Résumé :
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Communication n° 570. Statin drugs represent the major improvement in the treatment of hypercholesterolemia. Beneficial effects of these drugs are numerous. Nevertheless, statins present side effects on muscle function characterized by myalgia, cramps, fatigue and exercise intolerance which prove to be very invalidating. Among treated patients, it has been estimated that 2 to 7% are affected by these effects. This incidence seems however underestimated. In the present study, we evaluated by laser scanning fluorescence microscopy and by oxygraphy, the effects of acute applications of simvastatin on mitochondrial function in human skeletal muscle fibres dissected from muscle biopsies taken from the vastus lateralis muscle of healthy individuals. Simvastatin induced a dose-dependent inhibition of mitochondrial respiration with both palmitoyl-carnitine and pyruvate as the initial substrate. Analysis of respiratory chain complexes shows primarily an inhibition of complex I. Consequently, this depolarized the inner mitochondrial membrane resulting in the permeability transition pore (PTP) opening and Ca2+ efflux from both PTP and Na+/Ca2+ exchanger. As a consequence, this cascade of events induced a major alteration of muscular Ca2+ homeostasis resulting in a Ca-dependent proteolytic process by activation of calpains. Taken together, these effects may largely contribute to the statin-induced myotoxicity.
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