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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 7

Atrogin-1 knockdown reduces lovastatin-induced muscle damage in zebrafish embryos.

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Atrogin-1 knockdown reduces lovastatin-induced muscle damage in zebrafis...
Zebrafish embryos (20 hpf) were treated with lovastatin (0.5 μM) for 12 hours. Atrogin-1 mRNA was measured by PCR (A) and zebrafish atrogin-1 protein by Western blotting (B). Five embryos were used for each analysis. (C) Western blot probed for atrogin-1 using protein lysates (20 μg/lane) derived from control zebrafish embryos, zebrafish embryos injected with morpholino against atrogin-1, adult zebrafish muscle, adult zebrafish kidney, and adult zebrafish liver. Five embryos were used for each analysis. (D) Myosin heavy-chain staining of representative control and atrogin-1 knockdown embryos. Note that suppression of atrogin-1 protects from statin-induced damage. Original magnification, ×200. (E) Quantitation of muscle damage. Classes of morphological phenotypes are as described in Figure 5 legend. Note that at each lovastatin concentration, the injection of morpholinos against atrogin-1 almost completely abolishes the damage caused by lovastatin. Numbers of embryos quantitated are 235, 182, 197, and 202 for the controls and 220, 204, 240, and 215 for the atrogin-1 knockdowns at lovastatin concentrations of 0, 0.05, 0.5, and 1.0 μM, respectively. (F) Muscle fiber diameter was measured following myosin heavy-chain staining as described in Methods. At least 500 fibers were measured at each lovastatin concentration. Results were graphed as the ratio of mean experimental fiber size ± SEM/mean control fiber size ± SEM. Control fiber size: 7.60 ± 0.19 μM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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