Mechanism of HMG-CoA Reductase Inhibitor-Induced Contractile Dysfunction in Rat Cultured Skeletal Muscle

Abstract

HMG-CoA reductase inhibitors (statins), cholesterol-lowering drugs, cause contractile dysfunction of skeletal muscles as an adverse effect. We investigated the mechanism underlying this effect in cultured myofibers isolated from rats. Fluvastatin (Flv) for 3 days decreased caffeine- and ionomycin-induced contraction of myofibers and Ca(2+) release from sarcoplasmic reticulum. Ca(2+)-shortening curves measured in skinned myofibers indicated that myofibrillar Ca(2+) sensitivity was unaffected by Flv. A luciferin-luciferase assay revealed less ATP contents in Flv-treated myofibers. Among mevalonate metabolites, including geranylgeranylpyrophosphate (GGPP), farnesylpyrophosphate (FPP), coenzyme Q9, and coenzyme Q10, only GGPP prevented Flv-induced ATP reduction. A selective Rab geranylgeranyltransferase (GG transferase) inhibitor, perillyl alcohol (POH), and a specific GG transferase-I inhibitor, GGTI-298, both mimicked Flv in decreasing ATP and contraction. Mitochondrial membrane potential was decreased by Flv, and this effect was rescued by GGPP and mimicked by POH and GGTI-298. An endoplasmic reticulum (ER)-to-Golgi traffic inhibitor, brefeldin A, and a Rho inhibitor, membrane permeable exoenzyme C3 transferase, both decreased ATP. We conclude that statin-induced contractile dysfunction is due to reduced Ca(2+) release from SR and reduced ATP levels in myofibers with damaged mitochondria. GGPP depletion and subsequent inactivation of Rab1, possibly along with Rho, may underlie the mitochondrial damage by Flv.