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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 5

Lovastatin treatment disrupts myofiber structure in zebrafish embryos.

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Lovastatin treatment disrupts myofiber structure in zebrafish embryos.
(...
(A) Zebrafish embryos (20 hpf) were treated with concentrations of lovastatin ranging from 0.025 to 5.0 μM for 12 hours. Embryos were fixed and stained with antimyosin heavy chain antibody (F59) as described in Methods. Representative somite phenotypes are shown. All panels are side views, anterior, left. Original magnification, ×200. (B) Quantitation of muscle damage. Morphological phenotypes shown in A were grouped into 3 classes: class 1 changes include bowing, gap formation, and blocked/disrupted fibers; class 2 changes include irregular fibers and diffuse appearance; class 3 changes are typified by irregular somite boundaries. Percentage of embryos displaying specific class defects as a function of lovastatin concentration are shown. Numbers of embryos quantitated are 151, 178, 163, 185, 189, and 180 for the lovastatin concentrations of 0, 0.025, 0.05, 0.5, 1.0, and 5 μM, respectively.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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