ZFIN ID: ZDB-PUB-071118-40
The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity
Hanai, J.I., Cao, P., Tanksale, P., Imamura, S., Koshimizu, E., Zhao, J., Kishi, S., Yamashita, M., Phillips, P.S., Sukhatme, V.P., and Lecker, S.H.
Date: 2007
Source: J. Clin. Invest. 117(12): 3940-3951 (Journal)
Registered Authors: Kishi, Shuji, Sukhatme, Vikas, Yamashita, Michiaki
Keywords: none
MeSH Terms:
  • 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*
PubMed: 17992259 Full text @ J. Clin. Invest.
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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-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.
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