Simvastatin impairs myoblast proliferation and myotube formation of C2C12 myoblasts and in mouse skeletal muscle

Abstract Statins reduce cardiovascular complications in patients with high LDL-cholesterol but are associated with myopathy. We investigated the possibility that statins impair skeletal muscle regeneration by assessing simvastatin toxicity on C2C12 myoblasts and myotubes and mouse skeletal muscle. Simvastatin increased plasma membrane permeability and decreased the cellular ATP content in both myoblasts and myotubes, but with a stronger effect on myoblasts. While insulin prevented cytotoxicity up to 8 hours after addition of simvastatin to myotubes, prevention in myoblasts required simultaneous addition. Mevalonate and geranylgeraniol also prevented simvastatin-associated cytotoxicity on myoblasts and myotubes. Simvastatin impaired the phosphorylation of the insulin receptor (IR β), Akt ser473 and S6rp, and increased phosphorylation of AMPK thr172 in both myotubes and myoblasts, which was prevented by insulin and mevalonate. Simvastatin impaired oxygen consumption and increased superoxide production by myoblasts and myotubes and induced apoptosis via cytochromc c release. In addition, simvastatin impaired proliferation and fusion of myoblasts to myotubes by inhibiting the expression of the nuclear transcription factor MyoD and of the metalloprotease ADAM-12. Decreased expression of the proliferation factor Ki-67 and of ADAM-12 were also observed in gastrocnemius of mice treated with simvastatin. In conclusion, myoblasts were more susceptible to the toxic effects of simvastatin and simvastatin impaired myoblast proliferation and myotube formation. Impaired muscle regeneration represents a new mechanism of statin myotoxicity and may be important in statin-associated myopathy.