Oxidative stress has been shown to induce apoptosis in a variety of tissues, while insulin-like growth factor-I (IGF-I) can oppose this effect. We found that H2O2 promoted cell death and apoptosis in C2C12 myoblasts, an effect that was completely prevented by exogenous IGF-I. One downstream mediator of IGF-I survival signaling is the serine/threonine kinase Akt, of which three isoforms have been identified in mammals. We found that Akt1 and Akt3 act on pro-apoptotic target molecules in an isoform-specific manner. Both Akt1 and Akt3 were responsible for phosphorylating FoxO3a at S253 and FoxO1 at T24, while Akt1 alone phosphorylated Bad at S136 and FoxO3a at T32. Our results provide evidence for IGF-I-stimulated isoform-specific actions of Akt on molecules involved in promoting apoptosis. (C) 2009 Elsevier Inc. All rights reserved.