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

The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. Research Abstract Details 

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The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. Abstract Text:

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,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,

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.

The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. Publishing Authors By Initials

J Hanai,P Cao,P Tanksale,S Imamura,E Koshimizu,J Zhao,S Kishi,M Yamashita,PS Phillips,VP Sukhatme,SH Lecker,J Hanai,P Cao,P Tanksale,S Imamura,E Koshimizu,J Zhao,S Kishi,M Yamashita,PS Phillips,VP Sukhatme,SH Lecker,

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The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The Journal of clinical investigation

VOLUME: 117

Page Numbers: 3940-51

Journal Abbreviation: J. Clin. Invest.

ISSN: 0021-9738

DAY: 6

MONTH: Dec

YEAR: 2007

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

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LANGUAGE: eng

NlmUniqueID: 7802877

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Grant and Affiliation Information for The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity.

AFFILIATION: Renal Division, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.

Country: United States

AGENCY: United States NIDDK

GRANT: DK062307

ACRONYM: DK

MEDLINETA: J Clin Invest

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