Simvastatin induces impairment in skeletal muscle while heart is protected

Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are widely used to reduce plasma cholesterol concentration. However, statins are also known to induce various forms of muscular toxicity. We have previously shown that acute application of sim- vastatin on human skeletal muscle samples induced a cascade of cellular events originating from mitochondria and resulting in a global alteration of Ca 2+ homeostasis. The present study was designed to further define the origin of the mitochondria impairment and to understand the apparent lack of deleterious effect on the heart. Using fluorescence imaging analysis and oxygraphy on human and rat skinned skeletal muscle samples, we show that the simvastatin-induced mitochondria impairment results from inhibition of the com- plex I of respiratory chain. Similar simvastatin-induced mitochondria impairment and alteration of Ca 2+ homeostasis occur in perme- abilized but not in intact ventricular rat cardiomyocytes. In intact rat skeletal muscle fibers from the flexor digitorum brevis muscle, the simvastatin-induced alteration of Ca 2+ homeostasis is abolished when monocarboxylate transporter (MCT4) is inhibited. The impair- ment of complex I by simvastatin might be the primary step of its cellular deleterious effects leading to muscle fiber death. This mech- anism is seen specifically in skeletal muscles. This specificity should be in part attributed to a preferential uptake of statins by MCT4 that is not expressed in cardiomyocytes. � 2005 Elsevier Inc. All rights reserved.