p38-γ–dependent gene silencing restricts entry into the myogenic differentiation program

The mitogen-activated protein kinase p38-γ is highly expressed in skeletal muscle and is associated with the dystrophin glycoprotein complex; however, its function remains unclear. After induced damage, muscle in mice lacking p38-γ generated significantly fewer myofibers than wild-type muscle. Notably, p38-γ-deficient muscle contained 50% fewer satellite cells that exhibited premature Myogenin expression and markedly reduced proliferation. We determined that p38-γ directly phosphorylated MyoD on Ser199 and Ser200, which results in enhanced occupancy of MyoD on the promoter of myogenin together with markedly decreased transcriptional activity. This repression is associated with extensive methylation of histone H3K9 together with recruitment of the KMT1A methyltransferase to the myogenin promoter. Notably, a MyoD S199A/S200A mutant exhibits markedly reduced binding to KMT1A. Therefore, p38-γ signaling directly induces the assembly of a repressive MyoD transcriptional complex. Together, these results establish a hitherto unappreciated and essential role for p38-γ signaling in positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration.