Building Muscle: Molecular Regulation of Myogenesis

Abstract

SUMMARYThe genesis of skeletal muscle during embryonic development and postnatal life serves as a paradigm for stem and progenitor cell maintenance, lineage specification, and terminal differentiation. An elaborate interplay of extrinsic and intrinsic regulatory mechanisms controls myogenesis at all stages of development. Many aspects of adult myogenesis resemble or reiterate embryonic morphogenetic episodes, and related signaling mechanisms control the genetic networks that determine cell fate during these processes. An integrative view of all aspects of myogenesis is imperative for a comprehensive understanding of muscle formation. This article provides a holistic overview of the different stages and modes of myogenesis with an emphasis on the underlying signals, molecular switches, and genetic networks.

p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress

“…52 As discussed earlier, MyoD acts upstream of myogenin and transcriptionally activates myogenin. 8,9,13,14 We anticipated that p53 would repress endogenous myogenin transcription activated by ectopic MyoD and would not repress ectopic myogenin driven by a constitutive promoter. This experimental design allowed us to characterize myogenin function in either a p53-dependent or p53-independent manner.…”

“…p53 25,26,53,54 MyoD determines the myogenic lineage and acts upstream of p21 and myogenin. 8,9,13,56 Under normal conditions, expression of both p21 and myogenin is critical to establish the state of irreversible cell cycle arrest and terminal differentiation. 11,16,40 In contrast to the cell cycle arrest that promotes terminal differentiation under non-stressed conditions, it is known that cell cycle arrest induced by DNA damage is associated with decreased myogenic differentiation.…”

“…MyoD determines the myogenic lineage, whereas myogenin, a member of the MRF family, functions downstream of MyoD and plays a critical role in driving terminal differentiation as myogenin-null mice show a lethal deficiency of differentiated skeletal muscle. [8][9][10][11][12][13] The dynamic differentiation program of skeletal muscle is characterized by the orderly expression of genes and structural changes that can be recapitulated in vitro, as myogenic cells undergo cell cycle withdrawal and express early and then late differentiation genes with the formation of mononucleated myocytes to elongated multinucleated myotubes. 8,9,14 Under normal unstressed conditions, p53 has been shown to promote muscle differentiation in vitro.…”

“…[8][9][10][11][12][13] The dynamic differentiation program of skeletal muscle is characterized by the orderly expression of genes and structural changes that can be recapitulated in vitro, as myogenic cells undergo cell cycle withdrawal and express early and then late differentiation genes with the formation of mononucleated myocytes to elongated multinucleated myotubes. 8,9,14 Under normal unstressed conditions, p53 has been shown to promote muscle differentiation in vitro. [15][16][17][18][19][20] In contrast, under stress-associated conditions such as inflammation, chronic exposure to double-strand DNA breaks, and aging, enhanced p53 activity has been shown to correlate with skeletal muscle atrophy in vivo.…”

Rhabdomyosarcoma of Soft Tissues in an Adult Brook Trout (Salvelinus fontinalis)

“…Recent molecular studies have suggested that aRMS represents an arrested stage of development of undifferentiated myoblasts. The cause of the arrested stage of development could be related to the PAX-FKHR mutation and fusion, which leads to increased levels of MyoD1 and myogenin, resulting in cell proliferation and myogenic differentiation, respectively (Bentzinger et al, 2012;Caserto, 2013).…”