HIF-1alpha in endurance training: suppression of oxidative metabolism

Am J Physiol Regul Integr Comp Physiol. 2007 Nov;293(5):R2059-69. doi: 10.1152/ajpregu.00335.2007. Epub 2007 Sep 12.

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.

MeSH terms

  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Erythrocyte Count
  • Gene Expression / physiology
  • Hematocrit
  • Hemoglobins / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / blood
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Skeletal / enzymology
  • Muscle, Skeletal / metabolism
  • Myoblasts / physiology
  • Oxidation-Reduction
  • Oxygen / blood
  • Oxygen Consumption / genetics
  • Oxygen Consumption / physiology
  • Physical Conditioning, Animal / physiology*
  • Physical Endurance / physiology*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics

Substances

  • Hemoglobins
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Messenger
  • Cyclic AMP-Dependent Protein Kinases
  • Oxygen