title: HIF-1-driven skeletal muscle adaptations to chronic hypoxia: molecular insights into muscle physiology.
abstract: Skeletal muscle is a metabolically active tissue and the major body protein reservoir. Drop in ambient oxygen pressure likely results in a decrease in muscle cells oxygenation, reactive oxygen species (ROS) overproduction and stabilization of the oxygen-sensitive hypoxia-inducible factor (HIF)-1α. However, skeletal muscle seems to be quite resistant to hypoxia compared to other organs, probably because it is accustomed to hypoxic episodes during physical exercise. Few studies have observed HIF-1α accumulation in skeletal muscle during ambient hypoxia probably because of its transient stabilization. Nevertheless, skeletal muscle presents adaptations to hypoxia that fit with HIF-1 activation, although the exact contribution of HIF-2, I kappa B kinase and activating transcription factors, all potentially activated by hypoxia, needs to be determined. Metabolic alterations result in the inhibition of fatty acid oxidation, while activation of anaerobic glycolysis is less evident. Hypoxia causes mitochondrial remodeling and enhanced mitophagy that ultimately lead to a decrease in ROS production, and this acclimatization in turn contributes to HIF-1α destabilization. Likewise, hypoxia has structural consequences with muscle fiber atrophy due to mTOR-dependent inhibition of protein synthesis and transient activation of proteolysis. The decrease in muscle fiber area improves oxygen diffusion into muscle cells, while inhibition of protein synthesis, an ATP-consuming process, and reduction in muscle mass decreases energy demand. Amino acids released from muscle cells may also have protective and metabolic effects. Collectively, these results demonstrate that skeletal muscle copes with the energetic challenge imposed by O2 rarefaction via metabolic optimization.
authors: INRA, UMR 866 Dynamique Musculaire et Métabolisme, 34060, Montpellier, France. favier@supagro.inra.fr.|Université de Montpellier, 34090, Montpellier, France. favier@supagro.inra.fr.
authors: F B
authors: FB
authors: Favier
authors: INRA, UMR 866 Dynamique Musculaire et Métabolisme, 34060, Montpellier, France.|Université de Montpellier, 34090, Montpellier, France.
authors: F A
authors: FA
authors: Britto
authors: Laboratoire de Physiologie de l'Exercice EA 4338, Université de Lyon, Université Jean Monnet, 42000, Saint Etienne, France.
authors: D G
authors: DG
authors: Freyssenet
authors: Agence Française de Lutte contre le Dopage, 75007, Paris, France.
authors: X A
authors: XA
authors: Bigard
authors: INSERM, U1042 Hypoxie Physio-Pathologie, 38000, Grenoble, France.|Université Joseph Fourier, 38000, Grenoble, France.
authors: H
authors: H
authors: Benoit
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D053858:Metabolic Networks and Pathways; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D010100:Oxygen
keywords: Altitude; Atrophy; Hypoxia inducible factor; Metabolism; Mitochondria; Oxidative stress