title: Alterations to mitochondrial fatty-acid use in skeletal muscle after chronic exposure to hypoxia depend on metabolic phenotype.
abstract: We investigated the effects of chronic hypoxia on the maximal use of and sensitivity of mitochondria to different substrates in rat slow-oxidative (soleus, SOL) and fast-glycolytic (extensor digitorum longus, EDL) muscles. We studied mitochondrial respiration in situ in permeabilized myofibers, using pyruvate, octanoate, palmitoyl-carnitine (PC), or palmitoyl-coenzyme A (PCoA). The hypophagia induced by hypoxia may also alter metabolism. Therefore, we used a group of pair-fed rats (reproducing the same caloric restriction, as observed in hypoxic animals), in addition to the normoxic control fed ad libitum. The resting respiratory exchange ratio decreased after 21 days of exposure to hypobaric hypoxia (simulated elevation of 5,500 m). The respiration supported by pyruvate and octanoate were unaffected. In contrast, the maximal oxidative respiratory rate for PCoA, the transport of which depends on carnitine palmitoyltransferase 1 (CPT-1), decreased in the rapid-glycolytic EDL and increased in the slow-oxidative SOL, although hypoxia improved affinity for this substrate in both muscle types. PC and PCoA were oxidized similarly in normoxic EDL, whereas chronic hypoxia limited transport at the CPT-1 step in this muscle. The effects of hypoxia were mediated by caloric restriction in the SOL and by hypoxia itself in the EDL. We conclude that improvements in mitochondrial affinity for PCoA, a physiological long-chain fatty acid, would facilitate fatty-acid use at rest after chronic hypoxia independently of quantitative alterations of mitochondria. Conversely, decreasing the maximal oxidation of PCoA in fast-glycolytic muscles would limit fatty-acid use during exercise.NEW & NOTEWORTHYAffinity for low concentrations of long-chain fatty acids (LCFA) in mitochondria skeletal muscles increases after chronic hypoxia. Combined with a lower respiratory exchange ratio, this suggests facility for fatty acid utilization at rest. This fuel preference is related to caloric restriction in oxidative muscle and to hypoxia in glycolytic one. In contrast, maximal oxidation for LCFA is decreased by chronic hypoxia in glycolytic muscle and can explain glucose dependence at exercise.
authors.affiliation: Département des Environnements Opérationnels, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France; a.malgoyre@yahoo.fr.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Malgoyre
authors.affiliation: Laboratoire de Bioénergétique Fondamentale et Appliquée, Université Joseph Fourier and Institut National de la Santé et de la Recherche Médicale U1055, Grenoble France.
authors.forename: Clovis
authors.initials: C
authors.lastname: Chabert
authors.affiliation: Centre de Recherche du Service de Santé des Armées, La Tronche, La Tronche, France; and.
authors.forename: Julia
authors.initials: J
authors.lastname: Tonini
authors.affiliation: Département des Environnements Opérationnels, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France.|Ecole du Val de Grâce, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Koulmann
authors.affiliation: Département des Environnements Opérationnels, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France.|Ecole du Val de Grâce, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Bigard
authors.affiliation: Département des Environnements Opérationnels, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Sanchez
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D002908:Chronic Disease; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D008657:Metabolic Clearance Rate; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology*; D010100:Oxygen / Q000378:metabolism; D010805:Physical Conditioning, Animal; D051381:Rats; D017208:Rats, Wistar
chemical_list: D005227:Fatty Acids; D005947:Glucose; D010100:Oxygen
keywords: chronic hypoxia; fatty acid; mitochondrial affinity; oxidative capacities; rat; skeletal muscle