Mechanism of Statin-Induced Contractile Dysfunction in Rat Cultured Skeletal Myofibers

Journal of Pharmacological Sciences

Masaya Yamamoto²  Satoshi Waguri²  Junko Kimura¹  Syoko Tanaka¹  Kazuho Sakamoto¹  Tomoyuki Ono¹  Anna Mizuno¹ 

[1] Department of Pharmacology, School of Medicine, Fukushima Medical University, Japan;Department of Anatomy and Histology, School of Medicine, Fukushima Medical University, Japan

关键词: statin;    skeletal muscle;    prenylation;    mitochondria;    autophagy;   

DOI  :  10.1254/jphs.10229FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(34)Cited-By(9)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 Ca2+ 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.

【 授权许可】

Unknown