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Research ArticleCardiology Free access | 10.1172/JCI32741
1Renal Division and Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 2National Research Institute of Fisheries Science, Yokohama, Japan. 3Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA. 4Tokyo University of Marine Science and Technology, Tokyo, Japan. 5Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA. 6Scripps Mercy Hospital, San Diego, California, USA.
Address correspondence to: Vikas P. Sukhatme or Stewart H. Lecker, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. Phone: (617) 667-2147; Fax: (617) 667-5276; E-mail: vsukhatm@bidmc.harvard.edu (V.P. Sukhatme); slecker@bidmc.harvard.edu (S.H. Lecker).
Find articles by Hanai, J. in: JCI | PubMed | Google Scholar
1Renal Division and Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 2National Research Institute of Fisheries Science, Yokohama, Japan. 3Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA. 4Tokyo University of Marine Science and Technology, Tokyo, Japan. 5Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA. 6Scripps Mercy Hospital, San Diego, California, USA.
Address correspondence to: Vikas P. Sukhatme or Stewart H. Lecker, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. Phone: (617) 667-2147; Fax: (617) 667-5276; E-mail: vsukhatm@bidmc.harvard.edu (V.P. Sukhatme); slecker@bidmc.harvard.edu (S.H. Lecker).
Find articles by Cao, P. in: JCI | PubMed | Google Scholar
1Renal Division and Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 2National Research Institute of Fisheries Science, Yokohama, Japan. 3Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA. 4Tokyo University of Marine Science and Technology, Tokyo, Japan. 5Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA. 6Scripps Mercy Hospital, San Diego, California, USA.
Address correspondence to: Vikas P. Sukhatme or Stewart H. Lecker, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. Phone: (617) 667-2147; Fax: (617) 667-5276; E-mail: vsukhatm@bidmc.harvard.edu (V.P. Sukhatme); slecker@bidmc.harvard.edu (S.H. Lecker).
Find articles by Tanksale, P. in: JCI | PubMed | Google Scholar
1Renal Division and Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 2National Research Institute of Fisheries Science, Yokohama, Japan. 3Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA. 4Tokyo University of Marine Science and Technology, Tokyo, Japan. 5Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA. 6Scripps Mercy Hospital, San Diego, California, USA.
Address correspondence to: Vikas P. Sukhatme or Stewart H. Lecker, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. Phone: (617) 667-2147; Fax: (617) 667-5276; E-mail: vsukhatm@bidmc.harvard.edu (V.P. Sukhatme); slecker@bidmc.harvard.edu (S.H. Lecker).
Find articles by Imamura, S. in: JCI | PubMed | Google Scholar
1Renal Division and Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 2National Research Institute of Fisheries Science, Yokohama, Japan. 3Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA. 4Tokyo University of Marine Science and Technology, Tokyo, Japan. 5Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA. 6Scripps Mercy Hospital, San Diego, California, USA.
Address correspondence to: Vikas P. Sukhatme or Stewart H. Lecker, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. Phone: (617) 667-2147; Fax: (617) 667-5276; E-mail: vsukhatm@bidmc.harvard.edu (V.P. Sukhatme); slecker@bidmc.harvard.edu (S.H. Lecker).
Find articles by Koshimizu, E. in: JCI | PubMed | Google Scholar
1Renal Division and Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 2National Research Institute of Fisheries Science, Yokohama, Japan. 3Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA. 4Tokyo University of Marine Science and Technology, Tokyo, Japan. 5Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA. 6Scripps Mercy Hospital, San Diego, California, USA.
Address correspondence to: Vikas P. Sukhatme or Stewart H. Lecker, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. Phone: (617) 667-2147; Fax: (617) 667-5276; E-mail: vsukhatm@bidmc.harvard.edu (V.P. Sukhatme); slecker@bidmc.harvard.edu (S.H. Lecker).
Find articles by Zhao, J. in: JCI | PubMed | Google Scholar
1Renal Division and Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 2National Research Institute of Fisheries Science, Yokohama, Japan. 3Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA. 4Tokyo University of Marine Science and Technology, Tokyo, Japan. 5Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA. 6Scripps Mercy Hospital, San Diego, California, USA.
Address correspondence to: Vikas P. Sukhatme or Stewart H. Lecker, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. Phone: (617) 667-2147; Fax: (617) 667-5276; E-mail: vsukhatm@bidmc.harvard.edu (V.P. Sukhatme); slecker@bidmc.harvard.edu (S.H. Lecker).
Find articles by Kishi, S. in: JCI | PubMed | Google Scholar
1Renal Division and Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 2National Research Institute of Fisheries Science, Yokohama, Japan. 3Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA. 4Tokyo University of Marine Science and Technology, Tokyo, Japan. 5Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA. 6Scripps Mercy Hospital, San Diego, California, USA.
Address correspondence to: Vikas P. Sukhatme or Stewart H. Lecker, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. Phone: (617) 667-2147; Fax: (617) 667-5276; E-mail: vsukhatm@bidmc.harvard.edu (V.P. Sukhatme); slecker@bidmc.harvard.edu (S.H. Lecker).
Find articles by Yamashita, M. in: JCI | PubMed | Google Scholar
1Renal Division and Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 2National Research Institute of Fisheries Science, Yokohama, Japan. 3Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA. 4Tokyo University of Marine Science and Technology, Tokyo, Japan. 5Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA. 6Scripps Mercy Hospital, San Diego, California, USA.
Address correspondence to: Vikas P. Sukhatme or Stewart H. Lecker, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. Phone: (617) 667-2147; Fax: (617) 667-5276; E-mail: vsukhatm@bidmc.harvard.edu (V.P. Sukhatme); slecker@bidmc.harvard.edu (S.H. Lecker).
Find articles by Phillips, P. in: JCI | PubMed | Google Scholar
1Renal Division and Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 2National Research Institute of Fisheries Science, Yokohama, Japan. 3Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA. 4Tokyo University of Marine Science and Technology, Tokyo, Japan. 5Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA. 6Scripps Mercy Hospital, San Diego, California, USA.
Address correspondence to: Vikas P. Sukhatme or Stewart H. Lecker, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. Phone: (617) 667-2147; Fax: (617) 667-5276; E-mail: vsukhatm@bidmc.harvard.edu (V.P. Sukhatme); slecker@bidmc.harvard.edu (S.H. Lecker).
Find articles by Sukhatme, V. in: JCI | PubMed | Google Scholar
1Renal Division and Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 2National Research Institute of Fisheries Science, Yokohama, Japan. 3Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA. 4Tokyo University of Marine Science and Technology, Tokyo, Japan. 5Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA. 6Scripps Mercy Hospital, San Diego, California, USA.
Address correspondence to: Vikas P. Sukhatme or Stewart H. Lecker, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. Phone: (617) 667-2147; Fax: (617) 667-5276; E-mail: vsukhatm@bidmc.harvard.edu (V.P. Sukhatme); slecker@bidmc.harvard.edu (S.H. Lecker).
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Published November 8, 2007 - More info
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.