Simvastatin represses eukaryotic initiation factor 2B (eIF2B) expression and activity in C2C12 myoblasts with concomitant reductions in protein synthesis

Abstract

Statins are a widely prescribed class of cholesterol lowering drugs whose use is frequently associated with muscle related ailments. A number of mechanisms have been implicated in statin‐induced myotoxicity including alterations in both protein synthesis and protein degradation. The objective of the current study was to explore the mechanism(s) contributing to the statin‐induced reduction in protein synthesis in a muscle‐derived cell line. C2C12 myoblasts were treated with 10 μM simvastatin or vehicle alone for 24 h in low serum conditions. Cells exposed to simvastatin exhibited reduced rates of protein synthesis as evidenced by [35S] methionine incorporation into protein. The reduction in protein synthesis occurred with a concomitant repression of the guanine nucleotide exchange activity of eIF2B, a regulated and rate‐controlling enzyme known to affect global rates of protein synthesis. Simvastatin treatment also resulted in reduced expression of several subunits of the eIF2B heteropentameric complex at the protein level without alterations in expression of the mRNAs encoding the respective subunits. Finally, increased phosphorylation of the catalytic epsilon subunit at Ser535 was observed ‐ an event consistent with reduced eIF2B activity. These results suggest that repression of eIF2B expression and activity may contribute, at least in part, to the statin‐induced reduction in protein synthesis.Supported by grant DK15658