TY - JOUR T1 - Delineation of Myotoxicity Induced by 3-Hydroxy-3-methylglutaryl CoA Reductase Inhibitors in Human Skeletal Muscle Cells JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1032 LP - 1041 DO - 10.1124/jpet.105.086462 VL - 314 IS - 3 AU - Julia Sacher AU - Lukas Weigl AU - Martin Werner AU - Csaba Szegedi AU - Martin Hohenegger Y1 - 2005/09/01 UR - http://jpet.aspetjournals.org/content/314/3/1032.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -