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

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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 meva-lonate. 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 1μM simvastatin for 2 days, IGF-1-induced activation of ERK1/2 and Akt was significantly decreased. Although mRNA expression of the IGF-1 receptor β-chain (IGF-1Rβ) did not change, protein level of the 200 kDa IGF-1Rβ precursor was significantly increased by simvastatin in a dose-dependent manner. Mevalonate did not abolish the effect of simvastatin on IGF-1Rβ expression. These results suggest that simvastatin decreases IGF-1 signaling via a regulation of the post-translational modification of IGF-1Rβ in an HMG-CoA reductase inhibition-independent manner.
2007-02-16

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

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