The extracellular signals which regulate the myogenic program are transduced to the nucleus by mitogenactivated protein kinases (MAPKs). We have investigated the role of two MAPKs, p38 and extracellular signal-regulated kinase (ERK), whose activities undergo significant changes during muscle differentiation. p38 is rapidly activated in myocytes induced to differentiate. This activation differs from those triggered by stress and cytokines, because it is not linked to Jun-N-terminal kinase stimulation and is maintained during the whole process of myotube formation. Moreover, p38 activation is independent of a parallel promyogenic pathway stimulated by insulin-like growth factor 1. Inhibition of p38 prevents the differentiation program in myogenic cell lines and human primary myocytes. Conversely, deliberate activation of endogenous p38 stimulates muscle differentiation even in the presence of antimyogenic cues. Much evidence indicates that p38 is an activator of MyoD: (i) p38 kinase activity is required for the expression of MyoD-responsive genes, (ii) enforced induction of p38 stimulates the transcriptional activity of a Gal4-MyoD fusion protein and allows efficient activation of chromatin-integrated reporters by MyoD, and (iii) MyoD-dependent myogenic conversion is reduced in mouse embryonic fibroblasts derived from p38␣ ؊/؊ embryos. Activation of p38 also enhances the transcriptional activities of myocyte enhancer binding factor 2A (MEF2A) and MEF2C by direct phosphorylation. With MEF2C, selective phosphorylation of one residue (Thr293) is a tissue-specific activating signal in differentiating myocytes. Finally, ERK shows a biphasic activation profile, with peaks of activity in undifferentiated myoblasts and postmitotic myotubes. Importantly, activation of ERK is inhibitory toward myogenic transcription in myoblasts but contributes to the activation of myogenic transcription and regulates postmitotic responses (i.e., hypertrophic growth) in myotubes.In the past decade, much has been learned about the molecular mechanisms that govern myogenesis owing mainly to the discovery of two groups of myogenic transcription factors (4,45,62). The first group includes the myogenic regulatory factors (MRFs), which belong to the basic helix-loop-helix (bHLH) protein family. This MRF group consists of four members: Myf5, MyoD, myogenin, and MRF4, all of which are specifically expressed in skeletal muscles. One of the unique features of these MRFs is that when they are ectopically expressed in fibroblasts or certain other nonmuscle cells, each has the ability to initiate the myogenic program and convert nonmuscle cells to myogenic derivatives (9, 59). Myogenic bHLH proteins heterodimerize with other ubiquitous bHLH proteins (like the E2A gene products, E12, and E47) to efficiently bind a consensus DNA site: CANNTG (also called the E box) (4, 33). The second group of transcription factors important in muscle differentiation consists of four different myocyte enhancer binding factor 2 (MEF2) proteins, which belong to the MADS box...
