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Statin-induced muscle damage and atrogin-1 induction is the result of a geranylgeranylation defect

Peirang Cao^*, Jun-ichi Hanai^*,, Preeti Tanksale^*, Shintaro Imamura, Vikas P. Sukhatme^*, and Stewart H. Lecker^*,1

^* Renal Division and

Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; and

Food Technology and Biochemistry Division, National Research Institute of Fisheries Science, Yokohama, Japan

¹ Correspondence: Renal Division/DA517, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston MA 02215, USA. E-mail: slecker{at}bidmc.harvard.edu

Statins are widely used to treat hypercholesterolemia but can lead to a number of side effects in muscle, including rhabdomyolysis. Our recent findings implicated the induction of atrogin-1, a gene required for the development of muscle atrophy, in statin-induced muscle damage. Since statins inhibit many biochemical reactions besides cholesterol synthesis, we sought to define the statin-inhibited pathways responsible for atrogin-1 expression and muscle damage. We report here that lovastatin-induced atrogin-1 expression and muscle damage in cultured mouse myotubes and zebrafish can be prevented in the presence of geranylgeranol but not farnesol. Further, inhibitors of the transfer of geranylgeranyl isoprene units to protein targets cause statin muscle damage and atrogin-1 induction in cultured cells and in fish. These findings support the concept that dysfunction of small GTP-binding proteins lead to statin-induced muscle damage since these molecules require modification by geranylgeranyl moieties for their cellular localization and activity. Collectively, our animal and in vitro findings shed light on the molecular mechanism of statin-induced myopathy and suggest that atrogin-1 may be regulated by novel signaling pathways.—Cao, P., Hanai, J., Tanksale, P., Imamura, S., Sukhatme, V. P., Lecker, S. H. Statin-induced muscle damage and atrogin-1 induction is the result of a geranylgeranylation defect.

Key Words: atrophy • farnesylation

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