promote chronic muscle inflammation and weakness. We have performed low to high resolution genotyping to characterize the allelic profiles of HLA-A, -B, -Cw, -DRB1, and -DQA1 loci in a large population of North American Caucasian patients with IIM representing the major clinicopathologic groups (n = 571). We confirmed that alleles of the 8.1 ancestral haplotype were important risk markers for the development of IIM, and a random forests classification analysis suggested that within this haplotype, HLA-B*0801, DRB1*0301 and/ or closely linked genes are the principal HLA risk factors. In addition, we identified several novel HLA factors associated distinctly with 1 or more clinicopathologic groups of IIM. The DQA1*0201 allele and associated peptide-binding motif (KLPLFHRL) were exclusive protective factors for the CD8+ T cell-mediated IIM forms of polymyositis (PM) and inclusion body myositis (IBM) (pc < 0.005). In contrast, HLA-A*68 alleles were significant risk factors for dermatomyositis (DM) (pc = 0.0021), a distinct clinical group thought to involve a humorally mediated immunopathology. While the DQA1*0301 allele was detected as a possible risk factor for IIM, PM, and DM patients (p < 0.05), DQA1*03 alleles were protective factors for IBM (pc = 0.0002). Myositis associated with malignancies was the most distinctive group of IIM wherein HLA Class I alleles were the only identifiable susceptibility factors and a shared HLA-Cw peptide-binding motif (AGSHTLQWM) conferred significant risk (pc = 0.019). Together, these data suggest that HLA susceptibility markers distinguish different myositis phenotypes with divergent pathogenetic mechanisms. These variations in associated HLA polymorphisms may reflect responses to unique environmental triggers resulting in the tissue pathospecificity and distinct clinicopathologic syndromes of the IIM.
FASEB J. 2005 Nov 17;
Expression of toll-like receptors by human muscle cells in vitro and in vivo: TLR3 is highly expressed in inflammatory and HIV myopathies, mediates IL-8 release, and up-regulation of NKG2D-ligands
Schreiner B, Voss J, Wischhusen J, Dombrowski Y, Steinle A, Lochmuller H, Dalakas M, Melms A, Wiendl H.
The particular microenvironment of the skeletal muscle can be the site of complex immune reactions. Toll-like receptors (TLRs) mediate inflammatory stimuli from pathogens and endogenous danger signals and link the innate and adaptive immune system. We investigated innate immune responses in human muscle. Analyzing TLR1-9 mRNA in cultured myoblasts and rhabdomyosarcoma cells, we found constitutive expression of TLR3. The TLR3 ligand Poly (I:C), a synthetic analog of dsRNA, and IFN-gamma increased TLR3 levels. TLR3 was mainly localized intracellularly and regulated at the protein level. Poly (I:C) challenge 1) activated nuclear factor-kappaB (NF-kappaB), 2) increased IL-8 release, and 3) up-regulated NKG2D ligands and NK-cell-mediated lysis of muscle cells. We examined muscle biopsy specimens of 6 HIV patients with inclusion body myositis/polymyositis (IBM/PM), 7 cases of sporadic IBM and 9 nonmyopathic controls for TLR3 expression. TLR3 mRNA levels were elevated in biopsy specimens from patients with IBM and HIV-myopathies. Muscle fibers in inflammatory myopathies expressed TLR3 in close proximity of infiltrating mononuclear cells. Taken together, our study suggests an important role of TLR3 in the immunobiology of muscle, and has substantial implications for the understanding of the pathogenesis of inflammatory myopathies or therapeutic interventions like vaccinations or gene transfer.

October 2005
Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene
Haubenberger, D MD; Bittner, R E. MD; Rauch-Shorny, S MD; Zimprich, F MD, PhD; Mannhalter, C PhD; Wagner, L MD; Mineva, I PhD; Vass, K MD; Auff, E MD; Zimprich, A MD
Abstract: Mutations in the valosin-containing protein (VCP) on chromosome 9p13-p12 were recently found to be associated with hereditary inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD). We identified a novel missense mutation in the VCP gene (R159H; 688G>A) segregating with this disease in an Austrian family of four affected siblings, who exhibited progressive proximal myopathy and Paget disease of the bone but without clinical signs of dementia.
Discussion: A mutational hotspot in exon 5 was described at position 155 in IBMPFD in the original report on VCP mutations. Six presumably independent mutational events were observed at this codon, with four of them being R>H changes. The mutation described in our study is only four amino acids away from this mutational hotspot, and of the same type (R>H). Cross-species protein alignment shows strong conservation of this codon (see figure). These observations can be regarded as two further pieces of evidence that the R159H substitution is pathogenic.
The clinical features of our kindred differ in two respects from other published cases. Firstly, the course of disease at the time of examination seems somewhat milder than in the previously published families. For example, none of our described patients needed professional caregivers. Secondly, whereas all four affected siblings showed typical features of myopathy and Paget disease of the bone, none of them displayed signs of frontotemporal dementia. This may seem surprising because the typical age at onset of frontotemporal dementia in mutation carriers is reported to be at 53 years, yet all of our patients are over 60 years of age. Conversely, frontotemporal dementia has been shown to have a low penetrance in this trial. Only 30% of mutation carriers seem to develop dementia at all. Thus, families and individuals carrying mutations in the VCP gene show an astonishingly variable degree in the occurrence of the three cardinal phenotypes: myopathy, Paget disease, and dementia. This is further substantiated by the recent finding of a novel R155C mutation carrier who exhibited inclusion body myopathy and a novel type of frontotemporal demantia but no signs of Paget disease of the bone.
Whether the absence of dementia and the milder phenotype in our kindred is due to the specific nature of the present mutation remains to be determined by future phenotype-genotype correlations. More data on VCP mutations, its clinical and neuropathological phenotypes, and penetrance in IBMPFD families are needed to gain further insight into possible common pathomechanisms in this multisystem disorder.

October 2005
N Engl J Med. 2005 Oct 6;353(14):1489-501.
Sick chaperones, cellular stress, and disease.
Macario AJ, Conway de Macario E.
Cells maintain a complete set of functionally competent proteins normally and in the face of injury or stress with the use of various mechanisms, including systems of proteins called molecular chaperones. The typical function of a chaperone is to assist a nascent polypeptide chain to attain a functional conformation as a new protein and then to assist the protein's arrival at the site in the cell where the protein carries out its functions. It has become increasingly clear that disruption of chaperoning mechanisms contributes to aging and disease (chaperonopathies). This review outlines the involvement of defective chaperones in senescence and in several diseases. Since chaperones are ubiquitous, their deficiencies and defects are bound to affect diverse tissues and, hence, to be of interest to those in internal medicine, ophthalmology, neurology, immunology, endocrinology, pediatrics, and gerontology.
Inclusion-Body Myositis: In inclusion-body myositis, the commonest myopathy in persons older than 50 years of age, aB-crystallin has been found to be increased in muscle fibers, whether inclusion bodies are present or absent. These observations suggest that an increase in aB-crystallin precedes the formation of the inclusion bodies and could be a result of overexpression of the aB-crystallin gene in response to a stressor that is still to be identified.
October 2005
Transfusion. 2005 Oct;45(10):1640-57.
Use of intravenous immunoglobulin for treatment of neurologic conditions: a systematic review.
Fergusson D, Hutton B, Sharma M, Tinmouth A, Wilson K, Cameron DW, Hebert PC.
From the Clinical Epidemiology Program, Ottawa Health Research Institute, Ottawa, Ontario, Canada.
BACKGROUND: Given the increasing use of intravenous immunoglobulin (IVIG) for various neurologic conditions and uncertainty pertaining to its benefits and harms, a systematic review was conducted of randomized controlled trials (RCTs) evaluating IVIG for all neurologic indications for which there was at least one published trial. STUDY DESIGN AND METHODS: For this systematic review, a systematic search strategy was applied to MEDLINE (1966-June 2003) and the Cochrane Register of Controlled Trials (June 2003) to identify potentially eligible RCTs comparing IVIG to placebo or an active control. All dosage regimens were considered. Abstracts were excluded, and no restriction was placed on language of publication. Two investigators independently performed data extraction with a standardized form. Measures of effect were calculated for each trial independently, and studies were pooled based on clinical and methodologic judgment as to its appropriateness. Where pooling of trials was inappropriate, a qualitative discussion of findings is provided. RESULTS AND CONCLUSIONS: Thirty-seven trials representing 14 conditions were identified. IVIG is more effective than placebo for treatment of relapsing-remitting multiple sclerosis and idiopathic chronic inflammatory demyelinating polyneuropathy. There is also potential benefit for treatment of multifocal motor neuropathy, myasthenia gravis, dermatomyositis, stiff-person syndrome, and Lambert-Eaton myasthenic syndrome. There was insufficient evidence to determine whether IVIG therapy was more effective than plasma exchange for Guillain-Barre syndrome. There was also insufficient evidence regarding paraprotein-associated polyneuropathy. No evidence of benefit was observed for secondary progressive multiple sclerosis or inclusion body myositis.

Curr Opin Neurol. 2005 Oct;18(5):497-503.
Diagnosis, pathogenesis and treatment of inclusion body myositis.
Oldfors A, Lindberg C.
Goteborg Neuromuscular Center, Department of Pathology, Sahlgrenska University Hospital, Goteborg, Sweden bGoteborg Neuromuscular Center, Department of Neurology, Sahlgrenska University Hospital, Goteborg, Sweden.
PURPOSE OF REVIEW: We provide an update of progress gained from research into sporadic inclusion body myositis (s-IBM). RECENT FINDINGS: Most research on s-IBM has focused on the inflammatory reaction or the accumulation of pathological proteins in vacuolated muscle fibres. The inflammatory reaction is characterized by clonal expansions of lymphocytes, predominantly CD8 cytotoxic T cells, which invade and destroy muscle fibres. That costimulatory molecules have been identified demonstrates that muscle fibres can act as antigen presenting cells, and the expression of various chemokines in muscle indicates their importance in the immunopathogenesis of s-IBM. The region of interest for a susceptibility gene in the major histocompatibility complex has been narrowed, and for the first time it has been demonstrated that a chronic viral infection can trigger the inflammatory process leading to s-IBM. The nature of the accumulated material associated with the vacuoles has been extensively investigated over the past few years. Amyloid-b and phosphorylated tau protein in intracellular inclusions are a characteristic finding in s-IBM, which may lead to calcium dyshomeostasis and endoplasmic reticulum stress. The proteasomal system is upregulated, including immunoproteasomes. 'Molecular misreading' leading to ubiquitin mRNA mutations and accumulation of pathological ubiquitin in muscle fibres may be associated with proteasomal dysfunction. There is still no efficient treatment for s-IBM, but the effects of new, more specific immunotherapies have begun to be explored. SUMMARY: Recent findings indicate that both inflammatory reaction and abnormal protein accumulation are important for the pathogenesis in s-IBM. The link between them continues to await elucidation. See the article as a pdf file.
September 2005
Neurology India | September 2005 | Vol 53 | Issue 3
Protein aggregate myopathies
M. C. Sharma, H. H. Goebel
All India Institute of Medical Sciences, New Delhi, India and 1Department of Neuropathology, Johannes Gutenberg University Medical Center, Mainz, Germany
Protein aggregate myopathies (PAM) are an emerging group of muscle diseases characterized by structural abnormalities. Protein aggregate myopathies are marked by the aggregation of intrinsic proteins within muscle fibers and fall into four major groups or conditions: (1) desmin-related myopathies (DRM) that include desminopathies, a-B crystallinopathies, selenoproteinopathies caused by mutations in the, a-B crystallin and selenoprotein N1 genes, (2) hereditary inclusion body myopathies, several of which have been linked to different chromosomal gene loci, but with as yet unidentified protein product, (3) actinopathies marked by mutations in the sarcomeric ACTA1 gene, and (4) myosinopathy marked by a mutation in the MYH-7 gene. While PAM forms 1 and 2 are probably based on impaired extralysosomal protein degradation, resulting in the accumulation of numerous and diverse proteins (in familial types in addition to respective mutant proteins), PAM forms 3 and 4 may represent anabolic or developmental defects because of preservation of sarcomeres outside of the actin and myosin aggregates and dearth or absence of other proteins in these actin or myosin aggregates, respectively. The pathogenetic principles governing protein aggregation within muscle fibers and subsequent structural sarcomeres are still largely unknown in both the putative catabolic and anabolic forms of PAM. Presence of inclusions and their protein composition in other congenital myopathies such as reducing bodies, cylindrical spirals, tubular aggregates and others await clarification. The hitherto described PAMs were first identified by immunohistochemistry of proteins and subsequently by molecular analysis of their genes.
Hereditary inclusion body myopathies:
This group of disorders may be classified among the PAM because different proteins aggregate within muscle fibers, which contain autophagic vacuoles, and within tubulofilamentous aggregates which are the hallmark of inclusion body myopathies (IBM). . . . . A further parallel may exist between genetic and nongenetic DRM as well as hereditary and sporadic, inflammatory IBM. A common denominator of the DRM and IBM is probably an impaired, misguided, nonlysosomal protein degradation, the reason of which may easier be explained when dealing with mutant proteins, but still is hardly understood in sporadic acquired DRM and IBM. . . . Desmin-related myopathies and IBM, both of hereditary and acquired types, especially when involving mutant proteins may be caused by impaired extralysosomal protein degradation and aggregation . . . .

August 2005
Hum Pathol. 2005 Aug;36(8):917-21.
Positive troponin T without cardiac involvement in inclusion body myositis.
Schwarzmeier JD, Hamwi A, Preisel M, Resl C, Preusser M, Sluga E, Horcher E, Shehata MM.
Hematology Department, Internal Medicine I, Medical University of Vienna, A-1097 Vienna, Austria. josef.schwarzmeier@meduniwien.ac.at
Cardiac troponin T (cTnT) is considered as a specific marker for acute myocardial infarction. Here, we present a case with elevated cTnT, determined by a third-generation assay, without signs of a myocardial lesion. Routine investigation of a 66-year-old female patient with indolent B-cell lymphoma revealed increased serum levels of creatine kinase (CK), MB fraction of CK (CK-MB), and cTnT, although she did not complain of cardiac symptoms. Electrocardiographic monitoring, echocardiography, magnetic resonance computed angiography, and percutaneous coronary angiography excluded myocardial damage. However, the close follow-up showed a steady increase of CK-MB and cTnT levels and gradual development of weakness in both thighs. A biopsy of the right quadriceps muscle led to the diagnosis of inclusion body myositis. In contrast to cTnT, cardiac troponin I could not be detected retrospectively in any of her serum samples. These results demonstrate for the first time that cTnT is elevated in patients with inclusion body myositis.

August 2005
Neurology. 2005 Aug 9;65(3):420-5.
Messenger RNA degradation may be inhibited in sporadic inclusion body myositis.
Nakano S, Shinde A, Ito H, Ito H, Kusaka H.
Department of Neurology, Kansai Medical University, Moriguchi-city, Japan. nakanos@takii.kmu.ac.jp
OBJECTIVE: To integrate an immune-mediated mechanism and the disturbed protein expression in sporadic inclusion body myositis (IBM). BACKGROUND: In IBM, abnormal fibers harbor inclusions of some proteins found in the brains of patients with Alzheimer disease (AD). Poly(A)-binding protein 1 (PABP1) is the RNA binding protein that attaches to the poly(A) tail of mRNA and is involved in translation and mRNA degradation. Under stresses, mRNA combined with PABP1 forms cytoplasmic granules called stress granules. METHODS: Using 12 muscle biopsies with sporadic IBM and 46 controls, the authors localized PABP1 by immunohistochemistry, and poly(A)-containing RNA (poly(A)+ RNA) using the in situ hybridization method. They also immuno-localized HuR, one of the components of stress granules. RESULTS: In IBM, a proportion of fibers, including those vacuolated, showed an abnormal accumulation of PABP1 immuno-positive deposits. An immunofluorescence study indicated that large PABP1 positive deposits formed conglomerates with poly(A)+ RNA and PABP1 colocalized with HuR. Although PABP1-positive cytoplasmic inclusions were found in disease controls, their aggregates combined with poly(A)+ RNA were only detected in IBM. CONCLUSIONS: The localization of PABP1 positive deposits in inclusion body myositis (IBM) and other diseases may correspond to the stress granules that are formed under exposure to cellular stresses and the sites of mRNA turnover. The concomitant aggregation of poly(A)+ RNA that is specifically found in IBM may be due to the inhibition of mRNA degradation, which may affect translation. The authors speculate that an autoantibody against mRNA degradation machinery could play a role in this inhibition.

August 2005
Acta Neuropathol (Berl). 2005 Aug;110(2):173-7. Epub 2005 Jun 28.
Myostatin is increased and complexes with amyloid-b within sporadic inclusion-body myositis muscle fibers.
Wojcik S, Engel WK, McFerrin J, Askanas V.
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, 637 S. Lucas Ave, Los Angeles, CA, 90017-1912, USA, askanas@hsc.usc.edu.
Myostatin is a negative regulator of muscle mass and strength. Sporadic inclusion-body myositis (s-IBM) is the most common degenerative muscle disease of older persons and is characterized by pronounced muscle wasting. s-IBM is of unknown etiology and pathogenesis, and it lacks definitive treatment. We have now demonstrated in samples from 12 s-IBM biopsies that: (1) by light and electron microscopic immunocytochemistry, myostatin/myostatin precursor is accumulated within muscle fibers and co-localized with amyloid-b (Ab); (2) by immunoblots, both myostatin and myostatin precursor are increased; and (3) by immunoprecipitation, myostatin precursor complexes with Ab. Our study suggests that myostatin/myostatin precursor, either alone, or bound to Ab, may play a novel role in the pathogenesis of s-IBM.

August 2005
Microsc Res Tech. 2005 Aug 15;67(3-4):114-120 [Epub ahead of print]
Molecular pathology and pathogenesis of inclusion-body myositis.
Askanas V, Engel WK.
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, California 90017-1912.
We summarize the molecular phenotype, diagnostic criteria, and the newest advances related to seeking the pathogenic mechanism(s) of sporadic inclusion-body myositis (s-IBM), a muscle disease usually of persons over age 50. On the basis of our research, several processes seem to be important in relation to the still-speculative pathogenesis: 1) increased transcription and accumulation of amyloid-b precursor protein (AbPP), and accumulation of its proteolytic fragment Ab; 2) abnormal accumulation of cholesterol, caveolin-1, and apolipoprotein E; 3) oxidative stress; 4) accumulations of intramuscle fiber multiprotein aggregates; and 5) evidence that unfolded/misfolded proteins participate in s-IBM pathogenesis. Our basic hypothesis is that overexpression of AbPP within the aging muscle fibers is an early upstream event causing a subsequent pathogenic cascade.
We have presented what we consider the most relevant findings related to the pathogenesis of s-IBM. These have not yet provided a definitive cause and treatment, but they have pointed to potentially exciting avenues for exploring treatment approaches to benefiting s-IBM patients. Examples are identification of factors that would: 1) decrease intramuscle fiber expressions of b- and g-secretases which might lead to decreased production of intracellularly toxic oligomeric Ab42; 2) detoxify free radicals or prevent their formation within muscle fibers; 3) prevent misfolding/unfolding of muscle-fiber proteins and/or enhance their disposal; and 4) decrease protein aggregation.
Microsc. Res. Tech. 67:114-120, 2005. (c) 2005 Wiley-Liss, Inc. August, 2005

August 2005
Am J Pathol. 2005 Aug;167(2):517-26.
Proteasome Inhibition and Aggresome Formation in Sporadic Inclusion-Body Myositis and in Amyloid-{b} Precursor Protein-Overexpressing Cultured Human Muscle Fibers.
Fratta P, Engel WK, McFerrin J, Davies KJ, Lin SW, Askanas V.
USC Neuromuscular Center, Good Samaritan Hospital, 637 S. Lucas Ave., Los Angeles, CA 90017-1912. askanas@hsc.usc.edu.

The 26S proteasome system is involved in eliminating various proteins, including ubiquitinated misfolded/unfolded proteins, and its inhibition results in cellular accumulation of protein aggregates. Intramuscle-fiber ubiquitinated multiprotein-aggregates are char-acteristic of sporadic inclusion-body myositis (s-IBM) muscle fibers. Two major types of aggregates exist, containing either amyloid-b (Ab) or phosphorylated tau (p-tau). We have now asked whether abnormalities of the 26S proteasome contribute to s-IBM pathogenesis and whether the multiprotein aggregates have features of aggresomes. Using cultured human muscle fibers we also studied the effect of amyloid-b precursor protein (AbPP) overexpression on proteasome function and the influence of proteasome inhibition on aggresome formation. We report that in s-IBM muscle biopsies 26S proteasome subunits were immunodetected in the g-tubulin-associated aggresomes, which also contained Ab, p-tau, ubiquitin, and HSP70. In addition, a) expression of proteasome subunits was greatly increased, b) the 20Sa proteasome subunit co-immunoprecipitated with AbPP/Ab, and c) the three major proteasomal proteolytic activities were reduced. In cultured muscle fibers, AbPP-overexpressing fibers displayed diminished proteasomal proteolytic activities, and addition of proteasome inhibitor strikingly increased aggresome formation. Accordingly, proteasome dysfunction in s-IBM muscle fibers may play a role in accumulation of misfolded, potentially cytotoxic proteins and may be induced by increased intracellular AbPP/Ab.

July 2005
Acta Myol. 2005 Jul;24(1):17-24.
Sporadic inclusion-body myositis: a proposed key pathogenetic role of the abnormalities of the ubiquitin-proteasome system, and protein misfolding and aggregation.
Askanas V, Engel WK.
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, California 90017-1912, USA. askanas@hsc.usc.edu
Sporadic inclusion-body myositis (s-IBM), the most common muscle disease of older persons, is of unknown cause and there is no successful treatment. We summarize our most recent findings in s-IBM muscle fibers, which demonstrate abnormalities of the ubiquitin-proteasome system, and abnormal accumulation, misfolding and aggregation of proteins. We propose that these changes, possibly provoked by the aging intra-muscle fiber cellular milieu, and aggravated by the oxidative stress, play a key pathogenic role in s-IBM. This evidence strongly suggests that mechanisms other than the immune/inflammatory response play the important role in s-IBM muscle fiber degeneration.

June 2005
Glycobiology. 2005 Jun 29; [Epub ahead of print]
Use of a cell-free system to determine UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase activities in human Hereditary Inclusion Body Myopathy.
Sparks SE, Ciccone C, Lalor M, Orvisky E, Klootwijk R, Savelkoul PJ, Dalakas MC, Krasnewich DM, Gahl WA, Huizing M.
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.

Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive neuromuscular disorder associated with mutations in UDP-N-acetylglucosamine 2-epimerase (GNE)/N-acetylmannosamine kinase (MNK), the bi-functional and rate-limiting enzyme of sialic acid biosynthesis. We developed individual GNE and MNK enzymatic assays and determined reduced activities in cultured fibroblasts of patients with HIBM harboring missense mutations in either or both the GNE and MNK enzymatic domains. To assess the effects of individual mutations on enzyme activity, normal and mutated GNE/MNK enzymatic domains were synthesized in a cell-free in vitro transcription-translation system and subjected to the GNE and MNK enzymatic assays. This cell-free system was validated for both GNE and MNK activities, and revealed that mutations in one enzymatic domain (in GNE, G135V, V216A, and R246W; in MNK, A631V, M712T) affected not only that domain's enzyme activity, but also the activity of the other domain. Moreover, studies of the residual enzyme activity associated with specific mutations revealed a discrepancy between the fibroblasts and the cell-free systems. Fibroblasts exhibited higher residual activities of both GNE and MNK than the cell-free system. These findings add complexity to the tightly regulated system of sialic acid biosynthesis. This cell-free approach can be applied to other glycosylation pathway enzymes that are difficult to evaluate in whole cells because their substrate specificities overlap with those of ancillary enzymes.

June 2005
Neurobiol Aging. 2005 Jun 9; [Epub ahead of print]
Pathogenic accumulation of APP in fast twitch muscle of IBM patients and a transgenic model.
Sugarman MC, Kitazawa M, Baker M, Caiozzo VJ, Querfurth HW, Laferla FM.
Department of Neurobiology and Behavior, University of California, 1109 Gillespie Neuroscience Facility, Irvine, CA 92697-4545, USA.

Inclusion body myositis (IBM) is the most common age-related degenerative skeletal muscle disorder. The aberrant intracellular accumulation of the b-amyloid (Ab) peptide within skeletal muscle is a pathological hallmark of IBM. Skeletal muscle is comprised of both slow and fast twitch fibers, which are present in different proportions in various muscles. It remains unclear if fast and/or slow twitch fibers are differentially involved in IBM pathogenesis. To better understand the molecular pathogenesis of IBM, we analyzed human IBM muscle biopsies and muscle from a transgenic mouse model of IBM (MCK-bAPP). Here we report that the majority of histopathologically-affected fibers in human IBM biopsies were type II fast fibers. Skeletal muscle from MCK-bAPP mice exhibited higher transgene expression and steady-state levels of human bAPP in fast type IIB fibers compared to slow type I fibers. These findings indicate that fast twitch fibers may selectively accumulate and be more vulnerable to bAPP- and Ab-mediated damage in IBM. These findings also highlight parallels between the MCK-bAPP mice and the human IBM condition.

June 2005
Acta Neuropathol (Berl). 2005 Jun;109(6):576-82. Epub 2005 Jun 4.
a-chemokine receptors CXCR1-3 and their ligands in idiopathic inflammatory myopathies.
De Paepe B, De Keyzer K, Martin JJ, De Bleecker JL.
Department of Neurology, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium, jan.debleecker@UGent.be.

The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of neuromuscular disorders subdivided into polymyositis (PM), sporadic inclusion body myositis (sIBM) and dermatomyositis (DM). Chemokines play an essential role in sustained inflammation associated with IIM. We studied the distribution of the a-chemokine receptors CXCR1, 2, 3 and their ligands interferon-g (IFN-g)-inducible T cell a chemoattractant (I-TAC), IFN-g-inducible protein of 10 kDa (IP-10), monokine induced by IFN-g (MIG) and growth-related oncogene (GRO) in IIM using immunohistochemistry, immunofluorescence and Western blotting. Abundant expression of IP-10 was observed on macrophages and T cells surrounding and invading non-necrotic muscle fibers in PM and sIBM and in T cells in perimysial infiltrates of DM. IP-10 was also localized to blood vessel endothelial cells in all inflammatory and normal muscle tissues. The distribution of other a-chemokines was variable: Only low levels of MIG and I-TAC were detected; GRO was localized to the endomysial infiltrates of some PM and sIBM samples, but not in DM. Muscle tissues were invariably CXCR1 negative, while a subset of inflammatory cells in all IIM were CXCR2 positive. Strong CXCR3 expression was observed on the majority of T cells in each IIM. We describe the differential repertoire of a-chemokines in IIM, and offer additional proof of the predominance of Th1-driven reactions in the immunopathogenesis of all three diagnostic subgroups. We suggest the Th1-mediated immunity in general, and the CXCR3/IP-10 interaction in particular, as potential targets for novel therapeutic intervention in IIM.

June 2005
J Neurol. 2005 Jun 17; [Epub ahead of print]
Inclusion body myositis Clinical features and clinical course of the disease in 64 patients.
Badrising UA, Maat-Schieman ML, van Houwelingen JC, van Doorn PA, van Duinen SG, van Engelen BG, Faber CG, Hoogendijk JE, de Jager AE, Koehler PJ, de Visser M, Verschuuren JJ, Wintzen AR.
Dept. of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.

The clinical features of inclusion body myositis (IBM) were of minor importance in the design of consensus diagnostic criteria, mainly because of controversial views on the specificity of signs and symptoms, although some authors reported "typical"signs. To re-assess the clinical spectrum of IBM, a single investigator using a standard protocol studied a cohort of 64 patients cross-sectionally. Symptom onset was before the age of 50 years in 20% of cases. Only a few patients (14 %) started with weakness other than that of quadriceps, finger flexor or pharyngeal muscles. The sequence of power loss was erratic, but onset of symptoms with quadriceps weakness predicted an earlier onset of dysphagia in older patients (>/= 56 years) compared with younger ones (< 56 years) (p = 0.02). Despite widespread weakness patients had favourable scores on three commonly used function scales and they kept their employment. Complete wheel-chair dependency was rare (3 %). A dominant characteristic was the anatomical distribution of afflicted muscles: ventral extremity muscle groups were more affected than dorsal muscle groups and girdle muscles were least affected, the latter preserving postural stability. Ankylosis, especially in extension of the fingers,was frequently present. Together with the sparing of intrinsic hand muscles it was helpful in the preservation of many skilful movements.IBM has a unique distribution of muscle weakness. Ankylotic contractures are common. We feel that their joint impact on daily functioning is characteristic for the disease.

June 2005
Acta Neuropathol (Berl). 2005 Jun 28; [Epub ahead of print]
Myostatin is increased and complexes with amyloid-b within sporadic inclusion-body myositis muscle fibers.
Wojcik S, Engel WK, McFerrin J, Askanas V.
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, 637 S. Lucas Ave, Los Angeles, CA, 90017-1912, USA, askanas@hsc.usc.edu.

Myostatin is a negative regulator of muscle mass and strength. Sporadic inclusion-body myositis (s-IBM) is the most common degenerative muscle disease of older persons and is characterized by pronounced muscle wasting. s-IBM is of unknown etiology and pathogenesis, and it lacks definitive treatment. We have now demonstrated in samples from 12 s-IBM biopsies that: (1) by light and electron microscopic immunocytochemistry, myostatin/myostatin precursor is accumulated within muscle fibers and co-localized with amyloid-b (Ab); (2) by immunoblots, both myostatin and myostatin precursor are increased; and (3) by immunoprecipitation, myostatin precursor complexes with Ab. Our study suggests that myostatin/myostatin precursor, either alone, or bound to Ab, may play a novel role in the pathogenesis of s-IBM.

May 2005
J Neurol. 2005 May;252 Suppl 1:i14-i18.
IVIg in myasthenia gravis, Lambert Eaton myasthenic syndrome and inflammatory myopathies: current status.
Illa I.
Chief Neuromuscular Diseases Unit, Servei Neurologia, Hospital Sta Creu i Sant Pau, Universitat Autonoma de Barcelona, Avda Pare Claret #167, 08025, Barcelona, Spain, iilla@hsp.santpau.es.

Intravenous immunoglobulin (IVIg) is an effective tool for the treatment of diseases with immune pathogenesis. This article reviews the current knowledge of the benefits of treating with IVIg patients with myasthenia gravis (MG), Lambert Eaton myasthenic syndrome (LEMS), dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). MYASTHENIA GRAVIS : Treatment of MG with IVIg was reported to be beneficial in a number of case series and two randomised controlled trials, in which efficacy was measured by clinical improvement using myasthenic muscle score and decrease in anti-acetylcholine receptor antibodies (AchRAb). According to the results, IVIg could be recommended for crisis and severe exacerbation. In many other clinical conditions, such as response to treatment of mild or moderate exacerbation, changes in steroid dosage and before thymectomy, IVIg has also been reported to be helpful, but no controlled trials to confirm its efficacy have been performed. LAMBERT-EATON MYASTHENIC SYNDROME : A placebo-controlled crossover study reported a significant clinical improvement in the amplitude of the resting CMAP following IVIg treatment. Further experience from case reports also indicates that IVIg is useful in patients with LEMS, both as a short- and long-term treatment, especially when immunosuppressive drugs are not fully effective. INFLAMMATORY MYOPATHIES/DERMATOMYOSITIS: : In a double-blind placebo-controlled crossover trial in patients with DM resistant to other treatments, IVIg was shown to produce a significant increase of muscle strength as well as a marked improvement in immunopathological parameters in repeated muscle biopsies (before and after IVIg). Thus, IVIg is an important therapy in patients with DM resistant to other conventional therapies. POLYMYOSITIS: : No randomised trials have been undertaken. One study showed clinical improvement and a reduction in the need of prednisone in patients with chronic refractory PM. INCLUSION BODY MYOSITIS: Three controlled trials showed some muscle strength improvement, although the changes did not reach statistical significance. However improvement in swallowing was repeatedly observed, suggesting that some patients with severe dysphagia may derive a modest benefit from IVIg therapy. CONCLUSION : Controlled trials indicate that in MG, LEMS, and DM, IVIg at a total dose of 2 g/kg is a highly useful therapy. Uncontrolled trials and case reports indicate benefit in many different clinical situations, but further clinical investigation is required.

Researchers find etanercept helpful in small IBM study
TMA Medical Advisory Board Member Richard J. Barohn, MD, and others studied nine IBM patients who were treated with etanercept (Enbrel) to assess whether the drug - sometimes used with good effect in other forms of myositis - could slow the progression of weakness in inclusion body myositis (IBM). They treated the group of IBM patients with etanercept, a tumor necrosis factor inhibitor, and monitored disease progression in the patients.

In a retrospective pilot study the patients, meeting accepted diagnostic criteria, received 25 mgs of etanercept two times over a time period of 11 to 23 months for an average duration of 17 months [this is likely a misprint as Enbrel is usually given as 25mg 2x week or 50mg 1x week during a course of treatment]. The strength of the elbow flexors and handgrip was assessed at the beginning of the trial and again at six and 12 months. The data from the patients in the etanercept group were compared to a control group of six IBM patients who had undergone similar testing but who had not received the drug. The etanercept was well tolerated by the group of IBM patients who received it.

Researchers noted that grip strength improved in IBM patients treated with etanercept. In untreated patients, grip strength worsened. This difference was significant at 12 months. This preliminary data suggest that etancercept may affect disease progression in IBM. The researchers concluded that longer, prospective, controlled studies are warranted.

From: The Myositis Association, Outlook, Spring 2005, page 7. Reprinted with permission. Also see: Enbrel and sIBM.

International Scientific Conference on Sporadic Inclusion-Body Myositis

TMA Medical Advisory Board members Valerie Askanas, MD, PhD, Professor of Neurology and Pathology at the University of Southern California Keck School of Medicine in Los Angeles, and Marinos C. Dalakas, MD, Chief, Neuromuscular Diseases Section at the National Institute of Neurological Disorders and Stroke, NIH, in Bethesda MD, organized the first international scientific conference on sporadic inclusion-body myositis January 26-28, 2005, in Los Angeles. W. King Engel, MD, Professor of Neurology and Pathology at the University of Southern California Keck School of Medicine in Los Angeles, assisted in leading and developing the program agenda.

TMA sponsored this very successful first international scientific Conference on sporadic inclusion body myositis. The full title of the Conference was Frontiers of Research Potentially Relevant to Treatment of Inclusion-Body Myositis. Sporadic IBM is so named because, although it may have genetic components, it is not an inherited illness like hereditary IBM.

The purpose of this highly focused Conference was for the prominent scientists - all of whom were specifically invited - to identify priorities for further research and treatment. Those invited were leaders in research fields related to the disease process of sIBM. Conference organizers invited the world's leading experts on s-IBM, and also experts in the fields they identified as related: cellular disturbances in Alzheimer's Disease, protein degradation, oxidative stress, and immunology. Among the presenters was 2004 Nobel Laureate in Chemistry, Dr. Aaron Ciechanover from Israel. One of the major goals, said Dr. Askanas, was to involve Conference participants who are world-class basic scientists but who have not yet worked on s-IBM. She reported that the Conference was successful in this regard, as the attendees expressed their interest in participating in s-IBM research and developing various collaborations.

Conference Summary
Dr. Askanas provided the following report. The proceedings will be published in Neurology, the journal of the American Academy of Neurologists.

Sporadic inclusion-body myositis is the most common progressive muscle disease in people older than 50. It causes progressively severe weakness of all four limbs but no impairment of mental function. No successful treatment is currently available. Neither the cause of s-IBM nor the exact disease process is known. Two theories predominate: an amyloid-b-related degenerative process, and an autoimmune dysregulation. An intriguing feature is the accumulation within sIBM muscle fibers of amyloid-b (Ab), phosphorylated tau and several other Alzheimer-characteristic proteins. There is also prominent evidence of misfolding of proteins. The pronounced T-cell inflammation is also striking, characterized by activated, antigen-driven, cytotoxic CD8+ T cells.

The Conference opened with a lecture by Caleb E. Finch, PhD, a world expert on aging from the University of Southern California in Los Angeles. The scientific program opened with a lecture by Dr. W. King Engel. Dr. Engel devoted his presentation to clinical features, pathologic diagnostic criteria and the clinical course of s-IBM. In order to demonstrate to the basic scientists the clinical issues and the degree of disability caused by s-IBM, Dr. Engel presented two volunteer patients as part of his lecture. Two intense days of lectures followed.

Dr. Ciechanover gave a very stimulating, one-hour, after-dinner lecture, presenting the work that led to identifying the important role of ubiquitin in the degradation of proteins, the research that led to his Nobel Prize.

During the meeting and during the breaks, there were lively and intense discussions among the participants. Presentations and discussions at the Conference identified the following areas as worthy of further pursuit in the treatment for s-IBM:
= identify better compounds to treat an inflammatory component;
= develop new approaches to combat intra-cellular amyloidosis;
= seek new compounds to prevent oligomerization of amyloid-b4;
= seek new compounds to increase the function of the 26S proteasome system selectively in muscle.

Publication and distribution of the supplement (to Neurology) is being funded by the Muscular Dystrophy Association. Additional financial supportfor the Conference was provided by Crescent Healthcare, Inc.

From: The Myositis Association, Outlook, Spring, 2005, page 3. Reprinted with permission.

May 2005
Neurol Sci. 2005 May; 26 Suppl 1:s7-8.
Autoimmune muscular pathologies.
Dalakas MC.

Neuromuscular Diseases Section, NINDS, Bethesda, MD, USA, dalakasm@ninds.nih.gov.

The T cell-mediated mechanism responsible for Polymyositis and inclusion Body Myositis and the complement-mediated microangiopathy associated with Dermatomyositis are reviewed. The management of autoimmune myopathies with the presently available immunotherapeutic agents as well as new therapies and ongoing trials are discussed. b-chemokine receptor expression in idiopathic inflammatory myopathies.
March 2005
Muscle Nerve. 2005 Mar 16; [Epub ahead of print]
Muscle Nerve. 2005 May;31(5):621-7.
b-chemokine receptor expression in idiopathic inflammatory myopathies.
De Paepe B, De Bleecker JL.

Department of Neurology, Neuromuscular Laboratory, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.
b-chemokines attract and activate T cells and monocytes and have a key role in chronic inflammation. Certain b-chemokines, such as monocyte chemoattractant protein-1 (MCP-1), have been reported to be upregulated in the idiopathic inflammatory myopathies (IIM). We studied the distribution of b-chemokine receptors in polymyositis (PM), sporadic inclusion-body myositis (sIBM), dermatomyositis (DM), and control samples. CCR1-5 were localized to blood vessels in all samples. In addition, increased endothelial expression of CCR2A was observed in IIM. Subsets of inflammatory cells, identified as macrophages and T cells, in all three types of IIM expressed CCR2A, CCR2B, CCR3, CCR4, and CCR5. In contrast to an earlier report, we found CCR2B to be the most prominent MCP-1 receptor on inflammatory cells in IIM, especially in PM and sIBM. Strong CCR4 expression was present on myonuclei of regenerating muscle fibers. The prominence of the CCR2 receptors further underlines the importance of the interaction with their ligand MCP-1 in the immunopathogenesis of IIM and puts CCR2B forward as a potential target for future therapeutic intervention. Muscle Nerve, 2005.

May 2005
Neurobiol Aging. 2005 May;26(5):645-54.
Age- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders.
Caccamo A, Oddo S, Sugarman MC, Akbari Y, Laferla FM.
Department of Neurobiology and Behavior, University of California, Irvine, 1109 Gillespie Neuroscience Bldg., Irvine, CA 92697-4545, USA.
Accumulation of amyloid beta-protein (Abeta) is a fundamental feature of certain human brain disorders such as Alzheimer's disease (AD) and Down syndrome and also of the skeletal muscle disorder inclusion body myositis (IBM). Emerging evidence suggests that the steady-state levels of Abeta are determined by the balance between production and degradation. Although the proteolytic processes leading to Ab formation have been extensively studied, less is known about the proteases that degrade Ab, which include insulin-degrading enzyme (IDE) and neprilysin (NEP). Here we measured the steady-state levels of these proteases as a function of age and brain/muscle region in mice and humans. In the hippocampus, which is vulnerable to AD pathology, IDE and NEP steady-state levels diminish as function of age. By contrast, in the cerebellum, a brain region not marked by significant Abeta accumulation, NEP and IDE levels either increase or remain unaltered during aging. Moreover, the steady-state levels of IDE and NEP are significantly higher in the cerebellum compared to the cortex and hippocampus. We further show that IDE is more oxidized in the hippocampus compared to the cerebellum of AD patients. In muscle, we find differential levels of IDE and NEP in fast versus slow twitch muscle fibers that varies with aging. These findings suggest that age- and region-specific changes in the proteolytic clearance of Abeta represent a critical pathogenic mechanism that may account for the susceptibility of particular brain or muscle regions in AD and IBM.

April 2005
Brain Pathol. 2005 Apr;15(2):101-8.
Involvement of clusterin and the aggresome in abnormal protein deposits in myofibrillar myopathies and inclusion body myositis.
Ferrer I, Carmona M, Blanco R, Moreno D, Torrejon-Escribano B, Olive M.
Institut Neuropatologia, Servei Anatomia Patologica, IDIBELL-Hospital Universitari de Bellvitge, Spain. 8082ifa@comb.es
Myofibrillar myopathies (MM) are characterized morphologically by the presence of non-hyaline structures corresponding to foci of dissolution of myofibrils, and hyaline lesions composed of aggregates of compacted and degraded myofibrillar elements. Inclusion body myositis (IBM) is characterized by the presence of rimmed vacuoles, eosinophilic inclusions in the cytoplasm, rare intranuclear inclusions, and by the accumulation of several abnormal proteins. Recent studies have demonstrated impaired proteasomal expression and activity in MM and IBM, thus accounting, in part, for the abnormal protein accumulation in these diseases. The present study examines other factors involved in protein aggregation in MM and IBM. Clusterin is a multiple-function protein which participates in Ab-amyloid, PrP(res) and a-synuclein aggregation in Alzheimer disease, prionopathies and a-synucleinopathies, respectively. g-Tubulin is present in the centrosome and is an intracellular marker of the aggresome. Moderate or strong clusterin immunoreactivity has been found in association with abnormal protein deposits, as revealed by immunohistochemistry, single and double-labeling immunofluorescence and confocal microscopy, in MM and IBM, and in target structures in denervation atrophy. g-Tubulin has also been observed in association with abnormal protein deposits in MM, IBM, and in target fibers in denervation atrophy. These morphological findings are accompanied by increased expression of clusterin and g-tubulin in muscle homogenates of MM and IBM cases, as revealed by gel electrophoresis and Western blots. Together, these observations demonstrate involvement of clusterin in protein aggregates, and increased expression of aggresome markers in association with abnormal protein inclusions in MM and IBM and in targets, as crucial events related to the pathogenesis of abnormal protein accumulation and degradation in these muscular diseases.

April 2005
Brain. 2005 Apr 27; [Epub ahead of print]
Gene expression profile in the muscles of patients with inflammatory myopathies: effect of therapy with IVIg and biological validation of clinically relevant genes.
Raju R, Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, 20892, USA.
To explore the biological significance of gene expression in the pathogenesis of inflammatory myopathies, we performed microarray experiments followed by real-time PCR and immunohistochemistry on muscle biopsies obtained before and after therapy from patients with dermatomyositis (DM) who improved and patients with inclusion body myositis (sIBM) who did not improve after controlled trials with three monthly intravenous immunoglobulin (IVIg) infusions. The pretreatment biopsies showed high expression of immunoglobulin, adhesion molecules, chemokines and cytokine genes in both sIBM and DM (sIBM > DM). In the repeated biopsies of DM patients who clinically improved, 2206 genes were downregulated more than 1.5-fold; in contrast, 1700 of the same genes remained unchanged in sIBM patients who did not improve. Genes markedly downregulated in DM, but not sIBM, were interleukin 22, Kallmann syndrome 1 (KAL-1), an adhesion molecule shown for the first time in muscle, ICAM-1, complement C1q, and several structural protein genes. Because mRNA for KAL-1 was selectively upregulated in vitro by transforming growth factor (TGF) b1, a fibrogenic cytokine immunolocalized in the endomysial connective tissue of pretreatment DM muscles, the downregulation of both TGF-b and KAL-1 after IVIg only in DM suggests that these molecules have a functional role in connective tissue proliferation and fibrosis. The improved muscles of DM, but not sIBM, showed upregulation of chemokines CXCL9 (Mig) and CXCL11, and several immunoglobulin-related genes, suggesting an effect on muscle remodelling and regeneration. The results suggest that IVIg modulates several immunoregulatory or structural muscle genes, but only a subset of them associated with inflammatory mediators, fibrosis and muscle remodelling are connected with the clinical response. Gene arrays, when combined with clinical assessments, may provide important information in the pathogenesis of inflammatory myopathies.
April 2005
Ann Rheum Dis. 2005 Apr;64(4):634-7.
Familial inflammatory inclusion body myositis.
Ranque-Francois B, Maisonobe T, Dion E, Piette JC, Chauveheid MP, Amoura Z, Papo T.

OBJECTIVE: To compare familial inflammatory inclusion body myositis (IBM) with hereditary inclusion body myopathies and sporadic IBM. PATIENTS AND METHODS: Clinical, biological, MRI, and histological data were analysed in two siblings with inflammatory IBM and compared with those of patients with sporadic and hereditary IBM. RESULTS: Both patients had a clinical phenotype of sporadic IBM, which differs from hereditary myopathies because of late age of onset-respectively 65 and 66 years, and different pattern of muscular involvement-asymmetric, mainly distal but also involving quadriceps. MRI showed selective fatty infiltration and oedema in the extensor compartment of thigh muscles. The diagnosis of IBM was confirmed by muscle biopsy, showing muscle fibres containing numerous rimmed vacuoles, a characteristic shared by all types of IBM. In contrast with hereditary IBM, histological analysis also showed inflammatory mononuclear infiltrate invading non-necrotic fibres, ragged red and oxidase c negative fibres, and positive Congo red staining. Moreover, HLA class II typing disclosed DRb1 0301 haplotype, which is significantly related to sporadic but not to hereditary IBM. With steroid treatment and monthly intravenous immunoglobulins, the disease was stabilised in both patients at protracted follow up. CONCLUSION: Sporadic and familial inflammatory IBM share the same clinical, biological, MRI, and histological features.
April 2005
Curr Rheumatol Rep. 2005 Apr;7(2):115-24.
Exercise: an important component of treatment in the idiopathic inflammatory myopathies.
Alexanderson H.
Department of Physical Therapy, Rheumatology Unit D2:07, Karolinska University Hospital, Solna SE-171 76, Stockholm, Sweden. helene.alexandersson@karolinska.se.

Resistive exercise is controversial for patients with idiopathic inflammatory myopathies. This paper provides an update on exercise and clinical assessment in these patients. The few published studies on this topic report unchanged disease activity from a variety of exercise regimens in patients in all stages of disease. Reduced disability was achieved in patients with polymyositis and dermatomyositis. In one study a slightly reduced impairment was reported in patients with inclusion body myositis, while in another study no objective reduction of disability could be detected. An increasing number of valid and reliable outcome measures are available for patients with polymyositis and dermatomyositis, but for patients with inclusion body myositis reliable and sensitive outcome measures are still needed.
March 2005
J [of the] Neurol Sci. 2005 Mar 15;229-230(1):233-40. Epub 2004 Dec 16. [Elsevier]
Cholesterol homeostasis failure as a unifying cause of synaptic degeneration.
Koudinov AR, Koudinova NV.
Neurobiology of Lipids, P.O. Box 1665, Rehovot 76100, Israel; Russian Academy of Medical Sciences, Timoshenko St., 38-27, Moscow 121359, Russia.

We previously showed that fine tuning of neural cholesterol dynamics is essential for basic synapse function, plasticity and behavior. Significant experimental evidence indicates that cholinergic function, ionotropic and metabotropic receptor machinery, excessive tau phosphorylation, the change of amyloid b (Ab or Ab) biochemistry, neural oxidative stress reactions, and other features of neurodegeneration also depend on fine tuning of brain cholesterol homeostasis. This evidence suggest that (i) cholesterol homeostasis break is the unifying primary cause of sporadic and familial Alzheimer's disease (AD), neuromuscular diseases (particularly inclusion-body myositis), Niemann-Pick's type C disease and Down syndrome, and (ii) explains the overlap of neurodegenerative hallmarks across the spectrum of neurodegenerative diseases. Provided is evidence-based explanation of why extremely rare (but scientifically popular) cases of AD associated with mutations in amyloid b protein precursor (APP) and presenilin (PS) genes, are translated into the disorder via membrane cholesterol sensitivity of APP processing by secretases and Ab generation. The reciprocal effect of Ab on cholesterol synthesis, cellular uptake, efflux and esterification is summarized, as well as the potential implication of such biological function for the compensatory Ab-assisted restoration of the synaptic long-term potentiation (LTP) and resulting inability of tackling amyloid to cure AD.
Note: also see: Cholesterol and IBM.
March 2005
Biochem Biophys Res Commun. 2005 Mar 4;328(1):221-6.
No overall hyposialylation in hereditary inclusion body myopathy myoblasts carrying the homozygous M712T GNE mutation.
Salama I, Hinderlich S, Shlomai Z, Eisenberg I, Krause S, Yarema K, Argov Z, Lochmuller H, Reutter W, Dabby R, Sadeh M, Ben-Bassat H, Mitrani-Rosenbaum S.
Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

Hereditary inclusion body myopathy (HIBM) is a unique group of neuromuscular disorders characterized by adult-onset, slowly progressive distal and proximal muscle weakness, which is caused by mutations in UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), the key enzyme in the biosynthetic pathway of sialic acid. In order to investigate the consequences of the mutated GNE enzyme in muscle cells, we have established cell cultures from muscle biopsies carrying either kinase or epimerase mutations. While all myoblasts carrying a mutated GNE gene show a reduction in their epimerase activity, only the cells derived from the patient carrying a homozygous epimerase mutation present also a significant reduction in the overall membrane bound sialic acid. These results indicate that although mutations in each of the two GNE domains result in an impaired enzymatic activity and the same HIBM phenotype, they do not equally affect the overall sialylation of muscle cells. This lack of correlation suggests that the pathological mechanism of the disease may not be linked solely to the well-characterized sialic acid pathway.
March 2005
Intern Med J. 2005 Mar;35(3):170-3.
Adult-onset inflammatory myopathy: North Canterbury experience 1989-2001.
Lynn SJ, Sawyers SM, Moller PW, O'donnell JL, Chapman PT.
Department of Rheumatology, Christchurch Hospital, Christchurch, New Zealand.

Abstract Aim: To perform a clinical audit of all patients diagnosed with inflammatory myopathy in the North Canterbury region.
Methods: A retrospective case note audit of patients with a discharge diagnosis of inflammatory myopathy from June 1989 to June 2001 was performed. The audit was based at Christchurch Hospital, New Zealand, which services a population of 430 000.
Results: Of 77 case notes reviewed, 44 patients were identified who were considered to fulfil clinical criteria for inflammatory myopathy. There was a female preponderance (80% female, 20% male). Diagnostic categories in descending order of frequency included: dermatomyositis (41%), polymyositis (39%), inclusion body myositis (IBM) (14%) and overlap syndromes (6%). Malignancy-associated myositis occurred in 20% overall (dermatomyositis 11%, polymyositis 9%). Delays in diagnosis and late age at presentation (average 72 years) were seen in the IBM group. Proximal limb weakness was common, but not universal at presentation (80%). A muscle biopsy was performed in all patients and electromyography in 82%. All were treated with high dose prednisone (0.5-1 mg/kg) of whom 29% were maintained on prednisone alone. Immunosuppressives/immunomodulators used included: azathioprine (58%), methotrexate (31%), intravenous immunoglobulin (13%), chlorambucil (13%), and cyclophosphamide (9%). Thirteen patients (42%) required more than one agent, with three trialling five agents. There were 59 relapses in 20 patients (45%), with mean time to first relapse of 7.8 months. At audit completion, 33% had deceased with malignancy and respiratory failure the main causes.
Conclusion: Inflammatory myopathy is a challenging condition in both diagnosis and management. Our audit has shown delays in the diagnosis of IBM, a relatively high incidence of malignancy and a notable risk of relapse and mortality.
March 2005
Curr Opin Rheumatol. 2005 Mar;17(2):164-71.
The role of exercise in the rehabilitation of idiopathic inflammatory myopathies.
Alexanderson H, Lundberg IE.
Department of Physical Therapy, Rheumatology Unit, Karolinska University Hospital, Solna, Stockholm, Sweden, and Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.

PURPOSE OF REVIEW: The objective of this review is to provide an update on exercise and clinical assessment in the idiopathic inflammatory myopathies.
RECENT FINDINGS: Polymyositis, dermatomyositis and inclusion body myositis are rare conditions with muscle weakness as a common prominent feature. Earlier, these patients were discouraged from active exercise due to a fear of increased muscle inflammation with recommendations to rest, perform range of motion exercises and in some cases, isometric exercises. However, beginning in the 1990s, studies reported reduced disability in patients with chronic polymyositis/dermatomyositis following resistive mild/moderate to intensive muscular training and aerobic endurance training, without signs of increased muscle inflammation. Patients with active, recent onset disease seem to benefit from mild/moderate muscular exercise without signs of increased muscle inflammation. There is no evidence of increased muscle inflammation following exercise in inclusion body myositis. However the beneficial effects are unclear as one study report increased muscle strength, while the other could not achieve impairment reduction.
SUMMARY: Studies evaluating active exercise in IIM support the notion of safety and benefits. However, large multi-center studies are needed to fully establish the safety and benefits of different types of exercise. Data indicate that active exercise, adapted to disease activity and disability should be included in the rehabilitation of patients in all stages of IIM. The newly developed and validated outcome measures for patients with polymyositis and dermatomyositis help assess the effects of interventions on disease activity and disability in clinical trials and in clinical practice. However, there are no sensitive and valid outcome measure for patients with inclusion body myositis.
Feb 2005
Neuromuscul Disord. 2005 Feb;15(2):177-84. Epub 2004 Dec 10.
a-Dystroglycan does not play a major pathogenic role in autosomal recessive hereditary inclusion-body myopathy.
Broccolini A, Gliubizzi C, Pavoni E, Gidaro T, Morosetti R, Sciandra F, Giardina B, Tonali P, Ricci E, Brancaccio A, Mirabella M.
Department of Neuroscience, Catholic University, L.go A. Gemelli 8, 00168 Rome, Italy.

Mutations of the GNE gene are responsible for autosomal recessive hereditary inclusion-body myopathy (HIBM). In this study we searched for the presence of any significant abnormality of a-dystroglycan (a-DG), a highly glycosylated component of the dystrophin-glycoprotein complex, in 5 HIBM patients which were previously clinically and genetically characterized. Immunocytochemical and immunoblot analysis showed that a-DG extracted from muscle biopsies was normally expressed and displayed its typical molecular mass. Immunoblot analysis on the wheat germ lectin-enriched glycoprotein fraction of muscles and primary myotubes showed a reduced amount of a-DG in 4 out of 5 HIBM patients, compared to normal and other diseased muscles. However, such altered lectin-binding behaviour, possibly reflecting a partial hyposialylation of a-DG, did not affect the laminin binding properties of a-DG. Therefore, the subtle changes within the a-DG glycosylation pattern, detected in HIBM muscles, likely do not play a key pathogenic role in this disorder.

Feb 2005
Neuropathol Appl Neurobiol. 2005 Feb;31(1):70-9.
Expression of the b chemokines CCL3, CCL4, CCL5 and their receptors in idiopathic inflammatory myopathies.
Civatte M, Bartoli C, Schleinitz N, Chetaille B, Pellissier JF, Figarella-Branger D.
Laboratoire de Biopathologie Nerveuse et Musculaire (EA 3281), Faculte de Medecine Timone, Universite de la Mediterranee, Institut de Physiopathologie Humaine de Marseille (I.P.H.M), FR125 Marseille.

The idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterized by chronic lymphocytic and macrophagic infiltration in muscle. Because the mechanism for recruitment of these cells probably involves chemokines, we focused on the study of the expression pattern of some b chemokines and receptors because it may provide a basis for selective immunotherapy. The expression of CCL3 (MIP-1a), CCL4 (MIP-1b), CCL5 (RANTES) and their main receptors (CCR1 and CCR5) was studied by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry in a series of 16 IIM and five controls (four normal muscles and one tonsil). Except for CCL5, strong expression was observed by RT-PCR with all molecules in all IIM subtypes in comparison to control muscle. Immunohistochemistry revealed diffuse CCL4 expression in all vessels in dermatomyositis. In both polymyositis and sporadic inclusion body myositis (s-IBM) it was restricted to vessels in the vicinity of inflammatory exudates. CCL5 expression was low, restricted to a few inflammatory cells in all IIM; CCR1 expression was mainly restricted to macrophages and s-IBM endothelial cells, whereas CCR5 was localized in inflammatory cells invading non-necrotic muscle fibres. Expressions of both receptors were also recorded in few muscle fibres. In conclusion, the upregulation of b chemokines and receptors in IIM and their differential expression by various cells may contribute to chronic inflammation and to the peculiar distribution of inflammatory exudates in these diseases.
Jan 2005
Clin Neuropathol. 2005 Jan-Feb;24(1):36-41.
Inclusion body myopathy associated with motor neuron syndrome: three case reports.
Cafforio G, Pistolesi S, D'Avino C, Galluzzi F, Patricelli A, Solito B, Fontanini G, Siciliano G.
Department of Neuroscience, University of Pisa, Italy.

BACKGROUND: Hereditary inclusion body myopathy (h-IBM) is an autosomal-recessive or autosomal-dominant hereditary disease characterized by peculiar findings in muscle biopsies which resemble those occurring in inclusion body myositis (IBM). The absence of an inflammatory infiltrate in myofibers in h-IBM is a relevant differential criterion between the two pathologies. Motor neuron diseases (MND) represent a group of disorders involving both upper and lower motor neurons, characterized by fasciculations, progressive muscle weakness, and muscle atrophy. The most common form and prototype of MND is the amyotrophic lateral sclerosis (ALS) or Charcot's Disease, a progressive and fatal neurodegenerative disorder occurring in late adulthood. The pathogenesis of ALS remains still unknown, a variety of hypotheses having been proposed to account for the disease. The association of both pathologies is not common and offers new hypotheses about the pathogenic mechanisms in skeletal muscle and nervous system degeneration.
PATIENTS AND METHODS: Described are three case reports in which we observed the clinical, laboratory and histopathological association of IBM and MND. In one case, dementia was also present. Muscle data was obtained by muscle biopsies and immunohistochemistry, while diagnosis of MND was supported by common neurophysiological techniques.
RESULTS: The accumulation of phosphorylated neurofilaments with a hereditary IBM-like pattern in skeletal muscle fibers without accumulation of amyloid-beta protein was observed.
CONCLUSIONS: A better knowledge of the mechanisms in cellular death cascade could explain the pathogenesis of these different degenerative disorders.
Jan 2005
Lancet Neurol. 2005 Jan;4(1):6-7. Review.
Neuromuscular disorders: molecular and therapeutic insights.
Mastaglia FL.
Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia. flmast@cyllene.uwa.edu.au

I have selected studies published in 2004 that made a substantial original contribution to our understanding of mechanisms or to the treatment of neuromuscular disorders and have opened up new directions for investigation.
Sporadic inclusion-body myositis (sIBM) is the most common myopathy that presents in patients over age 50 years and is characterised pathologically by abnormal protein aggregates in muscle fibres and by a cytotoxic CD8 lymphocytic response. There has long been debate about the relation between these two features, and the identity of the antigens involved in the immune response is not known. The strong association of sIBM with HLA-DR3 (DRB1*0301) has until now been regarded as evidence of a primary autoimmune pathogenesis in this disorder. The mapping study of the class II and central MHC region of chromosome 6 by Price and colleagues 1 casts doubt on this interpretation and strongly suggests that the association is not with DRB1*0301 itself but with another gene on the 8·1 ancestral haplotype in linkage disequilibrium with DRB1*0301, and which might not be part of the immune process. The study also showed that susceptibility to sIBM is linked not only to the 8·1 ancestral haplotype but also, in some individuals, to the 35·2 haplotype, confirming the complexity of genetic factors in sIBM. However, the studies of Fratta and coworkers 2 - showing the presence in muscle fibres of potentially toxic aberrant protein transcripts (e.g., ubiquitin UBB+1) that can interfere with proteasomal degradative mechanisms - provide another possible explanation for the abnormal protein accumulation and for the generation of antigenic peptides that could be driving the T-cell response.
1 Price P, Santoso L, Mastaglia F, et al. Two major histocompatibility complex haplotypes influence susceptibility to sporadic inclusion body myositis: critical evaluation of an association with HLA-DR3. Tissue Antigens 2004; 64: 575 - 80.
2 Fratta P, Engel WK, Van Leeuwen FW, Hol EM, Vattemi G, Askanas V. Mutant ubiquitin UBB+1 is accumulated in sporadic inclusion body myositis muscle fibers. Neurology 2004; 63: 1114 - 17.
3 Meredith C, Herrmann R, Parry C, et al. Mutations in the slow skeletal muscle .ber myosin heavy chain gene (MYH7) cause Laing early-onset distal myopathy (MPD1). Am J Hum Genet 2004; 75: 703 - 08.
4 Yuki N, Susuki K, Koga M, et al. Carbohydrate mimicry between human ganglioside GM1 and Campylobacter jejuni lipooligosaccharide causes Guillain-Barré syndrome. Proc Natl Acad Sci USA 2004; 101: 11404 - 09.
5 van Koningsveld, Schmitz PIM, Van Der Meche FGA, et al. Effects of methylprednisolone when added to standard treatment with intravenous immunoglobulin for Guillain-Barré syndrome: randomised trial. Lancet 2004; 363: 192 - 96.
Note: see the About IBM (section 16) for a description of these terms.
Jan 2005
Neurology. 2005 Jan 25;64(2):389.
Finger flexor weakness in inclusion body myositis.
Takamure, M. MD; Ken-ya Murata, MD, PhD; Makoto Kawahara, MD; and Satoshi Ueno, MD, PhD,
Nara, Japan

A 72-year-old woman with sporadic inclusion body myositis presented with slowly progressive weakness in her finger flexors and proximal lower limb. She was unable to flex her bilateral first digits and second digits at the proximal and distal interphalangeal joints, whereas the fourth and fifth digits were relatively spared (figure, A). Neither a sensory disturbance nor contractures were observed. The differences in muscle weakness between each digit correlated with the presence of fatty infiltrations, showing T1 hyperintensity, to the flexor pollicis longus and the specific areas within the flexor digitorum profundus and flexor digitorum superficialis1 (figure, B and C). These observations indicate that the disease process may progress patchily, not diffusely, within the involved muscles in inclusion body myositis. [Figures not reproduced here.]
Jan 2005
Neuromuscul Disord. 2005 Jan;15(1):32-9.
Diaphragmatic dysfunction in patients with idiopathic inflammatory myopathies.
Teixeira A, Cherin P, Demoule A, Levy-Soussan M, Straus C, Verin E, Zelter M, Derenne JP, Herson S, Similowski T.
UPRES EA 2397, Universite Pierre et Marie Curie Paris VI, Paris, France.

Polymyositis, dermatopolymyositis, and inclusion body myositis imply chronic inflammation of skeletal muscles. Pulmonary complications include aspiration pneumonia, interstitial pneumonitis, or respiratory muscle myositis. This study aims at better describing their impact on respiratory muscle. Twenty-three consecutive patients (12 PM, 5 DM, 6 IBM) were studied (static inspiratory and expiratory pressures; diaphragm function in terms of the mouth and transdiaphragmatic pressure responses to bilateral phrenic stimulation). Pulmonary parenchymatous abnormalities were mild (6 cases) or absent. The mouth pressure produced by phrenic stimulation was 6.83+/-3.01 cm H2O, with 18 patients (78%) diagnosed with diaphragm weakness (less than 10 cm H2O) and lower values in DM (4.35+/-1.48 cm H2O) than in IBM and in PM (P is less than 0.05). Diaphragm weakness is frequent and probably overlooked in inflammatory myopathies. Further studies are needed to delineate the clinical relevance of these results.