Inclusion-body myositis

Abstract

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, which provide a better understanding of the steps in the pathogenetic cascade. We suggest that s-IBM is primarily a myodegenerative disease. Intriguing are the phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer disease, the most common neurodegenerative disease of older persons. In s-IBM, abnormal accumulation of the amyloid-beta (Abeta) precursor protein and its proteolytic fragment, Abeta, associated with the aging intracellular milieu of the muscle fiber, appear to be key upstream pathogenic events. We propose that the identified abnormal accumulation, misfolding, and aggregation of proteins, perhaps provoked by the aging milieu and aggravated by the oxidative stress, lead to the s-IBM-specific vacuolar degeneration and atrophy of muscle fibers.

AβPP-overexpression and proteasome inhibition increase αB-crystallin in cultured human muscle: Relevance to inclusion-body myositis

“…Light-microscopic features of s-IBM muscle biopsies include vacuolated muscle fibers, accumulation of intra-muscle-fiber multiprotein aggregates, and various degrees of lymphocytic inflammation [2]. Two hypotheses regarding the key pathogenic mechanisms involved in s-IBM are: a) an amyloid-β-related myodegenerative process, and b) an immune dysregulation [reviewed in 2,3].…”

“…Light-microscopic features of s-IBM muscle biopsies include vacuolated muscle fibers, accumulation of intra-muscle-fiber multiprotein aggregates, and various degrees of lymphocytic inflammation [2]. Two hypotheses regarding the key pathogenic mechanisms involved in s-IBM are: a) an amyloid-β-related myodegenerative process, and b) an immune dysregulation [reviewed in 2,3]. Intriguingly, the s-IBM muscle-fiber phenotype has similarity to the Alzheimer-disease brain, such as accumulations of multiproteinaggregates containing proteins in congophilic alternate conformation, including amyloid-β (Aβ) [2].Reduction of 26S proteasome activity and features of aggresomes were recently demonstrated within s-IBM muscle fibers, and these were modeled in cultured human muscle by experimental overexpression of AβPP [4].…”

“…Two hypotheses regarding the key pathogenic mechanisms involved in s-IBM are: a) an amyloid-β-related myodegenerative process, and b) an immune dysregulation [reviewed in 2,3]. Intriguingly, the s-IBM muscle-fiber phenotype has similarity to the Alzheimer-disease brain, such as accumulations of multiproteinaggregates containing proteins in congophilic alternate conformation, including amyloid-β (Aβ) [2].Reduction of 26S proteasome activity and features of aggresomes were recently demonstrated within s-IBM muscle fibers, and these were modeled in cultured human muscle by experimental overexpression of AβPP [4]. Abnormal increase of AβPP/Aβ appears to be an early upstream step in the IBM pathogenesis because a) AβPP/Aβ accumulation appears to precede other detected abnormalities ins-IBM muscle fibers [2], and b) several aspects of the IBM phenotype were produced in cultured normal human muscle fibers (CHMFs) after experimental long-term overexpression of AβPP [5][6][7].…”

“…In other cells, Aβ oligomers are highly toxic, producing more cellular damage than fully fibrillar Aβ [12][13][14][15][16]. We have postulated that in s-IBM muscle fibers, Aβ toxicity may not be related to Aβ in the insoluble aggregates, but rather to a toxicity of its soluble oligomers and protofibrils [2].…”

Immune and myodegenerative pathomechanisms in inclusion body myositis

“…This is especially intriguing in light of the fact that IBM is refractory to common immunotherapies. Frequently, this lack of efficacy in targeting the immune system has given rise to the assumption that IBM might be primarily a myodegenerative disorder and the inflammatory component little more than an etiopathogenetic epiphenomenon 7, 102, 103. Although further investigation into the matter is needed, this recent study offers a different narrative, which would have substantial implications toward both the diagnosis and therapy of IBM 104…”