AMP-activated protein kinase, PKC: protein kinase C, CHC: α-cyano-4-hydroxycinnamate, MTT: 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide, OATP: organic anion transporting polypeptide, MRP: multidrug resistance-associated protein Involvement of monocarboxylate transporter 4 expression in statin-induced cytotoxicity

Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are the most widely used cholesterol-lowering agents for prevention of obstructive cardiovascular events. However, statins can cause a variety of skeletal muscle problems, and exercise leads to an increase in statin-induced muscle injury. Exercise induces the protein content of monocarboxylate transporter 4 (MCT4), which is expressed strongly in skeletal muscle and is thought to play a major role in the transport of metabolically important monocarboxylates such as L-lactate. We previously reported that α-cyano-4-hydroxycinnamate (CHC), an MCT4 inhibitor, increased the inhibition of growth of an RD cell line, as a model of in vitro skeletal muscle, induced by a statin. However, it is unclear whether statin-induced RD cell cytotoxicity is associated with MCT4 expression. We therefore examined the relationship between statin-induced cytotoxicity and MCT4 expression in RD cells. Atorvastatin reduced the number of viable cells and up-regulated MCT4, but not MCT1, mRNA level in a concentration-dependent manner. MCT4 knockdown suppressed atorvastatin, simvastatin and fluvastatin-induced reduction of cell viability and apoptosis compared with negative control-treated cells. In this study, we demonstrated that MCT4 expression is associated with statin-induced cytotoxicity.