科研之友
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摘要
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 (Fly) for 72 h decreased caffeine- and ionomycm-induced contraction of myofibers and Ca(2+) release from sarcoplasmic reticulum (SR) Ca(2+)-shortening curves measured in skinned myofibers indicated that myofibrillar Ca(2+) sensitivity was unaffected by Fly A luciferin luciferase assay revealed less ATP contents in Fly-treated myofibers Among mevalonate metabolites, including geranylgeranylpyrophosphate (GGPP), farnesylpyrophosphate (FPP), coenzyme Q9, and coenzyme Q10, only GGPP prevented Fly-induced ATP reduction A selective Rab geranylgeranyltransferase (GG transferase) inhibitor, perillyl alcohol (POH), and a specific GG transferase-I inhibitor, GGTI-298, both mimicked Fly in decreasing ATP and contraction Mitochondrial membrane potential was decreased by Fly, 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 Fly
- 出版日期2010-12
