title: 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 1α (HIF1α). However, whether HIF1α regulates skeletal myogenesis in vivo is not known. Here, we explored the role of HIF1α during murine skeletal muscle development and regeneration. Our results demonstrate that HIF1α is dispensable during embryonic and fetal myogenesis. However, HIF1α 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 HIF1α represses myogenesis through inhibition of canonical Wnt signaling. Our data provide the first evidence that HIF1α regulates skeletal myogenesis in vivo and establish a novel link between HIF and Wnt signaling in this context.
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Amar J
authors.initials: AJ
authors.lastname: Majmundar
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA Howard Hughes Medical Institute, 421 Curie Blvd., Philadelphia, PA 19104, USA.
authors.forename: David S M
authors.initials: DS
authors.lastname: Lee
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité 1037, Institut Claudius Regaud, Toulouse 31052, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Skuli
authors.affiliation: Department of Physics & Astronomy, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Rickson C
authors.initials: RC
authors.lastname: Mesquita
authors.affiliation: Department of Physics & Astronomy, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Meeri N
authors.initials: MN
authors.lastname: Kim
authors.affiliation: Department of Physics & Astronomy, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Arjun G
authors.initials: AG
authors.lastname: Yodh
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Nguyen-McCarty
authors.affiliation: Program in Cancer Biology, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China libo47@mail.sysu.edu.cn celeste2@mail.med.upenn.edu.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA Howard Hughes Medical Institute, 421 Curie Blvd., Philadelphia, PA 19104, USA libo47@mail.sysu.edu.cn celeste2@mail.med.upenn.edu.
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D007511:Ischemia / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D024510:Muscle Development / Q000502:physiology*; D018482:Muscle, Skeletal / Q000196:embryology* / Q000378:metabolism*; D009154:Mutation; D010100:Oxygen / Q000378:metabolism; D010477:Perfusion; D012038:Regeneration; D060449:Wnt Signaling Pathway
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen
keywords: HIF1α; Mouse; Myogenesis; Oxygen; Regeneration; Wnt