Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism

• DOI: 10.1038/ng.2007.62
• Publication Date: 2008-01-06T18:46:46Z
• Authors: Julián Aragonés; Martin Schneider; Katie Van Geyte; Peter Fraisl; Tom Dresselaers; Massimiliano Mazzone; Ruud Dirkx; Serena Zacchigna; Hélène Lemieux; Nam Ho Jeoung; Diether Lambrechts; Tammie Bishop; Peggy Lafuste; Antonio Diez-Juan; Sarah K Harten; Pieter Van Noten; Katrien De Bock; Carsten Willam; Marc Tjwa; Alexandra Grosfeld; Rachel Navet; Lieve Moons; Thierry Vandendri...; Christophe Deroose; Bhathiya Wijeyekoon; Johan Nuyts; Benedicte Jordan; Robert Silasi-Mansat; Florea Lupu; Mieke Dewerchin; Chris Pugh; Phil Salmon; Luc Mortelmans; Bernard Gallez; Frans Gorus; Johan Buyse; Francis Sluse; Robert A Harris; Erich Gnaiger; Peter Hespel; Paul Van Hecke; Frans Schuit; Paul Van Veldhoven; Peter Ratcliffe; Myriam Baes; Patrick Maxwell; Peter Carmeliet
• Keywords: Genetics (clinical); Genetics; Models, Biological; Mice; 03 medical and health sciences; Oxygen Consumption; Glutamates; Genetics; Animals; Carbon Radioisotopes; Hypoxia; Muscle, Skeletal; Nuclear Magnetic Resonance, Biomolecular; Genetics (clinical); Carbon Isotopes; 0303 health sciences; [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology; Homozygote; Carbon Dioxide; Fibroblasts; Embryo, Mammalian; Immunohistochemistry; Animals; Carbon Dioxide; Carbon Isotopes; Carbon Radioisotopes; Embryo, Mammalian; Energy Metabolism; Fibroblasts; Glucose; Glutamates; Homozygote; Hypoxia; Immunohistochemistry; Mice; Mitochondria; Models, Biological; Muscle, Skeletal; Nuclear Magnetic Resonance, Biomolecular; Oxidation-Reduction; Oxygen Consumption; Procollagen-Proline Dioxygenase; Tomography, X-Ray Computed; Basal Metabolism; Mitochondria; 3. Good health; Glucose; Basal Metabolism; Energy Metabolism; Oxidation-Reduction; [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology

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.