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). 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.
Department of Pharmacology, School of Medicine, Fukushima Medical University, Fukushima 960-1295, Japan.
Syoko
S
Tanaka
Kazuho
K
Sakamoto
Masaya
M
Yamamoto
Anna
A
Mizuno
Tomoyuki
T
Ono
Satoshi
S
Waguri
Junko
J
Kimura
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005229:Fatty Acids, Monounsaturated / Q000009:adverse effects*; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D007211:Indoles / Q000009:adverse effects*; D008297:Male; D008931:Mitochondria, Muscle / Q000473:pathology; D009119:Muscle Contraction / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000166:cytology*; D009210:Myofibrils / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D011106:Polyisoprenyl Phosphates; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D020761:rab1 GTP-Binding Proteins
D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D011106:Polyisoprenyl Phosphates; D000077340:Fluvastatin; D000255:Adenosine Triphosphate; D020761:rab1 GTP-Binding Proteins; C002963:geranylgeranyl pyrophosphate; D002118:Calcium