p38 and extracellular signal-regulated kinases regulate the myogenic program at multiple steps

The extracellular signals which regulate the myogenic program are transduce d to the nucleus by mitogen-activated protein kinases (MAPKs). We have inve stigated the role of two MAPKs, p38 and extracellular signal-regulated kina se (ERK), whose activities undergo significant changes during muscle differ entiation. p38 is rapidly activated in myocytes induced to differentiate. T his activation differs from those triggered by stress and cytokines, becaus e it is not linked to Jun-N-terminal kinase stimulation and is maintained d uring the whole process of myotube formation. Moreover, p38 activation is i ndependent of a parallel promyogenic pathway stimulated by insulin-like gro wth factor 1. Inhibition of p38 prevents the differentiation program in myo genic cell lines and human primary myocytes. Conversely, deliberate activat ion of endogenous p38 stimulates muscle differentiation even in the presenc e of antimyogenic cues. Much evidence indicates that p38 is an activator of MyoD: (i) p38 kinase activity is required for the expression of MyoD-respo nsive genes, (ii) enforced induction of p38 stimulates the transcriptional activity of a Gal4-MyoD fusion protein and allows efficient activation of c hromatin-integrated reporters by MyoD, and (iii) MyoD-dependent myogenic co nversion is reduced in mouse embryonic fibroblasts derived from p38 alpha(- /-) embryos. Activation of p38 also enhances the transcriptional activities of myocyte enhancer binding factor 2A (MEF2A) and MEF2C by direct phosphor ylation. With MEF2C, selective phosphorylation of one residue (Thr293) is a tissue-specific activating signal in differentiating myocytes. Finally, ER K shows a biphasic activation profile, with peaks of activity in undifferen tiated myoblasts and postmitotic myotubes. Importantly, activation of ERK i s inhibitory toward myogenic transcription in myoblasts but contributes to the activation of myogenic transcription and regulates postmitotic response s (i.e., hypertrophic growth) in myotubes.