p38α MAPK Regulates Adult Muscle Stem Cell Fate by Restricting Progenitor Proliferation During Postnatal Growth and Repair

Stem cell function is essential for the maintenance of adult tissue homeostasis. Controlling the balance between self-renewal and differentiation is crucial to maintain a receptive satellite cell pool capable of responding to growth and regeneration cues. The mitogen-activated protein kinase p38 has been implicated in the regulation of these processes but its influence in adult muscle remains unknown. Using conditional satellite cell p38 knockout mice we have demonstrated that p38 restricts excess proliferation in the postnatal growth phase while promoting timely myoblast differentiation. Differentiation was still able to occur in the p38-null satellite cells, however, but was delayed. An absence of p38 resulted in a postnatal growth defect along with the persistence of an increased reservoir of satellite cells into adulthood. This population was still capable of responding to cardiotoxin-induced injury, resulting in complete, albeit delayed, regeneration, with further enhancement of the satellite cell population. Increased p38 phosphorylation accompanied the absence of p38, and inhibition of p38 ex vivo substantially decreased the myogenic defect. We have used genome-wide transcriptome analysis to characterize the changes in expression that occur between resting and regenerating muscle, and the influence p38 has on these expression profiles. This study provides novel evidence for the fundamental role of p38 in adult muscle homeostasis in vivo. STEM Cells2013;31:1597-1610