PMID:17992259

Citation	Hanai, J, Cao, P, Tanksale, P, Imamura, S, Koshimizu, E, Zhao, J, Kishi, S, Yamashita, M, Phillips, PS, Sukhatme, VP and Lecker, SH (2007) The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. J. Clin. Invest. 117:3940-51
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-1alpha, 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.
Links	PubMed PMC2066198 Online version:10.1172/JCI32741
Keywords	Animals; Cholesterol/metabolism; Heat-Shock Proteins/genetics; Heat-Shock Proteins/metabolism; Humans; Hydroxymethylglutaryl CoA Reductases/genetics; Hydroxymethylglutaryl CoA Reductases/metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects; Lovastatin/adverse effects; Mice; Muscle Fibers, Skeletal/enzymology; Muscle Fibers, Skeletal/pathology; Muscle Proteins/genetics; Muscle Proteins/metabolism; Muscle, Skeletal/enzymology; Muscle, Skeletal/pathology; Muscular Disorders, Atrophic/chemically induced; Muscular Disorders, Atrophic/enzymology; Muscular Disorders, Atrophic/genetics; Muscular Disorders, Atrophic/pathology; SKP Cullin F-Box Protein Ligases/genetics; SKP Cullin F-Box Protein Ligases/metabolism; Trans-Activators/genetics; Trans-Activators/metabolism; Transcription Factors/genetics; Transcription Factors/metabolism; Zebrafish/genetics; Zebrafish/metabolism; Zebrafish Proteins/genetics; Zebrafish Proteins/metabolism
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