title: HIF-1alpha in endurance training: suppression of oxidative metabolism.
abstract: During endurance training, exercising skeletal muscle experiences severe and repetitive oxygen stress. The primary transcriptional response factor for acclimation to hypoxic stress is hypoxia-inducible factor-1alpha (HIF-1alpha), which upregulates glycolysis and angiogenesis in response to low levels of tissue oxygenation. To examine the role of HIF-1alpha in endurance training, we have created mice specifically lacking skeletal muscle HIF-1alpha and subjected them to an endurance training protocol. We found that only wild-type mice improve their oxidative capacity, as measured by the respiratory exchange ratio; surprisingly, we found that HIF-1alpha null mice have already upregulated this parameter without training. Furthermore, untrained HIF-1alpha null mice have an increased capillary to fiber ratio and elevated oxidative enzyme activities. These changes correlate with constitutively activated AMP-activated protein kinase in the HIF-1alpha null muscles. Additionally, HIF-1alpha null muscles have decreased expression of pyruvate dehydrogenase kinase I, a HIF-1alpha target that inhibits oxidative metabolism. These data demonstrate that removal of HIF-1alpha causes an adaptive response in skeletal muscle akin to endurance training and provides evidence for the suppression of mitochondrial biogenesis by HIF-1alpha in normal tissue.
authors.affiliation: Div. of Biologicay, University of California, San Diego, La Jolla, CA 92093-0377, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Mason
authors.forename: Helene
authors.initials: H
authors.lastname: Rundqvist
authors.forename: Ioanna
authors.initials: I
authors.lastname: Papandreou
authors.forename: Roger
authors.initials: R
authors.lastname: Duh
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: McNulty
authors.forename: Richard A
authors.initials: RA
authors.lastname: Howlett
authors.forename: I Mark
authors.initials: IM
authors.lastname: Olfert
authors.forename: Carl Johan
authors.initials: CJ
authors.lastname: Sundberg
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Denko
authors.forename: Lorenz
authors.initials: L
authors.lastname: Poellinger
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004906:Erythrocyte Count; D015870:Gene Expression / Q000502:physiology; D006400:Hematocrit; D006454:Hemoglobins / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000097:blood / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D032446:Myoblasts / Q000502:physiology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000097:blood; D010101:Oxygen Consumption / Q000235:genetics / Q000502:physiology; D010805:Physical Conditioning, Animal / Q000502:physiology*; D010807:Physical Endurance / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
chemical_list: D006454:Hemoglobins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D017868:Cyclic AMP-Dependent Protein Kinases; D010100:Oxygen