Mechanism of statin-induced contractile dysfunction in rat cultured skeletal myofibers

An adverse effect of statins,cholesterol-lowering drugs,is contractile dysfunction of skeletal muscles. we investigated the mechanism underlying this effect in cultured myofibers isolated from rats. fluvastatin (flv) for 72 h decreased caffeine- and ionomycin-induced contraction of myofibers and ca 2+ release from sarcoplasmic reticulum (sr). ca2+- shortening curves measured in skinned myofibers indicated that myofibrillar ca2+ 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 ca2+ 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. ©2010 the japanese pharmacological society.