.
Research - What's New? 2010
Selected articles from the medical literature for 2010.
I have changed my strategy slightly and will now present only selected articles from the literature. For a complete review, please consult Pubmed, sponsored by the United States national Library of medicine.
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.
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
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.
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.
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: The Alberta Innovates – Health Solutions magazine, spring, 2010.
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.
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
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
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
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
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
.