Aragones, J and Schneider, M and Van Geyte, K and Fraisl, P and Dresselaers, T and Mazzone, M and Dirkx, R and Zacchigna, S and Lemieux, H and Jeoung, NH and Lambrechts, D and Bishop, T and Lafuste, P and Diez-Juan, A and Harten, SK and Van Noten, P and De Bock, K and Willam, C and Tjwa, M and Grosfeld, A and Navet, R and Moons, L and Vandendriessche, T and Deroose, C and Wijeyekoon, B and Nuyts, J and Jordan, B and Silasi-Mansat, R and Lupu, F and Dewerchin, M and Pugh, C and Salmon, P and Mortelmans, L and Gallez, B and Gorus, F and Buyse, J and Sluse, F and Harris, RA and Gnaiger, E and Hespel, P and Van Hecke, P and Schuit, F and Van Veldhoven, P and Ratcliffe, P and Baes, M and Maxwell, P and Carmeliet, P (2008) Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. NAT GENET , 40 (2) 170 - 180. 10.1038/ng.2007.62.
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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 Ppar alpha 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-2 alpha 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.
|Title:||Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism|
|Keywords:||ACTIVATED RECEPTOR-ALPHA, SKELETAL-MUSCLE, INDUCIBLE-FACTOR, OXIDATIVE STRESS, EXPRESSION, HIF, MICE, INCREASES, ISCHEMIA, ANGIOGENESIS|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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