Résumé
Statin use may be limited by muscle side effects. Although incompletely understood to date, their pathophysiology may involve oxidative stress and impairments of mitochondrial function and of muscle Ca2+ homeostasis. In order to simultaneously assess these mechanisms, 24 male healthy volunteers were randomized to receive either simvastatin for 80mg daily or placebo for 8weeks. Blood and urine samples and a stress test were performed at baseline and at follow-up, and mitochondrial respiration and Ca2+ spark properties were evaluated on a muscle biopsy 4days before the second stress test. Simvastatin-treated subjects were separated according to their median creatine kinase (CK) increase. Simvastatin treatment induced a significant elevation of aspartate amino transferase (3.38±5.68 vs −1.15±4.32UI/L, P<0.001) and CK (−24.3±99.1±189.3vs 48.3UI/L, P=0.01) and a trend to an elevation of isoprostanes (193±408 vs12±53pmol/mmol creatinine, P=0.09) with no global change in mitochondrial respiration, lactate/pyruvate ratio or Ca2+ sparks. However, among statin-treated subjects, those with the highest CK increase displayed a significantly lower Vmax rotenone succinate and an increase in Ca2+ spark amplitude vs both subjects with the lowest CK increase and placebo-treated subjects. Moreover, Ca2+ spark amplitude was positively correlated with treatment-induced CK increase in the whole group (r=0.71, P=0.0045). In conclusion, this study further supports that statin induced muscular toxicity may be related to alterations in mitochondrial respiration and muscle calcium homeostasis independently of underlying disease or concomitant medication.
► Statin use may be limited by side effects, particularly myopathy. ► Statins might impair mitochondrial function and muscle Ca2+ signaling in muscle. ► This was tested among healthy volunteers receiving simvastatin 80mg daily for 8weeks. ► CK increase was associated with alterations in Ca2+ sparks and mitochondrial function.