NDLI: The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity

Content Provider	PubMed Central
Author	Hanai, Jun-ichi Cao, Peirang Preeti, Tanksale Imamura, Shintaro Koshimizu, Eriko Zhao, Jinghui Kishi, Shuji Yamashita, Michiaki Phillips, Paul S. Sukhatme, Vikas P. Lecker, Stewart H.
Copyright Year	2007
Abstract	Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, and are widely used to treat hypercholesterolemia. These drugs can lead to a number of side effects in muscle, including muscle fiber breakdown; however, the mechanisms of muscle injury by statins are poorly understood. We report that lovastatin induced the expression of atrogin-1, a key gene involved in skeletal muscle atrophy, in humans with statin myopathy, in zebrafish embryos, and in vitro in murine skeletal muscle cells. In cultured mouse myotubes, atrogin-1 induction following lovastatin treatment was accompanied by distinct morphological changes, largely absent in atrogin-1 null cells. In zebrafish embryos, lovastatin promoted muscle fiber damage, an effect that was closely mimicked by knockdown of zebrafish HMG-CoA reductase. Moreover, atrogin-1 knockdown in zebrafish embryos prevented lovastatin-induced muscle injury. Finally, overexpression of PGC-1α, a transcriptional coactivator that induces mitochondrial biogenesis and protects against the development of muscle atrophy, dramatically prevented lovastatin-induced muscle damage and abrogated atrogin-1 induction both in fish and in cultured mouse myotubes. Collectively, our human, animal, and in vitro findings shed light on the molecular mechanism of statin-induced myopathy and suggest that atrogin-1 may be a critical mediator of the muscle damage induced by statins.
Related Links	http://dx.doi.org/10.1172/JCI32741
Starting Page	3940
File Format	PDF
ISSN	00219738
Journal	The Journal of Clinical Investigation
Issue Number	12
Volume Number	117
Language	English
Publisher	American Society for Clinical Investigation
Publisher Date	2007-12-03
Access Restriction	Open
Rights Holder	American Society for Clinical Investigation
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Medicine

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