Sporadic inclusion-body myositis: A degenerative muscle disease associated with aging, impaired muscle protein homeostasis and abnormal mitophagy

Abstract

Sporadic inclusion-body myositis (s-IBM) is the most common degenerative muscle disease in which aging appears to be a key risk factor. In this review we focus on several cellular molecular mechanisms responsible for multiprotein aggregation and accumulations within s-IBM muscle fibers, and their possible consequences. Those include mechanisms leading to: a) accumulation in the form of aggregates within the muscle fibers, of several proteins, including amyloid-β42 and its oligomers, and phosphorylated tau in the form of paired helical filaments, and we consider their putative detrimental influence; and b) protein misfolding and aggregation, including evidence of abnormal myoproteostasis, such as increased protein transcription, inadequate protein disposal, and abnormal posttranslational modifications of proteins. Pathogenic importance of our recently demonstrated abnormal mitophagy is also discussed. The intriguing phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer and Parkinson's disease patients, the two most common neurodegenerative diseases associated with aging, are also discussed. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.

Inflammatory Muscle Diseases

“…of inflammatory signaling, such as interferon-γ-receptor signaling. 56 Compelling evidence suggests that aging, abnormal proteostasis (the network controlling proteins), 20 impaired autophagy, cell stress induced by MHC class I or nitric oxide, 21,57 long-standing inflammation, and proinflammatory cytokines such as interferon-γ and interleukin-1β 57,58 may cumulatively trigger or enhance degeneration, leading to further accumulation of stressor molecules and misfolded proteins 59 (Fig. 3).…”

Sporadic Inclusion Body Myositis

“…Şu an için çeşitli patolojik olayların kademeli olarak iç içe etkileşimi sonucu hastalığın ortaya çıktığı ileri sürülmektedir. 1,9 Hastalığın tanısal kriterleri ilk kez 1995 yı-lında Calabrese ve ark. tarafından tarif edilmiştir.…”

Sporadic inclusion body myositis: A review of recent clinical advances and current approaches to diagnosis and treatment

“…Muscle fibre degeneration is characterised by eosinophilic deposits within fibres, and rimmed vacuoles, that are hypothesised to arise from nuclear degeneration, (Chou 1968, Greenberg et al, 2006. Some investigators propose the multi-protein congophilic aggregates that accumulate within aged muscle fibres initiate the inflammatory reaction, recently reviewed in (Askanas et al, 2015). These multiprotein deposits include amyloid precursor protein, amyloid-beta 42, phosphorylated tau, alpha-synuclein, myostatin, dysferlin, heat-shock protein 70…”

“…The failure of other therapies, in addition to new insights into the pathogenesis of IBM (Askanas et al, 2015), has led to new directions for the treatment of the disease. These include a current multi-centre international phase 2b/3 doubleblinded placebo-controlled randomised controlled trial of bimagrumab (clinical trials identifier NCT01925209), which is a fully humanized monoclonal antibody that blocks the activin IIA and IIB receptors that bind myostatin and other ligands, thereby allowing uninhibited muscle growth and promoting muscle hypertrophy.…”

“…It is distinguished from other inflammatory myopathies clinically by its selective pattern of muscle weakness and wasting and progressive clinical course, and pathologically by the combination of inflammatory and myodegenerative features with multi-protein aggregates in muscle tissue. Because of these unique phenotypic characteristics, and the fact that the condition responds poorly to conventional forms of immune therapy, there is still debate as to whether IBM is a primary autoimmune disease of muscle or a degenerative myopathy with an associated vigorous immune response and secondary inflammatory component , Askanas et al, 2015.…”