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.
Aragonés
Julián
J
The Center for Transgene Technology and Gene Therapy, Katholieke Universiteit (K.U.) Leuven, Leuven, B-3000, Belgium.
Schneider
Martin
M
Van Geyte
Katie
K
Fraisl
Peter
P
Dresselaers
Tom
T
Mazzone
Massimiliano
M
Dirkx
Ruud
R
Zacchigna
Serena
S
Lemieux
Hélène
H
Jeoung
Nam Ho
NH
Lambrechts
Diether
D
Bishop
Tammie
T
Lafuste
Peggy
P
Diez-Juan
Antonio
A
Harten
Sarah K
SK
Van Noten
Pieter
P
De Bock
Katrien
K
Willam
Carsten
C
Tjwa
Marc
M
Grosfeld
Alexandra
A
Navet
Rachel
R
Moons
Lieve
L
Vandendriessche
Thierry
T
Deroose
Christophe
C
Wijeyekoon
Bhathiya
B
Nuyts
Johan
J
Jordan
Benedicte
B
Silasi-Mansat
Robert
R
Lupu
Florea
F
Dewerchin
Mieke
M
Pugh
Chris
C
Salmon
Phil
P
Mortelmans
Luc
L
Gallez
Bernard
B
Gorus
Frans
F
Buyse
Johan
J
Sluse
Francis
F
Harris
Robert A
RA
Gnaiger
Erich
E
Hespel
Peter
P
Van Hecke
Paul
P
Schuit
Frans
F
Van Veldhoven
Paul
P
Ratcliffe
Peter
P
Baes
Myriam
M
Maxwell
Patrick
P
Carmeliet
Peter
P
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
D002247:Carbon Isotopes; D002250:Carbon Radioisotopes; D005971:Glutamates; D002245:Carbon Dioxide; C522721:PHD1 protein, mouse; D011393:Procollagen-Proline Dioxygenase; D005947:Glucose