2016
DOI: 10.1126/scitranslmed.aad4583
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Targeting protein homeostasis in sporadic inclusion body myositis

Abstract: Sporadic inclusion body myositis (sIBM) is the commonest severe myopathy in patients over age 50. Previous therapeutic trials have targeted the inflammatory features of sIBM, but all have failed. Since protein dyshomeostasis may also play a role in sIBM, we tested the effects of targeting this feature of the disease. Using rat myoblast cultures, we found that up-regulation of the heat shock response with Arimoclomol reduced key pathological markers of sIBM in vitro. Furthermore, in mutant valosin-containing pr… Show more

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Cited by 111 publications
(106 citation statements)
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“…Protein homeostasis or “proteostasis” likely plays an important role in sIBM pathogenesis and is thus a tractable therapeutic target. 30 Our study reveals that several new chaperone components may be relevant and refine therapeutic strategies. Small heat shock proteins and other molecular chaperones are of particular interest since they facilitate proper protein folding and degradation of misfolded and aggregated proteins.…”
Section: Discussionmentioning
confidence: 85%
“…Protein homeostasis or “proteostasis” likely plays an important role in sIBM pathogenesis and is thus a tractable therapeutic target. 30 Our study reveals that several new chaperone components may be relevant and refine therapeutic strategies. Small heat shock proteins and other molecular chaperones are of particular interest since they facilitate proper protein folding and degradation of misfolded and aggregated proteins.…”
Section: Discussionmentioning
confidence: 85%
“…In this study [60] Arimoclomol was found to ameliorate s-IBM-like pathology both in vitro , in primary rodent muscle cells induced to develop either the degenerative or the inflammatory features of s-IBM, as well as in vivo , in mice over-expressing mutant VCP (p97 in mouse) which have a phenotypic spectrum that includes inclusion body myopathy. In addition, in a randomized, double blind, placebo-controlled, proof-of-concept trial of Arimoclomol for the treatment of s-IBM in human patients, Arimoclomol was found to be safe and well tolerated.…”
Section: Session 4 – Vcp Function and Dysfunction: Pre-clinical Stmentioning
confidence: 99%
“…The most prominent mechanistic hypothesis for IBM myodegeneration implicates abnormal proteostasis, as many proteins associated with neurodegenerative disease (e.g. TDP-43, p62, amyloid-β, and αβ-crystallin) are reported to aggregate in the cytosol of IBM-affected myofibers [2, 12, 23]. Ca 2+ dysregulation contributes to abnormal proteostasis by promoting mitochondrial reactive oxygen species (ROS) production and perturbing protein folding in the endoplasmic reticulum (ER) lumen [18, 31].…”
Section: Introductionmentioning
confidence: 99%