Insulin-like growth factor-mediated muscle cell survival: Central roles for Akt and cyclin-dependent kinase inhibitor p21

Polypeptide growth factors activate specific transmembrane receptors, leadi ng to the induction of multiple intracellular signal transduction pathways which control cell function and fate. Recent studies have shown that growth factors promote cell survival by stimulating the serine-threonine protein kinase Akt, which appears to function primarily as an antiapoptotic agent b y inactivating death-promoting molecules. We previously established C2 musc le cell lines lacking endogenous expression of insulin-like growth factor I I (IGF-II). These cells underwent apoptotic death in low-serum differentiat ion medium but could be maintained as viable myoblasts by IGF analogues tha t activated the IGF-I receptor or by unrelated growth factors such as plate let-derived growth factor BE (PDGF-BB), Here we show that IGF-I promotes mu scle cell survival through Akt-mediated induction of the cyclin dependent k inase inhibitor p21. Treatment of myoblasts with IGF-I or transfection with an inducible Akt maintained muscle cell survival and enhanced production o f p21, and ectopic expression of p21 was able to sustain viability in the a bsence of growth factors. Blocking of p21 protein accumulation through a sp ecific p21 antisense cDNA prevented survival regulated by IGF-I or Akt but did not block muscle cell viability mediated by PDGF-BB. Our results define Akt as an intermediate and p21 as a critical effector of an IGF-controlled myoblast survival pathway that is active during early myogenic differentia tion and show that growth factors are able to maintain cell viability by in ducing expression of pro-survival molecules.