title: Hypoxia Inhibits Myogenic Differentiation through p53 Protein-dependent Induction of Bhlhe40 Protein.
abstract: Satellite cells are muscle-resident stem cells capable of self-renewal and differentiation to repair injured muscles. However, muscle injury often leads to an ischemic hypoxia environment that impedes satellite cell differentiation and reduces the efficiency of muscle regeneration. Here we performed microarray analyses and identified the basic helix-loop-helix family transcription factor Bhlhe40 as a candidate mediator of the myogenic inhibitory effect of hypoxia. Bhlhe40 is strongly induced by hypoxia in satellite cell-derived primary myoblasts. Overexpression of Bhlhe40 inhibits Myog expression and mimics the effect of hypoxia on myogenesis. Inhibition of Bhlhe40, conversely, up-regulates Myog expression and promotes myogenic differentiation. Importantly, Bhlhe40 knockdown rescues myogenic differentiation under hypoxia. Mechanistically, Bhlhe40 binds to the proximal E-boxes of the Myog promoter and reduces the binding affinity and transcriptional activity of MyoD on Myog. Interestingly, hypoxia induces Bhlhe40 expression independent of HIF1α but through a novel p53-dependent signaling pathway. Our study establishes a crucial role of Bhlhe40 in mediating the repressive effect of hypoxia on myogenic differentiation and suggests that inhibition of Bhlhe40 or p53 may facilitate muscle regeneration after ischemic injuries.
authors.affiliation: From the Departments of Animal Science and.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: From the Departments of Animal Science and.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Liu
authors.affiliation: From the Departments of Animal Science and.
authors.forename: Zuojun
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Biochemistry and.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.affiliation: Biochemistry and Center for Cancer Research, Purdue University, West Lafayette, Indiana 47906.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Liu
authors.affiliation: From the Departments of Animal Science and Center for Cancer Research, Purdue University, West Lafayette, Indiana 47906 skuang@purdue.edu.
authors.forename: Shihuan
authors.initials: S
authors.lastname: Kuang
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D000860:Hypoxia / Q000473:pathology*; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism; D018008:Myogenin / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D018008:Myogenin; D016159:Tumor Suppressor Protein p53; C491539:Bhlhe40 protein, mouse; C503801:Myog protein, mouse
keywords: basic helix-loop-helix transcription factor (bHLH); differentiation; hypoxia; muscle regeneration; p53; skeletal muscle