Insulin-like growth factor-I (IGF-I) regulates muscle differentiation through phosphatidylinositol 3-kinase (PI 3-kinase), Also it was recently reported that PI 3-kinase is involved in the activation of phospholipase C-gamma1 (PLC-gamma1), We investigated whether PLC-gamma1 therefore plays a role in IGF-I-induced muscle differentiation using H9c2 rat cardiac myoblasts as a model. IGF-I was able to activate PLC-gamma1 via both PI3-kinase-dependent and tyrosine phosphorylation-dependent mechanisms in this model. However, PI 3-kinase appeared to play a more important role than tyrosine phosphorylation in IGF-I activation of PLC-gamma1, In addition, PLC-gamma1. activation was independent of Akt/ protein kinase B (Akt/PKB), Importantly, PLC-gamma1 was involved in IGF-I-induced muscle differentiation in parallel with Akt/PKB, Taken together, these results suggest that IGF-I regulation of muscle differentiation is dependent on the activation of PLC-gamma1 and Akt/PKB, both of which are downstream mediators of PI 3-kinase.