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

Abstract

Acute muscle injury and physiological stress from chronic muscle diseases and aging lead to impairment of skeletal muscle function. This raises the question of whether p53, a cellular stress sensor, regulates muscle tissue repair under stress conditions. By investigating muscle differentiation in the presence of genotoxic stress, we discovered that p53 binds directly to the myogenin promoter and represses transcription of myogenin, a member of the MyoD family of transcription factors that plays a critical role in driving terminal muscle differentiation. This reduction of myogenin protein is observed in G1-arrested cells and leads to decreased expression of late but not early differentiation markers. In response to acute genotoxic stress, p53-mediated repression of myogenin reduces post-mitotic nuclear abnormalities in terminally differentiated cells. This study reveals a mechanistic link previously unknown between p53 and muscle differentiation, and suggests new avenues for managing p53-mediated stress responses in chronic muscle diseases or during muscle aging. Cell Death and Differentiation (2015) 22, 560-573; doi:10.1038/cdd.2014; published online 12 December 2014The tumor suppressor p53 promotes cell cycle arrest or apoptosis in response to diverse stress signals such as DNA damage, thus preventing propagation of genetically compromised cells. [1][2][3] Among the diverse functions attributed to p53, a growing body of evidence supports its role in regulation of differentiation and maintenance of cellular function and integrity. 1,[4][5][6][7] For example, p53 represses Nanog to maintain genetic stability of the stem cell pool by promoting differentiation of mouse embryonic stem cells (mESCs) after DNA damage. 6 Skeletal muscle differentiation, a key step during muscle tissue formation, is orchestrated by the MyoD family of myogenic regulatory factors (MRFs). 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. [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. [21][22][23][24][25] In addition, it has been shown that p53 and its downstream effectors are required for an inflammatory cytokine-mediated inhibition of myogenic differentiation in vitro. 22 Int...

Hypoxia Inhibits Myogenic Differentiation through p53 Protein-dependent Induction of Bhlhe40 Protein

“…Importantly, inhibition of p53 partially rescued the differentiation defects of hypoxia-treated myoblasts, indicating that hypoxia regulates Bhlhe40 at least partially through p53. In a recent study, p53 has been reported to inhibit the transcription of Myog directly by binding to the promoter of Myog under genotoxic stress (39). Our study sheds light on an alternative avenue through which p53 regulates Myog.…”

Regulatory T Cells Promote Myositis and Muscle Damage in Toxoplasma gondii Infection

“…While myogenin is important for myotube terminal differentiation and fusion, its expression has been show to inhibit myoblast responsiveness to epidermal growth factors (50). Additionally, decreased myogenin expression may represent a myogenic checkpoint to ensure genetic stability in differentiated cells and proper regeneration (51). Taken together, these data suggest that pathogenic Tregs may cause a defective myogenic differentiation program through modulating macrophage subsets.…”

A systematic review of p53 regulation of oxidative stress in skeletal muscle

“…Therefore, analysis of the regulation of key myogenic regulatory factors by p53 was examined under irradiation stress. The results indicate a direct role for p53 transcriptional repression of myogenin, with the likely purpose of ensuring adequate time for DNA damage repair and chromosomal segregation [92]. Furthermore, a time course was evaluated leading to the conclusion that a two-phase conditional regulation by p53 exists.…”

“…The role of p53 on skeletal muscle differentiation following DNA damage is a field of interest because of its implications for the regenerative capacity of muscle. Previous work has revealed that p53 maintains the genetic stability of mouse embryonic stem (MES) cells following DNA damage by repressing Nanog, a cancer-stem cell marker, to then regulate and promote differentiation [92,93]. Regulation of MES cells is of key importance since skeletal muscle originates through myogenesis from the mesoderm, one of the three primary germ layers.…”

“…Regulation of MES cells is of key importance since skeletal muscle originates through myogenesis from the mesoderm, one of the three primary germ layers. Depending on the exposure time and intensity, p53 activation is required for cytokine-mediated inhibition of myogenic differentiation via TNF-α-driven apoptotic augmentation, leading to muscle atrophy [77,92,94]. Therefore, analysis of the regulation of key myogenic regulatory factors by p53 was examined under irradiation stress.…”