Muscle regeneration recapitulates many aspects of embryonic myogenesis and is an important homeostatic process of the adult skeletal muscle, which, after development, retains the capacity to regenerate in response to appropriate stimuli, activating the muscle compartment of stem cells, namely, satellite cells, as well as other precursor cells. Moreover, significant evidence suggests that while stem cells represent an important determinant for tissue regeneration, a “qualified” environment is necessary to guarantee and achieve functional results. It is therefore plausible that the loss of control over these cell fate decisions could lead to a pathological transdifferentiation, leading to pathologic defects in the regenerative process. This review provides an overview about the general aspects of muscle development and discusses the cellular and molecular aspects that characterize the five interrelated and time-dependent phases of muscle regeneration, namely, degeneration, inflammation, regeneration, remodeling, and maturation/functional repair. 1. Muscle Regeneration Recapitulates Many Aspects of Development Regenerative potential, robust in lower vertebrates, is gradually lost in higher vertebrates such as mammals [1–5]. Nevertheless, mammalian tissues, including skeletal muscle, are capable of homeostasis and regeneration, partially recapitulating the embryonic developmental program. Muscle development and regeneration share common features because the molecular program that underlines prenatal development is reactivated for tissue reconstruction after injury [6–8] (Figure 1). Regenerative medicine has therefore gained important insights through the study of developmental biology. Figure 1: 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,
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