title: Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism.
abstract: HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Pparalpha pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2alpha and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress.
authors.affiliation: The Center for Transgene Technology and Gene Therapy, Katholieke Universiteit (K.U.) Leuven, Leuven, B-3000, Belgium.
authors.forename: Julián
authors.initials: J
authors.lastname: Aragonés
authors.forename: Martin
authors.initials: M
authors.lastname: Schneider
authors.forename: Katie
authors.initials: K
authors.lastname: Van Geyte
authors.forename: Peter
authors.initials: P
authors.lastname: Fraisl
authors.forename: Tom
authors.initials: T
authors.lastname: Dresselaers
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.forename: Ruud
authors.initials: R
authors.lastname: Dirkx
authors.forename: Serena
authors.initials: S
authors.lastname: Zacchigna
authors.forename: Hélène
authors.initials: H
authors.lastname: Lemieux
authors.forename: Nam Ho
authors.initials: NH
authors.lastname: Jeoung
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Tammie
authors.initials: T
authors.lastname: Bishop
authors.forename: Peggy
authors.initials: P
authors.lastname: Lafuste
authors.forename: Antonio
authors.initials: A
authors.lastname: Diez-Juan
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Harten
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Noten
authors.forename: Katrien
authors.initials: K
authors.lastname: De Bock
authors.forename: Carsten
authors.initials: C
authors.lastname: Willam
authors.forename: Marc
authors.initials: M
authors.lastname: Tjwa
authors.forename: Alexandra
authors.initials: A
authors.lastname: Grosfeld
authors.forename: Rachel
authors.initials: R
authors.lastname: Navet
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
authors.forename: Thierry
authors.initials: T
authors.lastname: Vandendriessche
authors.forename: Christophe
authors.initials: C
authors.lastname: Deroose
authors.forename: Bhathiya
authors.initials: B
authors.lastname: Wijeyekoon
authors.forename: Johan
authors.initials: J
authors.lastname: Nuyts
authors.forename: Benedicte
authors.initials: B
authors.lastname: Jordan
authors.forename: Robert
authors.initials: R
authors.lastname: Silasi-Mansat
authors.forename: Florea
authors.initials: F
authors.lastname: Lupu
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.forename: Chris
authors.initials: C
authors.lastname: Pugh
authors.forename: Phil
authors.initials: P
authors.lastname: Salmon
authors.forename: Luc
authors.initials: L
authors.lastname: Mortelmans
authors.forename: Bernard
authors.initials: B
authors.lastname: Gallez
authors.forename: Frans
authors.initials: F
authors.lastname: Gorus
authors.forename: Johan
authors.initials: J
authors.lastname: Buyse
authors.forename: Francis
authors.initials: F
authors.lastname: Sluse
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.forename: Erich
authors.initials: E
authors.lastname: Gnaiger
authors.forename: Peter
authors.initials: P
authors.lastname: Hespel
authors.forename: Paul
authors.initials: P
authors.lastname: Van Hecke
authors.forename: Frans
authors.initials: F
authors.lastname: Schuit
authors.forename: Paul
authors.initials: P
authors.lastname: Van Veldhoven
authors.forename: Peter
authors.initials: P
authors.lastname: Ratcliffe
authors.forename: Myriam
authors.initials: M
authors.lastname: Baes
authors.forename: Patrick
authors.initials: P
authors.lastname: Maxwell
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000818:Animals; D001481:Basal Metabolism; D002245:Carbon Dioxide / Q000378:metabolism; D002247:Carbon Isotopes / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000378:metabolism; D004622:Embryo, Mammalian; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005971:Glutamates / Q000378:metabolism; D006720:Homozygote; D000860:Hypoxia / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000235:genetics / Q000502:physiology; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000235:genetics; D014057:Tomography, X-Ray Computed
chemical_list: D002247:Carbon Isotopes; D002250:Carbon Radioisotopes; D005971:Glutamates; D002245:Carbon Dioxide; C522721:PHD1 protein, mouse; D011393:Procollagen-Proline Dioxygenase; D005947:Glucose