Sporadic Inclusion-Body Myositis and Hereditary Inclusion-Body Myopathies

Askanas, Valerie; Engel, W. King

doi:10.1001/archneur.55.7.915

Cited by 64 publications

(33 citation statements)

References 19 publications

(19 reference statements)

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“…Mitochondrial dysfunction and oxidative stress, which is increased in s-IBM muscle fibres [23][24][25] , are known to stimulate aggregation of amyloidogenic proteins 26 . Moreover, overexpression of βAPP and accumulation of amyloid-β are early changes in muscle fibres prior to the development of structural abnormalities 27 , and over-expression of βAPP in human myoblasts in vitro leads to the development of structural mitochondrial abnormalities and loss of COX activity 28 .…”

Section: Discussionmentioning

confidence: 99%

Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms

Mastaglia

Rojana-udomsart

James

et al. 2013

Neuromuscular Disorders

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Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms.Neuromuscular Disorders, 23 (12 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractA polyT repeat in an intronic polymorphism (rs10524523) in the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of amyloid-β and other proteins into mitochondria, has been implicated in Alzheimer's disease and APOE-TOMM40genotypes have been shown to modify disease risk and age at onset of symptoms. Because of the similarities between Alzheimer's disease and sporadic inclusion body myositis (s-IBM), and the importance of amyloid-β and mitochondrial changes in s-IBM, we investigated whether variation in poly-T repeat lengths in rs10524523 also influence susceptibility and age at onset in a cohort of 90Caucasian s-IBM patients (55 males; age 69.1± 9.6). In carriers of APOE ε3/ε3 or ε3/ε4, genotypes with a very long (VL) poly-T repeat were under-represented in s-IBM compared to controls and were associated with a later age at symptom onset, suggesting that these genotypes may be protective.Our study is the first to suggest that polymorphisms in genes controlling mitochondrial function can influence susceptibility to s-IBM and have disease modifying effects. However, further studies in other s-IBM populations are needed to confirm these findings, as well as expression studies of different TOMM40 alleles in muscle tissue.

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Section: Discussionmentioning

confidence: 99%

Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms

Mastaglia

Rojana-udomsart

James

et al. 2013

Neuromuscular Disorders

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“…The abnormal deposition of cross-linked proteins including amyloids and other unknown proteins may induce muscle fiber destruction in s-IBM, as proposed by Askanas and Engel [4]. Interestingly, we found that the total TGase activity was elevated 16-fold in the diseased tissue, which is reflected in an increased number of products from TGase catalysis, ε(γ-glutamyl)lysine cross-links, from ∼2/10,000 in normal muscle to ∼60/10,000 residues [18].…”

Section: Discussionmentioning

confidence: 99%

“…They are sharing the common and characteristic feature of muscle degeneration mediated by an inflammatory process [1, 2, 3, 4]. IMs are currently treated with immunosuppressants or immunomodulating drugs.…”

Section: Introductionmentioning

confidence: 99%

Increase in Transglutaminase 2 in Idiopathic Inflammatory Myopathies

Choi

Kim

2004

Eur Neurol

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Idiopathic inflammatory myopathies (IMs), including dermatomyositis (DM), polymyositis (PM), and sporadic inclusion body myositis (s-IBM), are characterized by inflammatory cell infiltration in muscle tissue and muscle fiber destruction, which leads to muscle weakness. Although the cause of IMs is unclear, an autoimmune pathogenesis may be involved in initiating the muscle inflammation. Recently, we have found an aberrant expression of transglutaminase 2 (TGase 2) in s-IBM, which is closely associated with insoluble inclusion body formation. TGase 2 is a cross-linking enzyme that generates a conformational change of molecules via a covalent isopeptide bond. The increase in the level of TGase 2 expression and the inappropriate presentation of substrates/cross-linked aggregates to the immune system may contribute to the autoimmune aspects of IMs. We investigated whether or not an increase in TGase 2 expression is a common factor in muscle inflammation. Duchenne muscular dystrophy (DMD) and normal tissues were employed as controls. Using immunocytochemistry and quantitative RT-PCR, the level of TGase 2 expression was found to be specifically increased in PM and DM, but not in DMD and normal controls. Therefore, the targeting of TGase inhibition in IMs will be a challenging therapeutic approach that should be investigated in the near future.

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“…1 The abbreviations used are: AD, Alzheimer's disease; HSV, herpes simplex virus; A␤ (42), ␤-amyloid peptide ( necrotic, atrophic, angulated myofibers (18). Their sparse occurrence, however, make it likely that clinical muscle weakness arises from a more widespread or generalized metabolic defect, for instance related to oxidative stress (19) that can possibly lead to mitochondrial failure, calcium dyshomeostasis and/or a disorder of filament function and cytoskeletal protein interactions. Calcium dysregulation for example, could be limited to myofibers affected with inclusions or also involve normal appearing myofibers, which harbor undetectable but nevertheless toxic levels of intracellular soluble oligomeric ␤-amyloid species (see Ref.…”

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Calcium Dyshomeostasis in β-Amyloid and Tau-bearing Skeletal Myotubes

Christensen

Shtifman

Allen

et al. 2004

Journal of Biological Chemistry

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The relative scarcity of inclusion-affected muscle cells or markers of cell death in inclusion body myositis (IBM) is in distinction to the specific and early intracellular deposition of several Alzheimer's Disease (AD)-related proteins. The current study examined the possible correlation between myotube ␤-amyloid and/or Tau accumulations and a widespread mishandling of intracellular muscle calcium concentration that could potentially account for the unrelenting weakness in affected patients. Cultured myogenic cells (C 2 C 12 ) expressed ␤-amyloid-42 (A␤ 42 ) and fetal Tau peptides, as human transgenes encoded by herpes simplex virus, either individually or concurrently. Co-expression of A␤ 42 in C 2 C 12 myotubes resulted in hyperphosphorylation of Tau protein that was not observed when Tau was expressed alone. Resting calcium concentration and agonist-induced RyR-mediated Ca 2؉ release were examined using calcium-specific microelectrodes and Fluo-4 epifluorescence, respectively. Co-expression of A␤ 42 and Tau cooperatively elevated basal levels of myoplasmic-free calcium, an effect that was accompanied by depolarization of the plasma membrane. Sarcoplasmic reticulum (SR) calcium release, induced by KCl depolarization, was not affected by A␤ 42 or Tau. In contrast, expression of A␤ 42 , Tau, or A␤ 42 together with Tau resulted in enhanced sensitivity of ryanodine receptors to activation by caffeine. Notably, expression of ␤-amyloid, alone, was sufficient to result in an increased sensitivity to direct activation by caffeine. Current results indicate that amyloid proteins cooperate to raise resting calcium levels and that these effects are associated with a passive SR Ca 2؉ leak and Tau hyperphosphorylation in skeletal muscle.

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Sporadic Inclusion-Body Myositis and Hereditary Inclusion-Body Myopathies

Cited by 64 publications

References 19 publications

Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms

Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms

Increase in Transglutaminase 2 in Idiopathic Inflammatory Myopathies

Calcium Dyshomeostasis in β-Amyloid and Tau-bearing Skeletal Myotubes

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