Efficient adult skeletal muscle regeneration in mice deficient in p38β, p38γ and p38δ MAP kinases

Adult skeletal muscle is a very stable tissue containing a small population of myofiber-associated quiescent satellite cells compared with late embryonic/neonatal skeletal muscle, which contains highly proliferating myoblasts and small actively growing myofibers, suggesting that specific regulatory pathways may control myogenesis at distinct developmental stages. The p38 MAPK signaling pathway is central for myogenesis, based on studies using immortalized and neonatal primary myoblasts in vitro. However, the contribution of this pathway to adult myogenesis has never been investigated. Four p38 isoforms (p38 alpha, p38 beta, p38 gamma and p38 delta) exist in mammalian cells, being p38a and p38. the most abundantly expressed isoforms in adult skeletal muscle. Given the embryonic/neonatal lethality of p38 alpha-deficient mice, here we investigate the relative contribution of p38 beta, p38 gamma and p38 delta to adult myogenesis. Regeneration and myofiber growth of adult muscle proceeds with similar efficiency in mice lacking p38 beta, p38 gamma and p38 delta as in wild-type control mice. In agreement with this, there is no difference in adult primary myoblasts behavior in vitro among the different genotypes. Importantly, the pattern of p38 activation (ascribed to p38 alpha) remains unperturbed during satellite cell-mediated myogenesis in vitro and adult muscle regeneration in wild type and p38 beta-, p38 gamma- and p38 delta-deficient mice, rendering p38 alpha as the essential p38 isoform sustaining adult myogenesis. This study constitutes the first analysis addressing the functionality of p38 beta, p38 gamma and p38 delta in satellite cell-dependent adult muscle regeneration and growth.