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The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity
Jun-ichi Hanai, … , Vikas P. Sukhatme, Stewart H. Lecker
Jun-ichi Hanai, … , Vikas P. Sukhatme, Stewart H. Lecker
Published November 8, 2007
Citation Information: J Clin Invest. 2007;117(12):3940-3951. https://doi.org/10.1172/JCI32741.
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Research Article Cardiology

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

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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.

Authors

Jun-ichi Hanai, Peirang Cao, Preeti Tanksale, Shintaro Imamura, Eriko Koshimizu, Jinghui Zhao, Shuji Kishi, Michiaki Yamashita, Paul S. Phillips, Vikas P. Sukhatme, Stewart H. Lecker

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Figure 10

PGC-1α reduces lovastatin-induced atrogin-1 expression and muscle damage in C2C12 myotubes.

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PGC-1α reduces lovastatin-induced atrogin-1 expression and muscle damage...
(A) C2C12 myotubes infected for 68 hours with control adenovirus or adenovirus bearing PGC-1α were visualized by GFP. 5 μM lovastatin or vehicle was present for the final 48 hours. Original magnification, ×100. (B) Western blot for atrogin-1 in control-infected or PGC-1α–infected C2C12 myotube cultures in the presence of increasing concentrations of lovastatin (0–5 μM) for 48 hours. Expression of mitochondrial electron transport proteins cytochrome oxidase IV and cytochrome c were monitored by immunoblot. Note that lovastatin-induced atrogin-1 expression in the presence of PGC-1α is suppressed.

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