title: Effect of a high dose of simvastatin on muscle mitochondrial metabolism and calcium signaling in healthy volunteers.
abstract: 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 Ca(2+) homeostasis. In order to simultaneously assess these mechanisms, 24 male healthy volunteers were randomized to receive either simvastatin for 80 mg daily or placebo for 8 weeks. Blood and urine samples and a stress test were performed at baseline and at follow-up, and mitochondrial respiration and Ca(2+) spark properties were evaluated on a muscle biopsy 4 days 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±4.32 UI/L, P<0.001) and CK (-24.3±99.1±189.3 vs 48.3 UI/L, P=0.01) and a trend to an elevation of isoprostanes (193±408 vs 12±53 pmol/mmol creatinine, P=0.09) with no global change in mitochondrial respiration, lactate/pyruvate ratio or Ca(2+) sparks. However, among statin-treated subjects, those with the highest CK increase displayed a significantly lower Vmax rotenone succinate and an increase in Ca(2+) spark amplitude vs both subjects with the lowest CK increase and placebo-treated subjects. Moreover, Ca(2+) 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.
authors: CHRU Montpellier, 34295 Montpellier Cedex 5, France. f-galtier@chu-montpellier.fr
authors: F
authors: F
authors: Galtier
authors: T
authors: T
authors: Mura
authors: E
authors: E
authors: Raynaud de Mauverger
authors: H
authors: H
authors: Chevassus
authors: A
authors: A
authors: Farret
authors: J-P
authors: JP
authors: Gagnol
authors: F
authors: F
authors: Costa
authors: A
authors: A
authors: Dupuy
authors: P
authors: P
authors: Petit
authors: J P
authors: JP
authors: Cristol
authors: J
authors: J
authors: Mercier
authors: A
authors: A
authors: Lacampagne
mesh_terms: D000328:Adult; D001219:Aspartate Aminotransferases / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D003402:Creatine Kinase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005500:Follow-Up Studies; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D028421:Isoprostanes / Q000378:metabolism; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects*; D013386:Succinates / Q000378:metabolism; D055815:Young Adult
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D028421:Isoprostanes; D013386:Succinates; D012402:Rotenone; D019821:Simvastatin; D001219:Aspartate Aminotransferases; D003402:Creatine Kinase