C2C12 myoblasts are more sensitive to the toxic effects of simvastatin than myotubes and show impaired proliferation and myotube formation

Statins reduce cardiovascular complications in patients with high LDL-cholesterol but are associated with myopathy. We compared the toxicity of simvastatin of C2C12 myoblasts and myotubes. Since myoblasts can proliferate and fuse to myotubes, myoblasts can be considered as satellite cells and myotubes as mature muscle fibers. 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 h after addition of simvastatin to myotubes, prevention in myoblasts required simultaneous addition. Mevalonate and geranylgeraniol prevented simvastatin-associated cytotoxicity in both myoblasts and myotubes. Simvastatin impaired the phosphorylation of the insulin receptor (IR beta), 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 cytochrome 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 may represent a new mechanism of statin myotoxicity.

Automated summary

Simvastatin has different toxic effects on myoblasts and myotubes, with a stronger impact on myoblasts. It impairs myoblast proliferation and myotube formation, potentially representing a new mechanism of statin myotoxicity.