Phosphatidylinositol 3-kinase-Akt pathway plays a critical role in early cardiomyogenesis by regulating canonical Wnt signaling.

We have recently reported that activation of phosphatidylinositol 3-kinase (PI3K) plays a critical role in the early stage of cardiomyocyte differentiation of P19CL6 cells. We here examined molecular mechanisms of how PI3K is involved in cardiomyocyte differentiation. DNA chip analysis revealed that expression levels of Wnt-3a were markedly increased and that the Wnt/beta-catenin pathway was activated temporally during the early stage of cardiomyocyte differentiation of P19CL6 cells. Activation of the Wnt/beta-catenin pathway during this period was required and sufficient for cardiomyocyte differentiation of P19CL6 cells. Inhibition of the PI3K/Akt pathway suppressed the Wnt/beta-catenin pathway by activation of glycogen synthase kinase-3beta (GSK-3beta) and degradation of beta-catenin. Suppression of cardiomyocyte differentiation by inhibiting the PI3K/Akt pathway was rescued by forced expression of a nonphosphorylated, constitutively active form of beta-catenin. These results suggest that the PI3K pathway regulates cardiomyocyte differentiation through suppressing the GSK-3beta activity and maintaining the Wnt/beta-catenin activity.