Role of Phosphoinositide 3-OH Kinase p110β in Skeletal Myogenesis

Phosphoinositide 3-OH kinase (PI3K) regulates a number of developmental and physiologic processes in skeletal muscle; however, the contributions of individual PI3K p110 catalytic subunits to these processes are not well-defined. To address this question, we investigated the role of the 110-kDa PI3K catalytic subunit beta (p110 beta) in myogenesis and metabolism. In C2C12 cells, pharmacological inhibition of p110 beta delayed differentiation. We next generated mice with conditional deletion of p110 beta in skeletal muscle (p110 beta muscle knockout [ p110 beta-mKO] mice). While young p110 beta-mKO mice possessed a lower quadriceps mass and exhibited less strength than control littermates, no differences in muscle mass or strength were observed between genotypes in old mice. However, old p110 beta-mKO mice were less glucose tolerant than old control mice. Overexpression of p110 beta accelerated differentiation in C2C12 cells and primary human myoblasts through an Akt-dependent mechanism, while expression of kinase-inactive p110 beta had the opposite effect. p110 beta overexpression was unable to promote myoblast differentiation under conditions of p110 beta inhibition, but expression of p110 beta was able to promote differentiation under conditions of p110 beta inhibition. These findings reveal a role for p110 beta during myogenesis and demonstrate that long-term reduction of skeletal muscle p110 beta impairs whole-body glucose tolerance without affecting skeletal muscle size or strength in old mice.