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 Ppar 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 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.

1. The Center for Transgene Technology and Gene Therapy, Katholieke Universiteit (K.U.) Leuven, Leuven, B-3000, Belgium.
2. Department of Transgene Technology and Gene Therapy, Flanders Institute for Biotechnology (VIB), Leuven, B-3000, Belgium.
3. Biomedical MRI Unit, K.U. Leuven, Leuven, B-3000, Belgium.
4. Laboratory of Cell Metabolism, K.U. Leuven, Leuven, B-3000, Belgium.
5. Medical University of Innsbruck, Department of Transplant Surgery, D. Swarovski Research Laboratory, Innsbruck, A-6020 Austria.
6. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
7. The Henry Wellcome Building for Molecular Physiology, Oxford, OX3 7BN, UK.
8. Division of Medicine, Hammersmith Campus, Imperial College London, London, W12 ONN, UK.
9. Exercise and Health Laboratory, Faculty of Kinesiology and Rehabilitation Sciences, K.U. Leuven, B-3001 Leuven, Belgium.
10. Laboratory of Bioenergetics and Molecular Physiology, Department of Life Sciences, University of Liege, 4000 Liege, Belgium.
11. Department of Nuclear Medicine, University Hospital, K.U. Leuven, Leuven, B-3000 Belgium.
12. Biomedical Magnetic Resonance Unit, Medicinal Chemistry and Radiopharmacy, U.C. Louvain, B-1200 Brussels, Belgium.
13. Cardiovascular Research Program, Oklahoma Medical Research Foundation, Oklahoma 73104, USA.
14. Skyscan NV, B-2630 Aartselaar, Belgium.
15. Diabetes Research Center, Free University of Brussels, B-1090 Brussels, Belgium.
16. Laboratory for Physiology, Immunology and Genetics of Domestic Animals, Department of Biosystems, K.U. Leuven, Leuven, B-3001, Belgium.
17. Gene Expression Unit, Department of Molecular Cell Biology, K.U. Leuven, Leuven, B-3000, Belgium.
18. Department of Molecular Cell Biology, Laboratorium for Lipid Biochemistry and Protein Interactions (LIPIT), K.U. Leuven, B-3000 Belgium.
19. Current addresses: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg, Germany (M.S.) and Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany (C.W.).
20. These authors contributed equally to this work.

Correspondence to: Peter Carmeliet^1,2 e-mail: peter.carmeliet@med.kuleuven.be

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