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2010

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2010.

From what I can see, 2010 has been a disappointing year and no major advances in IBM research have taken place.

A promising secondary approach is the use of follistatin gene therapy in order to try to stimulate muscle generation in order to counterbalance the dystrophic effects of IBM. A presentation appears below summarizing this approach. A new way of controlling the activity of myostatin, a protein that reduces muscle mass and strength, has successfully been tested in monkeys. The group of Professor Jerry Mendell, USA has injected a harmless virus into the muscles of six monkeys. The virus carried the gene for follistatin, a protein known to reduce myostatin activity. As a result the monkeys' muscles grew bigger and stronger. This gene therapy approach could potentially be useful to treat people affected by a number of neuromuscular disorders, although its benefit in humans remains to be shown in clinical trial.

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

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


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TDP-43 plasma levels do not differentiate sporadic inclusion body myositis from other inflammatory myopathies.
Kuiperij HB, Abdo WF, van Engelen BG, Schelhaas HJ, Verbeek MM.
Acta Neuropathol. 2010 Dec;120(6):825-6. Epub 2010 Nov 3. No abstract available.
PMID: 21046407 We conclude that TDP-43 plasma levels do not distinguish myopathies with TDP-43-containing inclusions in muscle fibers from those not having this TDP-43 pathology, likely due to physiological release of non-pathological TDP-43. Further studies measuring p-TDP-43 are indicated to investigate if elimination of non-pathological TDP-43 protein might improve the discriminating power of the test.

Follistatin gene therapy


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Curr Opin Rheumatol. 2010 Nov;22(6):651-7.
Mitochondrial pathology in immune and inflammatory myopathies.
Varadhachary AS, Weihl CC, Pestronk A.
Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri, USA.
Abstract
PURPOSE OF REVIEW: Acquired immune and inflammatory myopathies (IIMs) are typically subdivided into dermatomyositis, polymyositis and inclusion body myositis. However, many types of IIMs do not fit well into this scheme. Several myopathologic and autoantibody features of IIMs, that are not considered in standard classifications, are useful for defining individual disorders. We will review one set of myopathologic features that occur in some IIMs, mitochondrial abnormalities, and consider its diagnostic, treatment-related and pathogenic implications.
RECENT FINDINGS: Myopathologic changes that indicate mitochondrial disorders are often widespread in regions of muscle fiber abnormality in dermatomyositis. They distinguish dermatomyositis with vascular pathology from other inflammatory myopathies with skin changes that have prominent perimysial connective tissue lesions, but no mitochondrial, abnormalities. Mitochondrial abnormalities in scattered muscle fibers occur in sporadic inclusion body myositis and clinically similar disorders. Mitochondrial abnormalities in scattered nonnecrotic muscle fibers in IIM biopsies predict a poor response to immunosuppression.
SUMMARY: Muscle biopsy, including evaluation of mitochondrial stains, is important for the correct diagnosis of inflammatory myopathies. By recognizing the full range of distinctive myopathologic changes in the diverse group of IIMs, the clinician can improve diagnostic accuracy and apply appropriate treatment.
PMID: 20827203

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Curr Opin Neurol. 2010 Oct;23(5):482-8.
Sporadic inclusion body myositis: possible pathogenesis inferred from biomarkers.
Weihl CC, Pestronk A.
Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis, Missouri 63110, USA.
Abstract
PURPOSE OF REVIEW: The relevance of proteins that accumulate and aggregate in the muscle fibers of patients with sporadic inclusion body myositis (sIBM) is unknown. Many of these proteins also aggregate in other disorders, including Alzheimer's disease, leading to speculation that sIBM pathogenesis has similarities to neurodegenerative disorders. Our review will discuss current studies on these protein biomarkers and their utility in sIBM diagnosis.
RECENT FINDINGS: Two 'classical' components of sIBM aggregates (amyloid beta and phospho-tau) have been re-evaluated. Three additional components of aggregates (TDP-43, p62, and LC3) have been identified. The sensitivity and specificity of these biomarkers has been explored. Two studies suggest that TDP-43 may have clinical utility in distinguishing sIBM from other inflammatory myopathies. SUMMARY: The fact that sIBM muscle accumulates multiple protein aggregates with no single protein appearing in every sIBM patient biopsy suggests that it is not presently possible to place pathogenic blame on any single protein (i.e. amyloid beta or TDP-43). Instead changes in protein homeostasis may lead to the accumulation of different proteins that have a propensity to aggregate in skeletal muscle. Therapies aimed at improving protein homeostasis, instead of targeting a specific protein that may or may not accumulate in all sIBM patients, could be useful future strategies for this devastating and enigmatic disorder.
PMID: 20664349

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Curr Opin Pharmacol. 2010 Jun;10(3):346-52. Epub 2010 Apr 19.
Inflammatory muscle diseases: a critical review on pathogenesis and therapies.
Dalakas MC.
Department of Neurosciences, Imperial College, London, UK. m.dalakas@imperial.ac.uk
Abstract
Based on unique clinicopathological criteria, the most common immune inflammatory muscle disorders include Dermatomyositis (DM), Polymyositis (PM), Necrotizing Myositis (NM), and sporadic Inclusion Body Myositis (sIBM). DM is an undeniably a complement-mediated microangiopathy with destruction of capillaries, hypoperfusion, and inflammatory cell stress on the perifascicular regions. Necrotizing Myopathy is a poorly studied subacute myopathy triggered by toxic, viral, or autoimmune factors with macrophages as the final effector cells. In PM and IBM cytotoxic CD8-positive T-cells clonally expand in situ and invade MHC-I-expressing muscle fibers. In sIBM, in addition to autoimmune inflammation, there are degenerative features characterized by vacuolization and accumulation of stressor and amyloid-related molecules. Advances in the immunobiology of these disorders are discussed including the interaction between pro-inflammatory and beta-amyloid or stressor proteins. A critical review regarding tissue biomarkers and strategies for more effective treatments are presented. Copyright 2010 Elsevier Ltd. All rights reserved. PMID: 20409756

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Neuromuscul Disord. 2010 Jun;20(6):414-21. Epub 2010 Apr 21.
International Workshop on Inclusion Body Myositis held at the Institute of Myology, Paris, on 29 May 2009.
Benveniste O, Hilton-Jones D.
Hopitaux de Paris, Hopital Pitie-Salpetriere, Paris, France. olivier.benveniste@psl.aphp.fr
PMID: 20413309

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Neuropathol Appl Neurobiol. 2010 Dec 14. doi: 10.1111/j.1365-2990.2010.01153.x. [Epub ahead of print]
AN UPDATE ON INFLAMMATORY AND AUTOIMMUNE MYOPATHIES.
Dalakas MC.
Department of Neurosciences, Imperial College, London, UK and Department of Neurology Thomas Jefferson University, Philadelphia, PA, USA.
Abstract
The review provides an update on the diagnosis of the main subtypes of inflammatory myopathies including Dermatomyositis (DM), Polymyositis (PM), Necrotizing Autoimmune Myositis (NAM) and sporadic Inclusion Body Myositis (sIBM). The fundamental aspects on muscle pathology and the unique pathomechanisms of each subset are outlined and the diagnostic dilemmas concerning the distinction of PM from IBM and NAM are addressed. DM is a complement-mediated microangiopathy leading to destruction of capillaries, hypoperfusion and inflammatory cell stress on the perifascicular regions. NAM, is an increasingly recognized subacute myopathy triggered by statins, viral infections, cancer or autoimmuity with macrophages as the final effector cells causing fiber injury. In PM and IBM cytotoxic CD8-positive T-cells clonally expand in situ and invade MHC-I-expressing muscle fibers. The pathology of sIBM is complex because, in addition to the inflammatory mechanisms, there are degenerative features characterized by vacuolization and the accumulation of stressor and amyloid-related misfolded proteins. Inducible pro-inflammatory molecules, such as interleukin 1-beta, may enhance the accumulation of stressor proteins. The principles for more effective treatment strategies are discussed. 2010 The Author. Neuropathology and Applied Neurobiology 2010 British Neuropathological Society. PMID: 21155862

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J Biol Chem. 2010 Oct 27. [Epub ahead of print]
TNF-alpha induces macroautophagy and regulates MHC class II expression in human skeletal muscle cells.
Keller CW, Fokken C, Turville SG, Lunemann A, Schmidt J, Munz C, Lunemann JD.
Department of Neurology, University of Goettingen, Germany, Germany;
Abstract
Macroautophagy, a homeostatic process that shuttles cytoplasmic constituents into endosomal and lysosomal compartments, has recently been shown to deliver antigens for presentation on major histocompatibility complex (MHC) class II molecules. Skeletal muscle fibers show a high level of constitutive macroautophagy and express MHC class II molecules upon immune activation. We found that tumor necrosis factor (TNF)-alpha, a monokine overexpressed in inflammatory myopathies, led to a marked upregulation of macroautophagy in skeletal myocytes. Furthermore, TNF-alpha augmented surface expression of MHC class II molecules in interferon-gamma (IFN-gamma) treated myoblasts. The synergistic effect of TNF-alpha and IFN-gamma on the induction of MHC class II surface expression was not reflected by higher intracellular human leukocyte antigen (HLA)-DR levels and was reversed by macroautophagy inhibition, suggesting that TNF-alpha facilitates antigen processing via macroautophay for more efficient MHC class II loading. Muscle biopsies from patients with sporadic inclusion body myositis, a well defined myopathy with chronic inflammation, showed that over twenty percent of fibers that contained autophagosomes costained for MHC class II molecules and that more than forty percent of double positive muscle fibers had contact to CD4+ and CD8+ immune cells. These findings establish a mechanism through which TNF-alpha regulates both macroautophagy and MHC class II expression and suggest that macroautophagy mediated antigen presentation contributes to the immunological environment of the inflamed human skeletal muscle. PMID: 20980264

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Curr Opin Rheumatol. 2010 Nov;22(6):658-64.
Novel therapeutic approaches for inclusion body myositis.
Lloyd TE.
Department of Neurology, Johns Hopkins School of Medicine, 600 N. Wolfe St./Meyer 5-119, Baltimore, MD 21287, USA. tlloyd4@jhmi.edu
Abstract
PURPOSE OF REVIEW: This review will highlight recent advances in developing strategies to accelerate muscle regeneration and to slow muscle degeneration in myositis, focusing primarily on inclusion body myositis (IBM).
RECENT FINDINGS: Therapies for accelerating muscle regeneration, primarily through inhibition of myostatin, have shown promise in the laboratory and are now entering clinical trials. Recent studies have implicated autophagy, a key cellular process involved in clearance of ubiquitinated aggregates, in the pathogenesis of familial and sporadic inclusion body myositis (sIBM). IBM has joined a growing list of diseases known as TDP-43 proteinopathies, in which this protein becomes mislocalized to the cytoplasm; however, it is unclear whether these protein aggregates or others are pathogenic in this disease. SUMMARY: New discoveries of biomarkers in sIBM and new insights into the pathogenesis of familial IBM are opening novel therapeutic pathways for these disorders. In particular, drugs that stimulate autophagy, already in development for cancer and neurodegenerative diseases, are candidates for clinical trials. These disease-specific therapies combined with novel therapies to accelerate muscle regeneration hold promise for future therapy for this devastating disease.
PMID: 20827206

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J Neurol Neurosurg Psychiatry. 2010 Aug 22. [Epub ahead of print]
Increased [11C]PIB-PET levels in inclusion body myositis are indicative of amyloid {beta} deposition.
Maetzler W, Reimold M, Schittenhelm J, Vorgerd M, Bornemann A, Kotter I, Pfannenberg C, Reischl G, Schols L.
Hertie Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of Tuebingen, Germany.
PMID: 20732867

PubMed Link

Acta Neuropathol. 2010 Nov;120(5):661-6. Epub 2010 Aug 15.
Novel demonstration of amyloid-{beta} oligomers in sporadic inclusion-body myositis muscle fibers.
Nogalska A, D'Agostino C, Engel WK, Klein WL, 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. Abstract
Accumulation of amyloid-{beta} (amyloid {beta}) within muscle fibers has been considered an upstream step in the development of the s-IBM pathologic phenotype. amyloid {beta} 42, which is considered more cytotoxic than amyloid {beta} 40 and has a higher propensity to oligomerize, is preferentially increased in s-IBM muscle fibers. In Alzheimer disease (AD), low-molecular weight amyloid {beta} oligomers and toxic oligomers, also referred to as "amyloid {beta} -Derived Diffusible Ligands" (ADDLs), are considered strongly cytotoxic and proposed to play an important pathogenic role. ADDLs have been shown to be increased in AD brain. We now report for the first time that in s-IBM muscle biopsies amyloid {beta}-dimer, -trimer, and -tetramer are identifiable by immunoblots. While all the s-IBM samples we studied had amyloid {beta}-oligomers, their molecular weights and intensity varied between the patient samples. None of the control muscle biopsies had amyloid {beta} oligomers. Dot-immunoblots using highly specific anti-ADDL monoclonal antibodies also showed highly increased ADDLs in all s-IBM biopsies studied, while controls were negative. By immunofluorescence, in some of the abnormal s-IBM muscle fibers ADDLs were accumulated in the form of plaque-like inclusions, and were often increased diffusely in very small fibers. Normal and disease-controls were negative. By gold-immuno-electron microscopy, ADDL-immunoreactivities were in close proximity to 6-10 nm amyloid-like fibrils, and also were immunodecorating amorphous and floccular material. In cultured human muscle fibers, we found that inhibition of autophagy led to the accumulation of amyloid {beta} oligomers. This novel demonstration of amyloid {beta} 42 oligomers in s-IBM muscle biopsy provides additional evidence that intra-muscle fiber accumulation of amyloid {beta} 42 oligomers in s-IBM may contribute importantly to s-IBM pathogenic cascade. PMID: 20711838

PubMed Link

Curr Rheumatol Rep. 2010 Jun;12(3):221-8.
Theories of the pathogenesis of inclusion body myositis.
Greenberg SA. Department of Neurology, Division of Neuromuscular Disease, Brigham and Women's Hospital, and Children's Hospital Informatics Program, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. sagreenberg@partners.org
Abstract
Inclusion body myositis is a progressive disease of the skeletal muscle. Here, specific theories of its pathogenesis are reviewed and general considerations pertaining to modeling of this disease discussed. Understanding of inclusion body myositis disease mechanism remains extremely poor. Current published animal models do not represent the disease. Future studies need to consider the critical role of biomarkers and methodologic issues in their discovery. Article

PubMed Link

Med Sci Sports Exerc. 2010 Feb;42(2):250-4.
PURPOSE: We evaluated the efficacy of a moderate-intensity resistance training program combined with vascular occlusion by examining functional capacity, muscle morphology, and changes in the expression of genes related to muscle protein synthesis and proteolysis in a patient with IBM. METHODS: A 65-yr-old man with IBM resistant to all proposed treatments underwent resistance training with vascular occlusion for 12 wk. Leg press one-repetition maximum; thigh cross-sectional area; balance, mobility, and muscle function; quality of life; and blood markers of inflammation and muscle damage were assessed at baseline and after the 12-wk program. The messenger RNA (mRNA) expression levels of mechanogrowth factor, mammalian target of rapamycin, atrogin-1, and muscle RING finger-1 were also quantified. RESULTS: After the 12-wk training program, the patient's leg press one-repetition maximum, balance and mobility function, and thigh cross-sectional area increased 15.9%, 60%, and 4.7%, respectively. All Short Form-36 Health Survey Questionnaire subscales demonstrated improvements as well, varying from 18% to 600%. mRNA expression of mechanogrowth factor increased 3.97-fold, whereas that of atrogin-1 decreased 0.62-fold. Muscle RING finger-1 and mammalian target of rapamycin mRNA levels were only slightly altered, 1.18- and 1.28-fold, respectively. Importantly, the exercise did not induce disease flare. CONCLUSIONS: We describe a novel, and likely the first, nonpharmacological therapeutic tool that might be able to counteract the muscle atrophy and the declining strength that usually occur in IBM.

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J Vis Exp. 2010 Jun 5;(40). pii: 1894. doi: 10.3791/1894.
we have recently observed that restricting muscle blood flow using tourniquet cuffs in association with moderate intensity resistance training in an IBM patient produced a significant gain in muscle mass and function, along with substantial benefits in quality of life. Thus, a new non-pharmacological approach for IBM patients has been proposed. Herein, we describe the details of a proposed protocol for vascular occlusion associated with a resistance training program for this population.
We presented a novel, and likely the first, non pharmacological therapeutic tool able to counteract the muscle atrophy and decline of strength that usually occurs in patients with IBM under conventional treatment. Resistance training with vascular occlusion is a relatively novel training method, but results are very encouraging. We have found that after a 12-wk training program, an IBM patient's leg press one-repetition maximum, balance and mobility function, and thigh cross-sectional area increased 15.9%, 60%, and 4.7%, respectively. Health Survey Questionnaire subscales demonstrated improvements ranging from 18% to 600% and mRNA expression of mechanogrowth factor increased 3.97-fold, whereas that of atrogin-1 decreased 0.62-fold4,5. This video describes in details the protocol of a resistance training program with vascular occlusion for this population. The appropriate determination of full vascular occlusion pressure is essential for the correct implementation of this training modality and it may be applied to any patient undergoing regular resistance exercise program. Equipments required consist of a vascular Doppler, two customized tourniquets cuffs with pressure manometers and a regular training facility. Moreover, we recommend that each training session is supervised by at least one physical trainer in order to ensure the safety and efficacy of the proposed method.

PubMed Link

Neurobiol Dis. 2010 May 18. [Epub ahead of print]
Effects of nonsteroidal anti-inflammatory drugs on amyloid-beta pathology in mouse skeletal muscle.
Beckett TL, Niedowicz DM, Studzinski CM, Weidner AM, Webb RL, Holler CJ, Ahmed RR, Levine H 3rd, Murphy MP.
If AD and sIBM are linked, then treatments that lower Abeta in brain may prove useful for sIBM. To test this hypothesis, transgenic mice that over express APP in skeletal muscle were treated for 6 months with a variety of non-steroidal anti-inflammatory drugs (NSAIDs; naproxen, ibuprofen, carprofen or R-flurbiprofen), a subset of which reduce Abeta in brain and cultured cells. Only ibuprofen lowered Abeta in muscle, and this was not accompanied by corresponding improvements in phenotype. These results indicate that the effects of NSAIDs in the brain may be different from other tissues, and that Abeta alone cannot account for skeletal muscle dysfunction in these mice. Copyright 2010. Published by Elsevier Inc. PMID: 20493261

Dr. Chris White, a Calgary physician describes IBM. Source: Alberta Innovates- Health Solutions magazine, spring, 2010.


PubMed Link not up yet

Expert Opin. Med. Diagn. (2010) 4(3): 241-250
Pathomechanisms of inflammatory myopathies: recent advances and implications for diagnosis and therapies
Jens Schmidt and Marinos C Dalakas
The main challenge in the diagnosis of the inflammatory myopathies remains the distinction of PM from the inflammatory dystrophies and necrotising myopathy; the second even bigger challenge is what causes IBM and how to treat it.
[Opinion: nothing new here in an article that is quite self serving to the researcher's own research and approach.] Article here.

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J Gene Med. 2010 May;12(5):403-12.
Hereditary inclusion body myopathy: single patient response to GNE gene Lipoplex therapy.
Nemunaitis G, et al
In summary, we have demonstrated proof of principle that local replacement of normal GNE gene and consequent local sialylated glycocojungate expression can safely and positively affect muscle function in a single individual with HIBM. Further studies will be necessary to fully characterize GNE protein expression and enzymatic activity. Development of therapeutic GNE-Lipoplex is underway and will incorporate an evaluation of the safety and effectiveness of intravenous delivery in additional animal models and in less severely affected individuals with HIBM. ARTICLE

PubMed Link

Curr Rheumatol Rep. 2010 Jun;12(3):221-8.
Theories of the pathogenesis of inclusion body myositis.
Greenberg SA.
Trends: Good for Researchers, Bad for Patients
Two roads lie before researchers contemplating the pursuit of relevant disease mechanisms in IBM: pursue unbiasedly generated or fortuitously found clues, or join a trend. The former is more likely to produce scientific advances helpful to patients, the latter safer and more likely to produce grant funding and successful publication helpful to the researcher.

Conclusions
After two to three decades of intense interest in IBM, there is almost no understanding as to the cause of this disease and the mechanisms by which myofibers are injured. Large gaps exist between the identification of disease biomarkers and their causal relationships to muscle injury. Currently advocated animal models do not represent this disease and should not be relied upon for therapeutic development. Careful attention to biomarker specificity, quantitation, and methodology is crucial to progress for patients with IBM. Article

PubMed Link

Curr Opin Pharmacol. 2010 Apr 19.
[Epub ahead of print] Inflammatory muscle diseases: a critical review on pathogenesis and therapies.
Dalakas MC.
In PM and IBM cytotoxic CD8-positive T-cells clonally expand in situ and invade MHC-I-expressing muscle fibers. In sIBM, in addition to autoimmune inflammation, there are degenerative features characterized by vacuolization and accumulation of stressor and amyloid-related molecules. Advances in the immunobiology of these disorders are discussed including the interaction between pro-inflammatory and beta-amyloid or stressor proteins. A critical review regarding tissue biomarkers and strategies for more effective treatments are presented.
Article

PubMed Link

Benveniste O, Hilton-Jones D. International Workshop on Inclusion Body Myositis held at the Institute of Myology, Paris, on 29 May 2009.
Neuromuscul Disord (2010), doi:10.1016/j.nmd.2010.03.014
International Workshop on Inclusion Body Myositis held at the Institute of Myology, Paris, on 29 May 2009 Article

PubMed Link

Nat Rev Rheumatol. 2010 Mar;6(3):129-37. Epub 2010 Feb 2.
Immunotherapy of myositis: issues, concerns and future prospects.
Dalakas MC.
The most common reason for therapeutic failure is that the treatment targets the wrong disease, often owing to poor distinction of polymyositis from difficult-to-treat mimics such as sporadic IBM, necrotizing myopathies and inflammatory dystrophies. Evidence from uncontrolled studies suggests that polymyositis and dermatomyositis respond to treatment with prednisone at least to some degree.

Although a number of patients with IBM might show a transient response to steroid therapy, the majority do not. Methotrexate, ciclosporin, azathioprine or mycophenolate mofetil are largely ineffective, although some patients might initially respond to some degree. Ivig can provide some benefit to a small proportion of patients for a short period of time, especially for those with dysphagia, but its overall effect is disappointing. Article


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Neurosci Lett. 2010 May 3;474(3):140-3. Epub 2010 Mar 15.
Increased BACE1 mRNA and noncoding BACE1-antisense transcript in sporadic inclusion-body myositis muscle fibers--possibly caused by endoplasmic reticulum stress.
Nogalska A, Engel WK, Askanas V
Our study demonstrated for the first time that a) in s-IBM biopsies BACE1-AS and BACE1 transcripts were significantly increased, suggesting that their increased expression can be responsible for the increase of BACE1 protein; and b) experimental induction of ER stress significantly increased both BACE1-AS and BACE1 transcripts, suggesting that ER stress can participate in their induction in s-IBM muscle. Accordingly, decreasing BACE1 through a targeted downregulation of its regulatory BACE1-AS, or reducing ER stress, might be therapeutic strategies in s-IBM, assuming that it would not impair any normal cellular functions of BACE1.

PubMed Link

Clin Rheumatol. 2010 May;29(5):555-8. Epub 2010 Jan 27.
Inclusion body myositis in a patient with long standing rheumatoid arthritis treated with anti-TNFalpha and rituximab.
Vordenbaumen S, Neuen-Jacob E, Richter J, Schneider M.
The case of a 57-year-old patient with long standing rheumatoid arthritis (RA) who developed muscle wasting and weakness of the quadriceps femoris after initiation of anti-TNFalpha treatment is presented. Further workup including muscle biopsy revealed IBM. Initiation of rituximab for continuing synovial inflammation led to remission of RA, but no amelioration of muscle weakness was noted.

PubMed Link

Nat Rev Rheumatol. 2010 Mar;6(3):129-37. Epub 2010 Feb 2.
Immunotherapy of myositis: issues, concerns and future prospects.
Dalakas MC.
Novel agents are emerging as potential treatment options for all forms of myositis. This Review highlights common pitfalls in therapy, discusses emerging new therapies, and provides a practical therapeutic algorithm.

PubMed Link

J Neurochem. 2010 Jan;112(2):389-96. Epub 2009 Oct 29.
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, Engel WK, Askanas V
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 Thr724. Accordingly, treatment with lithium, or other GSK3beta inhibitors, might benefit s-IBM patients.

PubMed Link

Hum Mol Genet. 2010 May 1;19(9):1741-55. Epub 2010 Feb 10.
Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone.
Custer SK, Neumann M, Lu H, Wright AC, Taylor JP.
Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone.

PubMed Link

Acta Myol. 2009 Oct;28(2):66-71.
Sporadic inclusion body myositis: variability in prevalence and phenotype and influence of the MHC.
Mastaglia FL.
Our recent observations indicate that the clinical phenotype at presentation is also quite variable and that the influence of the MHC is more complex than previously appreciated with HLA alleles also having modifying effects on the age-at-onset, severity and rate of progression of the disease. Recent recombinant mapping studies of polymorphisms in the Class II/III regions of the MHC by our group have further refined the susceptibility region and have identified a number of candidate genes warranting further investigation. The significance of these findings for the pathogenesis of the disease is discussed.

PubMed Link

Eur J Neurol. 2010 Feb 23. [Epub ahead of print]
TREX1 mutations are not associated with sporadic inclusion body myositis.
Cox FM, Boon EM, van der Lans CA, Bakker E, Verschuuren JJ, Badrising UA.
TREX1 mutations do not play a role in the pathogenesis of sIBM.

PubMed Link

Clin Exp Immunol. 2009 Dec;158 Suppl 1:34-42.
Clinical applications of intravenous immunoglobulins in neurology.
Hughes RA, Dalakas MC, Cornblath DR, Latov N, Weksler ME, Relkin N.
In patients with inclusion body myositis, IVIg was not shown to be effective.

PubMed Link

Nat Rev Neurosci. 2010 Mar;11(3):155-9. Epub 2009 Dec 23.
Prion-like mechanisms in neurodegenerative diseases.
Frost B, Diamond MI.
Many non-infectious neurodegenerative diseases are associated with the accumulation of fibrillar proteins. These diseases all exhibit features that are reminiscent of those of prionopathies, including phenotypic diversity and the propagation of pathology. Furthermore, emerging studies of amyloid-beta, alpha-synuclein and tau - proteins implicated in common neurodegenerative diseases - suggest that they share key biophysical and biochemical characteristics with prions. Propagation of protein misfolding in these diseases may therefore occur through mechanisms similar to those that underlie prion pathogenesis. If this hypothesis is verified in vivo, it will suggest new therapeutic strategies to block propagation of protein misfolding throughout the brain.

PubMed Link

PLoS One. 2010 Feb 11;5(2):e9170.
Cytotoxic aggregation and amyloid formation by the myostatin precursor protein.
Starck CS, Sutherland-Smith AJ.
Myostatin, a negative regulator of muscle growth, has been implicated in sporadic inclusion body myositis (sIBM). sIBM is the most common age-related muscle-wastage disease with a pathogenesis similar to that of amyloid disorders such as Alzheimer's and Parkinson's diseases. Myostatin precursor protein (MstnPP) has been shown to associate with large molecular weight filamentous inclusions containing the Alzheimer's amyloid beta peptide in sIBM tissue, and MstnPP is upregulated following ER stress. The mechanism for how MstnPP contributes to disease pathogenesis is unknown. Here, we show for the first time that MstnPP is capable of forming amyloid fibrils in vitro. Importantly, MstnPP aggregates and protofibrils have a negative effect on the viability of myoblasts. These novel results show that the myostatin precursor protein is capable of forming amyloid structures in vitro with implications for a role in sIBM pathogenesis.

PubMed Link

J Cell Biol. 2009 Dec 14;187(6):875-88.
Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease.
Ju JS, Fuentealba RA, Miller SE, Jackson E, Piwnica-Worms D, Baloh RH, Weihl CC.
These data implicate VCP in autophagy and suggest that impaired autophagy explains the pathology seen in IBMPFD muscle, including TDP-43 accumulation.
Quotation: We demonstrate that loss of VCP activity impairs autophagy. Specifically, LC3-positive vacuoles fail to mature into autolysosomes, resulting in the accumulation of nondegradative autophagosomes. Moreover, measures of autophagic flux are impaired in cells lacking a functional VCP. Expression of the IBMPFD mutant VCP-RH or -AE leads to similar results with dysfunctional autophagosomes accumulating at RVs in IBMPFD patient and transgenic mouse muscle. TDP-43 accumulation in the cytosol occurs in IBMPFD mutant-expressing cells and animals as well as with chemical inhibition of autophagosome maturation in vitro and in vivo. Our data suggest that IBMPFD is a disorder of autophagosome maturation resulting in dysfunctional autophagy.

PubMed Link

Rheumatol Int. 2010 Jan 1. [Epub ahead of print]
Treatment of inclusion body myositis: is low-dose intravenous immunoglobulin the solution?
Recher M, Sahrbacher U, Bremer J, Arndt B, Steiner U, Fontana A.
Here, we present the informative case of a 70-year-old woman with diagnosed inclusion body myositis that showed progressive muscle weakness without treatment and following immuno-suppressive treatment with corticosteroids and azathioprine. A trial with low-dose intravenous immunoglobulins was started at that time. The patient responded rapidly to low dose IVIG treatment with amelioration of muscle strength and normalization of CK serum activities. Our results demonstrate that IBM patients may respond to low-dose IVIG treatment which has important clinical and economic consequences.

Mail Bill: btillier@shaw.ca

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