HIF-1α Directly Controls WNT7A Expression During Myogenesis
Federica Cirillo, Giulia Resmini, Elia Angelino, Michele Ferrara, Adriana Tarantino, Marco Piccoli, Paola Rota, Andrea Ghiroldi, Michelle M. Monasky, Giuseppe Ciconte, Carlo Pappone, Andrea Graziani, Luigi Anastasia
Abstract
Herein we unveil that HIF-1α directly regulates WNT7A expression during myogenesis. In fact, chromatin immunoprecipitation and site-directed mutagenesis experiments revealed two distinct Hypoxia Response Elements (HREs) that are specific HIF-1α binding sites on the WNT7A promoter. Remarkably, a pharmacological activation of HIF-1α induced WNT7A expression and enhanced muscle differentiation. On the other hand, silencing of WNT7A using CRISPR/Cas9 genome editing blocked the effects of HIF-1α activation on myogenesis. Finally, treatment with prolyl hydroxylases inhibitors improved muscle regeneration in vitro and in vivo in a CTX-induced muscle injury mouse model, paving the way for further studies to test its efficacy on acute and chronic muscular pathologies.