Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism
Copyright policy )Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism
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.
- University of Erlangen-Nuremberg Germany
- DePaul University United States
- University of Turin Italy
- University of Oxford United Kingdom
- Université Catholique de Louvain Belgium
HOMEOSTASIS, Genetics (clinical); Genetics, INCREASES, ANGIOGENESIS, Mice, Glutamates, Carbon Radioisotopes, OXIDATIVE STRESS, ADAPTATION, Hypoxia, 11 Medical and Health Sciences, Genetics (clinical), Genetics & Heredity, Carbon Isotopes, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Homozygote, Life sciences, Immunohistochemistry, ISCHEMIA, Mitochondria, RESPIRATION, Sciences du vivant, SKELETAL-MUSCLE, Life Sciences & Biomedicine, Oxidation-Reduction, ACTIVATED RECEPTOR-ALPHA, INDUCIBLE-FACTOR, EXPRESSION, 3001 Agricultural biotechnology, Procollagen-Proline Dioxygenase, HIF-1-ALPHA, Biochimie, biophysique & biologie moléculaire, Models, Biological, 3105 Genetics, Oxygen Consumption, Genetics, HIF, Animals, Muscle, Skeletal, Nuclear Magnetic Resonance, Biomolecular, Science & Technology, 06 Biological Sciences, Carbon Dioxide, Fibroblasts, Embryo, Mammalian, 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, ALPHA, MICE, Glucose, 3102 Bioinformatics and computational biology, Basal Metabolism, Tomography, X-Ray Computed, Energy Metabolism, Biochemistry, biophysics & molecular biology, Developmental Biology
HOMEOSTASIS, Genetics (clinical); Genetics, INCREASES, ANGIOGENESIS, Mice, Glutamates, Carbon Radioisotopes, OXIDATIVE STRESS, ADAPTATION, Hypoxia, 11 Medical and Health Sciences, Genetics (clinical), Genetics & Heredity, Carbon Isotopes, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Homozygote, Life sciences, Immunohistochemistry, ISCHEMIA, Mitochondria, RESPIRATION, Sciences du vivant, SKELETAL-MUSCLE, Life Sciences & Biomedicine, Oxidation-Reduction, ACTIVATED RECEPTOR-ALPHA, INDUCIBLE-FACTOR, EXPRESSION, 3001 Agricultural biotechnology, Procollagen-Proline Dioxygenase, HIF-1-ALPHA, Biochimie, biophysique & biologie moléculaire, Models, Biological, 3105 Genetics, Oxygen Consumption, Genetics, HIF, Animals, Muscle, Skeletal, Nuclear Magnetic Resonance, Biomolecular, Science & Technology, 06 Biological Sciences, Carbon Dioxide, Fibroblasts, Embryo, Mammalian, 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, ALPHA, MICE, Glucose, 3102 Bioinformatics and computational biology, Basal Metabolism, Tomography, X-Ray Computed, Energy Metabolism, Biochemistry, biophysics & molecular biology, Developmental Biology
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