Schematic representation of muscle formation during embryonic development and adult regeneration. (a) Developmental myogenesis occurs in two distinct waves of differentiation that are characterized by a specific and sequential pattern of muscle-related gene expression (red arrows). Skeletal muscles are derived from somites, which receive signals from the neighboring tissues, namely, axial structures (neural tube and notochord), dorsal ectoderm, and lateral mesoderm that in turn induce the activation (blue arrows) of muscle regulatory factors. Shh (from the notochord) and Wnt1/3 and Wnt11 and IGFs (from dorsal neural tube) signaling have been demonstrated to regulate the expression of Myf5. Pax3 and Myf5 independently regulate MyoD expression, whereas Myf5 regulates the transient expression of MRF4. Myf5 and MyoD independently activate the expression of Myogenin, which promotes the expression of Myosin. (b) Illustration of the lineage progression of adult myogenesis during muscle regeneration, which recapitulates many of the cellular and molecular aspects of muscle development illustrated in panel (a). Environmental cues (Notch, IGF-1, Wnt, etc.) influence the activity of satellite cells (green arrows). Notch and IGF-1 signaling stimulate the proliferation of satellite cells, whereas Wnt signaling is involved in the transition from proliferation to the differentiation phase of myoblasts. Notch signaling is also necessary for the maintenance of the quiescent state of satellite cells. Depending on MyoD activity, satellite cells can follow one of two fates: they may maintain Myf5 expression while downregulating MyoD and self-renewing; alternatively, they maintain MyoD expression and differentiate. Quiescent satellite cells express Pax3 and Pax7. Pax7 regulates MyoD and Myf5 expression (blue arrows). Myf5 regulates the expression of MyoD, which in turn promotes the expression of myogenin and MRF4 (blue arrows). Myogenin promotes the expression of Myosin (blue arrows).
