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Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase occasionally cause myopathy characterized by weakness, pain, and elevated serum creatine phosphokinase (CK). In this study, we investigated the effects of simvastatin, an HMG-CoA reductase inhibitor, on the viability and insulin-like growth factor-1 (IGF-1) signaling in differentiating C2C12 mouse myoblast cells. Simvastatin decreased cell viability and CK activity, a marker of myogenesis, in differentiating cells in a dose-dependent manner. Although the simvastatin-induced decrease in viability in proliferating and differentiated cells was completely abolished by mevalonate or geranylgeranyl-pyrophosphate, the inhibitory effects of simvastatin in differentiating cells were not abolished by mevalonate or isoprenoid derivatives of mevalonate. Moreover, the sensitivity of differentiating cells to simvastatin regarding cell viability was about 7 times higher than that of proliferating cells. After induction of differentiation in the presence of 1 microM simvastatin for 2 days, IGF-1-induced activation of ERK1/2 and Akt was significantly decreased. Although mRNA expression of the IGF-1 receptor beta-chain (IGF-1R beta) did not change, protein level of the 200 kDa IGF-1Rbeta precursor was significantly increased by simvastatin in a dose-dependent manner. Mevalonate did not abolish the effect of simvastatin on IGF-1Rbeta expression. These results suggest that simvastatin decreases IGF-1 signaling via a regulation of the post-translational modification of IGF-1Rbeta in an HMG-CoA reductase inhibition-independent manner.

journal of toxicological sciences

SIMVASTATIN REDUCES INSULIN-LIKE GROWTH FACTOR-1 SIGNALING IN DIFFERENTIATING C2C12 MOUSE MYOBLAST CELLS IN AN HMG-CoA REDUCTASE INHIBITION-INDEPENDENT MANNER