Cell cycle withdrawal promotes myogenic induction of Akt, a positive modulator of myocyte survival

During myogenesis, proliferating myoblasts withdraw from the cell cycle, ac quire an apoptosis-resistant phenotype, and differentiate into myotubes. Pr evious studies indicate that myogenic induction of the cyclin-dependent kin ase inhibitor p21 results in an inhibition of apoptotic cell death in addit ion to its role as a negative cell cycle regulator. Here we demonstrate tha t the protein encoded by the Akt proto-oncogene is induced in C2C12 cells d uring myogenic differentiation with a corresponding increase in kinase acti vity. In differentiating cultures, expression of dominant-negative forms of Akt increase the frequency of cell death whereas expression of wild-type A kt protects against death, indicating that Akt is a positive modulator of m yocyte survival. Antisense oligonucleotides against p21 block cell cycle wi thdrawal, inhibit Akt induction, and enhance cell death in differentiating myocyte cultures. Adenovirus-mediated transfer of wild-type or constitutive ly active Akt constructs confer partial resistance to cell death under cond itions where cell cycle exit is blocked by the antisense oligonucleotides. Collectively, these data indicate that cell cycle withdrawal facilitates th e induction of Akt during myogenesis, promoting myocyte survival.