Hypoxia inhibits myogenic differentiation through p53-dependent induction of Bhlhe40 [Cell Biology]

October 14th, 2015 by Wang, C., Liu, W., Liu, Z., Chen, L., Liu, X., Kuang, S.

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 analysis 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 Myogenin expression and mimics the effect of hypoxia on myogenesis. Inhibition of Bhlhe40 conversely upregulates Myogenin expression and promotes myogenic differentiation. Importantly, Bhlhe40 knockdown rescues myogenic differentiation under hypoxia. Mechanistically, Bhlhe40 binds to the proximal E-boxes of Myogenin promoter and reduces the binding affinity and transcriptional activity of MyoD on Myogenin. Interestingly, hypoxia induces Bhlhe40 expression independent of HIF1α, but through a novel p53-dependent signaling pathway. Together, 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.