title: Skeletal muscle hypoxia-inducible factor-1 and exercise.
abstract: Reduced oxygen levels in skeletal muscle during exercise are a consequence of increased oxygen consumption. The cellular response to hypoxia is conferred to a large extent by activation of the hypoxia-sensitive transcription factor hypoxia-inducible factor-1 (HIF-1). The target genes of HIF-1 increase oxygen transport through mechanisms such as erythropoietin-mediated erythropoiesis and vascular endothelial growth factor-induced angiogenesis and improve tissue function during low oxygen availability through increased expression of glucose transporters and glycolytic enzymes, which makes HIF-1 an interesting candidate as a mediator of skeletal muscle adaptation to endurance training. However, HIF-1 may also inhibit cellular oxygen consumption and mitochondrial oxidative metabolism, features discordant with the phenotype of a trained muscle. Skeletal muscle readily adjusts to altered functional demands. Adaptation of skeletal muscle to long-term aerobic training enables better aerobic performance at higher intensities through improved metabolic capacity and oxygen supply. The components of acute exercise that act as triggers for adaptation are still largely unknown; however, an early hypothesis was that local hypoxia acts as a possible stimulus for exercise adaptation. The hypoxia-sensitive subunit, HIF-1α, is stabilized in skeletal muscle in response to an acute bout of endurance exercise. However, long-term endurance exercise seems to attenuate the acute HIF-1α response. This attenuation is concurrent with an increase in expression of several negative regulators of the HIF system. We propose that the HIF-1α response is blunted in response to long-term exercise training through induction of its negative regulators and that this inhibition enables the enhanced oxidative metabolism that is part of a local physiological response to exercise.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Malene E
authors.initials: ME
authors.lastname: Lindholm
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Helene
authors.initials: H
authors.lastname: Rundqvist
mesh_terms: D000818:Animals; D015444:Exercise / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism* / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology*; D010805:Physical Conditioning, Animal / Q000502:physiology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit