PT  - JOURNAL ARTICLE
AU  - Julia Sacher
AU  - Lukas Weigl
AU  - Martin Werner
AU  - Csaba Szegedi
AU  - Martin Hohenegger
TI  - Delineation of Myotoxicity Induced by 3-Hydroxy-3-methylglutaryl CoA Reductase Inhibitors in Human Skeletal Muscle Cells
AID  - 10.1124/jpet.105.086462
DP  - 2005 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1032--1041
VI  - 314
IP  - 3
4099  - http://jpet.aspetjournals.org/content/314/3/1032.short
4100  - http://jpet.aspetjournals.org/content/314/3/1032.full
SO  - J Pharmacol Exp Ther2005 Sep 01; 314
AB  - 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