Genetic analysis of p38 MAP kinases in myogenesis:: fundamental role of p38α in abrogating myoblast proliferation

The p38 mitogen-activated protein kinase (MAPK) pathway plays a critical role in skeletal muscle differentiation. However, the relative contribution of the four p38 MAPKs (p38 alpha, p38 beta, p38 gamma and p38 delta) to this process is unknown. Here we show that myoblasts lacking p38a, but not those lacking p38b or p38d, are unable to differentiate and form multinucleated myotubes, whereas p38 gamma-deficient myoblasts exhibit an attenuated fusion capacity. The defective myogenesis in the absence of p38a is caused by delayed cell-cycle exit and continuous proliferation in differentiation-promoting conditions. Indeed, activation of JNK/cJun was enhanced in p38 alpha-deficient myoblasts leading to increased cyclin D1 transcription, whereas inhibition of JNK activity rescued the proliferation phenotype. Thus, p38 alpha controls myogenesis by antagonizing the activation of the JNK proliferation-promoting pathway, before its direct effect on muscle differentiation-specific gene transcription. More importantly, in agreement with the defective myogenesis of cultured p38 Delta/Delta myoblasts, neonatal muscle deficient in p38 alpha shows cellular hyperproliferation and delayed maturation. This study provides novel evidence of a fundamental role of p38a in muscle formation in vitro and in vivo.