HIF-1α Directly Controls WNT7A Expression During Myogenesis

Abstract

Herein we unveil that Hypoxia-inducible factor-1α (HIF-1α) directly regulates <i>WNT7A</i> expression during myogenesis. In fact, chromatin immunoprecipitation (ChiP) and site-directed mutagenesis experiments revealed two distinct hypoxia response elements (HREs) that are specific HIF-1α binding sites on the <i>WNT7A</i> promoter. Remarkably, a pharmacological activation of HIF-1α induced <i>WNT7A</i> expression and enhanced muscle differentiation. On the other hand, silencing of <i>WNT7A</i> using CRISPR/Cas9 genome editing blocked the effects of HIF-1α activation on myogenesis. Finally, treatment with prolyl hydroxylases (PHDs) inhibitors improved muscle regeneration <i>in vitro</i> and <i>in vivo</i> in a cardiotoxin (CTX)-induced muscle injury mouse model, paving the way for further studies to test its efficacy on acute and chronic muscular pathologies.