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CELLULAR AND MOLECULAR

Delineation of Myotoxicity Induced by 3-Hydroxy-3-methylglutaryl CoA Reductase Inhibitors in Human Skeletal Muscle Cells

Center of Biomolecular Medicine and Pharmacology (J.S., M.W., C.S., M.H.), Department of Anaesthesiology and Intensive Care Medicine (L.W.), Medical University of Vienna, Vienna, Austria

The 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) are widely used and well tolerated cholesterol-lowering drugs. In rare cases, side effects occur in skeletal muscle, including myositis or even rhabdomyolysis. However, the molecular mechanisms are not well understood that lead to these muscle-specific side effects. Here, we show that statins cause apoptosis in differentiated human skeletal muscle cells. The prototypical representative of statins, simvastatin, triggered sustained intracellular Ca²⁺ transients, leading to calpain activation. Intracellular chelation of Ca²⁺ completely abrogated cell death. Moreover, ryanodine also completely prevented the simvastatin-induced calpain activation. Nevertheless, an activation of the ryanodine receptor by simvastatin could not be observed. Downstream of the calpain activation simvastatin led to a translocation of Bax to mitochondria in a caspase 8-independent manner. Consecutive activation of caspase 9 and 3 execute apoptotic cell death that was in part reversed by the coadministration of mevalonic acid. Conversely, the simvastatin-induced activation of calpain was not prevented by mevalonic acid. These data delineate the signaling cascade that leads to muscle injury caused by statins. Our observations also have implications for improving the safety of this important medication and explain to some extent why physical exercise aggravates skeletal muscle side effects.

Address correspondence to: Dr. Martin Hohenegger, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Waehringerstrasse 13A, 1090 Vienna, Austria. E-mail: martin.hohenegger{at}meduniwien.ac.at

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