Phosphoinositide 3-kinase induces the transcriptional activity of MEF2 proteins during muscle differentiation.

The activity of phosphoinositide 3-kinase (PI3-K) is essential for the differentiation of skeletal muscle cells by largely unknown mechanisms. Here we show that inhibition of PI3-K activity by the pharmacological agent LY294002 affects early processes of myoblast differentiation including the transcriptional activation of myogenin. Previous studies indicated that transcription of myogenin was dependent on MyoD and MEF2 proteins. We find that expression of a dominant negative form of PI3-K or growth in the presence of LY294002 inhibits cellular activity of MEF2 but not of MyoD. Evidence reveals that whereas MEF2 transcriptional activity is inhibited, its DNA binding activity remains unaffected. Recent studies demonstrated that phosphorylation by p38 mitogen-activated protein kinase (MAPK) induced transcriptional activity of MEF2 proteins. We show that the phosphorylation of MEF2 occurring during muscle differentiation is prevented if the activity of PI3-K is inhibited. However, our results also indicate that p38 MAPK is not affected by PI3-K in muscle cells. Nevertheless, p38 MAPK can substitute for PI3-K in the induction of MEF2 and muscle transcription. Together, these findings indicate that PI3-K affects skeletal muscle differentiation by inducing phosphorylation and transcriptional activity of MEF2 proteins in a parallel but distinct route from p38 MAPK.