HIF modulation of Wnt signaling regulates skeletal myogenesis in vivo.

ABSTRACT: Deeper insight into the molecular pathways that orchestrate skeletal myogenesis should enhance our understanding of, and ability to treat, human skeletal muscle disease. It is now widely appreciated that nutrients, such as molecular oxygen (O2), modulate skeletal muscle formation. During early stages of development and regeneration, skeletal muscle progenitors reside in low O2 environments before local blood vessels and differentiated muscle form. Moreover, low O2 availability (hypoxia) impedes progenitor-dependent myogenesis in vitro through multiple mechanisms, including activation of hypoxia inducible factor 1? (HIF1?). However, whether HIF1? regulates skeletal myogenesis in vivo is not known. Here, we explored the role of HIF1? during murine skeletal muscle development and regeneration. Our results demonstrate that HIF1? is dispensable during embryonic and fetal myogenesis. However, HIF1? negatively regulates adult muscle regeneration after ischemic injury, implying that it coordinates adult myogenesis with nutrient availability in vivo. Analyses of Hif1a mutant muscle and Hif1a-depleted muscle progenitors further suggest that HIF1? represses myogenesis through inhibition of canonical Wnt signaling. Our data provide the first evidence that HIF1? regulates skeletal myogenesis in vivo and establish a novel link between HIF and Wnt signaling in this context.

SUBMITTER: Majmundar AJ 

PROVIDER: S-EPMC4510864 | biostudies-other | 2015 Jul

REPOSITORIES: biostudies-other