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

• Published in: Journal of Pharmacological Sciences 2010, Vol.114(4), pp.454-463
• Main Authors: Tanaka, Syoko, Sakamoto, Kazuho, Yamamoto, Masaya, Mizuno, Anna, Ono, Tomoyuki, Waguri, Satoshi, Kimura, Junko
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Animals; Autophagy; Calcium - metabolism; Cells, Cultured; Fatty Acids, Monounsaturated - adverse effects; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects; Indoles - adverse effects; Male; mitochondria; Mitochondria, Muscle - pathology; Muscle Contraction - drug effects; Muscle, Skeletal - cytology; Myofibrils - drug effects; Myofibrils - metabolism; Myofibrils - ultrastructure; Polyisoprenyl Phosphates; prenylation; rab1 GTP-Binding Proteins; Rats; Rats, Wistar; Sarcoplasmic Reticulum - metabolism; skeletal muscle; statin
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.10229FP

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.