Possible mechanisms underlying statin-induced skeletal muscle toxicity in L6 fibroblasts and in rats.
3-Hydroxy-3-methylglutaryl CoA reductase inhibitors (statins) are safe and well-tolerated therapeutic drugs. However, they occasionally induce myotoxicity such as myopathy and rhabdomyolysis. Here, we investigated the mechanism of statin-induced myotoxicity in L6 fibroblasts and in rats in vivo. L6 fibroblasts were differentiated and then treated with pravastatin, simvastatin, or fluvastatin for 72 h. Hydrophobic simvastatin and fluvastatin decreased cell viability in a dose-dependent manner via apoptosis characterized by typical nuclear fragmentation and condensation and caspase-3 activation. Both hydrophobic statins transferred RhoA localization from the cell membrane to the cytosol. These changes induced by both hydrophobic statins were completely abolished by the co-application of geranylgeranylpyrophosphate (GGPP). Y27632, a Rho-kinase inhibitor, mimicked the hydrophobic statin-induced apoptosis. Hydrophilic pravastatin did not affect the viability of the cells. Fluvastatin was continuously infused (2.08 mg/kg at an infusion rate of 0.5 mL/h) into the right internal jugular vein of the rats in vivo for 72 h. Fluvastatin infusion significantly elevated the plasma CPK level and transferred RhoA localization in the skeletal muscle from the cell membrane to the cytosol. In conclusion, RhoA dysfunction due to loss of lipid modification with GGPP is involved in the mechanisms of statin-induced skeletal muscle toxicity.
Itagaki
Mai
M
Division of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, Otaru, Japan.
Takaguri
Akira
A
Kano
Seiichiro
S
Kaneta
Shigeru
S
Ichihara
Kazuo
K
Satoh
Kumi
K
D000577:Amides / Q000494:pharmacology; D000730:Androstadienes / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D018929:Cell Culture Techniques / Q000379:methods; D002470:Cell Survival / Q000187:drug effects; D003402:Creatine Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage / Q000633:toxicity; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D007211:Indoles / Q000008:administration & dosage / Q000633:toxicity; D007262:Infusions, Intravenous; D007739:L Cells; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017035:Pravastatin / Q000008:administration & dosage / Q000633:toxicity; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D019821:Simvastatin / Q000008:administration & dosage / Q000633:toxicity; D013347:Subcellular Fractions / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D000077191:Wortmannin; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000577:Amides; D000730:Androstadienes; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D011725:Pyridines; C108830:Y 27632; D000077340:Fluvastatin; D019821:Simvastatin; D054460:rho-Associated Kinases; D003402:Creatine Kinase; D053148:Caspase 3; D020742:rhoA GTP-Binding Protein; D017035:Pravastatin; D000077191:Wortmannin