Sporadic inclusion-body myositis: Conformational multifactorial ageing-related degenerative muscle disease associated with proteasomal and lysosomal inhibition, endoplasmic reticulum stress, and accumulation of amyloid-β42 oligomers and phosphorylated tau

Askanas, Valerie; Engel, W. King

doi:10.1016/j.lpm.2010.11.024

Cited by 70 publications

(73 citation statements)

References 150 publications

(262 reference statements)

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“…Amyloid diseases are proteotoxic disorders, which can affect the nervous system, like in the case of Alzheimer’s (AD), the most common form of dementia 1 , but also other organs, as exemplified by amyloidosis-associated kidney disease 2 and inclusion body myositis (IBM) 3 . To date, no efficient therapy is available for AD 4 , a disease with a strong component of amyloid-β (Aβ) aggregation 1 .…”

mentioning

confidence: 99%

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

Sorrentino

Romani

Mouchiroud

et al. 2017

Nature

532

424

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Alzheimer’s disease (AD) is a common and devastating disease characterized by the aggregation of amyloid-β peptide (Aβ), yet we know relatively little about the underlying molecular mechanisms or how to treat AD patients. Here, we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in Aβ proteotoxic diseases in human, mouse and C. elegans, and which involves the UPRmt and mitophagy pathways. Using the worm model of Aβ proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed the induction of this mitochondrial stress response as key to maintain mitochondrial proteostasis and health. Importantly, boosting mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms, and in AD transgenic mice. Our data support the relevance of enhancing mitochondrial proteostasis to delay Aβ proteotoxic diseases, such as AD.

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confidence: 99%

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

Sorrentino

Romani

Mouchiroud

et al. 2017

Nature

532

424

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“…183, 184, 185 It is therefore considered to be more cytotoxic and the predominant isoform to be accumulated as oligomers in IBM muscle 186, 187. Congophilic A β is detected in up to 70% of IBM muscle fibers and mostly found in nonvacuolated areas 188. A β peptides are generated via the sequential cleavage of the transmembrane glycoprotein APP by the protease β ‐site of the APP cleaving enzyme 1 (BACE1) and the γ ‐secretase complex 189, 190, 191.…”

Section: Degenerative Pathomechanisms In Ibmmentioning

confidence: 99%

Immune and myodegenerative pathomechanisms in inclusion body myositis

Keller

Schmidt

Lünemann

2017

Ann Clin Transl Neurol

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Inclusion Body Myositis (IBM) is a relatively common acquired inflammatory myopathy in patients above 50 years of age. Pathological hallmarks of IBM are intramyofiber protein inclusions and endomysial inflammation, indicating that both myodegenerative and inflammatory mechanisms contribute to its pathogenesis. Impaired protein degradation by the autophagic machinery, which regulates innate and adaptive immune responses, in skeletal muscle fibers has recently been identified as a potential key pathomechanism in IBM. Immunotherapies, which are successfully used for treating other inflammatory myopathies lack efficacy in IBM and so far no effective treatment is available. Thus, a better understanding of the mechanistic pathways underlying progressive muscle weakness and atrophy in IBM is crucial in identifying novel promising targets for therapeutic intervention. Here, we discuss recent insights into the pathomechanistic network of mutually dependent inflammatory and degenerative events during IBM.

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“…The remarkable pathologic features of sIBM present as vacuolated muscle fibers, accumulations of abnormal proteins that are similar to the pathogens of Alzheimer's and Parkinson's diseases in the brain [4][5][6][7]. Although the exact mechanisms of sIBM remain unclear, strong evidence suggests that the primary cause could be endoplasmic reticulum (ER) stress, unfolded protein response, lysosomal inhibition, and dysfunction of protein degradation systems including autophagy [8][9][10].…”

Section: Introduction *mentioning

confidence: 99%

Effects of long-term resistance exercise training on autophagy in rat skeletal muscle of chloroquine-induced sporadic inclusion body myositis

Kwon¹,

Lee²,

Lima³

et al. 2015

J. Exerc. Nutr, Biochem.

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Insu Kwon, Youngil Lee, Ludmila M. Cosio-Lima, Joon-Yong Cho and Dong-Chul Yeom. Effects of long-term resistance exercise training on autophagy in rat skeletal muscle of chloroquine-induced sporadic inclusion body myositis. JENB., Vol. 19, No. 3, pp.225-234, 2015 [Purpose] We examined whether resistance exercise training restores impaired autophagy functions caused by Chloroquine (CQ)-induced Sporadic Inclusion Body Myositis (sIBM) in rat skeletal muscle.[Methods] Male wistar rats were randomly assigned into three groups: Sham (n = 6), CQ (n = 6), and CQ + Exercise (CE, n = 6). To create a rat model of sIBM, rats in the CQ and CE group were intraperitoneally injected with CQ 5 days a week for 16 weeks. Rats in the CE group performed resistance exercise training 3 times a week for 8 weeks in conjunction with CQ starting from week 9 to week 16. During the training period, maximal carrying load, body weight, muscle weight, and relative muscle weight were measured. Autophagy responses were examined by measuring specific markers.[Results] While maximal carrying capacity for resistance exercise training was dramatically increased in the CE group, no significant changes occurred in the skeletal muscle weight as well as in the relative muscle weight of CE compared to the other groups. CQ treatment caused significant increases in the levels of Beclin-1 and p62, and decreases in the levels of LAMP-2 proteins. Interestingly, no significant differences in the LC3-II/I ratio or the LC3-II protein levels were observed. Although CQ-treatment groups suppressed the levels of the potent autophagy inducer, BNIP3, p62 levels were decreased in only the CE group.[Conclusion] Our findings demonstrate that sIBM induced by CQ treatment results in muscle degeneration via impaired autophagy and that resistance exercise training improves movable loading activity. Finally, regular exercise training may provide protection against sIBM by enhancing the autophagy flux through p62 protein.

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Sporadic inclusion-body myositis: Conformational multifactorial ageing-related degenerative muscle disease associated with proteasomal and lysosomal inhibition, endoplasmic reticulum stress, and accumulation of amyloid-β42 oligomers and phosphorylated tau

Cited by 70 publications

References 150 publications

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

Immune and myodegenerative pathomechanisms in inclusion body myositis

Effects of long-term resistance exercise training on autophagy in rat skeletal muscle of chloroquine-induced sporadic inclusion body myositis

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