Wang Chao, Liu Weiyi, Liu Zuojun, Chen Long, Liu Xiaoqi, Kuang Shihuan
From the Departments of Animal Science and.
Biochemistry and.
J Biol Chem. 2015 Dec 11;290(50):29707-16. doi: 10.1074/jbc.M115.688671. Epub 2015 Oct 14.
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.
卫星细胞是肌肉组织中的干细胞，能够自我更新并分化以修复受损肌肉。然而，肌肉损伤常导致缺血缺氧环境，这会阻碍卫星细胞的分化并降低肌肉再生效率。在此，我们进行了微阵列分析，并确定碱性螺旋-环-螺旋家族转录因子Bhlhe40是缺氧对成肌抑制作用的候选介导因子。在卫星细胞来源的原代成肌细胞中，缺氧强烈诱导Bhlhe40表达。Bhlhe40的过表达抑制Myog表达，并模拟缺氧对肌生成的影响。相反，抑制Bhlhe40会上调Myog表达并促进成肌分化。重要的是，敲低Bhlhe40可挽救缺氧条件下的成肌分化。从机制上讲，Bhlhe40与Myog启动子的近端E-box结合，降低MyoD对Myog的结合亲和力和转录活性。有趣的是，缺氧诱导Bhlhe40表达不依赖于HIF1α，而是通过一条新的p53依赖性信号通路。我们的研究确立了Bhlhe40在介导缺氧对成肌分化的抑制作用中的关键作用，并表明抑制Bhlhe40或p53可能有助于缺血性损伤后的肌肉再生。
