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

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2007-11, Vol.293 (5), p.R2059-R2069
• Main Authors: Mason, Steven D., Rundqvist, Helene, Papandreou, Ioanna, Duh, Roger, McNulty, Wayne J., Howlett, Richard A., Olfert, I. Mark, Sundberg, Carl Johan, Denko, Nicholas C., Poellinger, Lorenz, Johnson, Randall S.
• Format: Article
• Language: English
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00335.2007

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-1α (HIF-1α), which upregulates glycolysis and angiogenesis in response to low levels of tissue oxygenation. To examine the role of HIF-1α in endurance training, we have created mice specifically lacking skeletal muscle HIF-1α 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-1α null mice have already upregulated this parameter without training. Furthermore, untrained HIF-1α 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-1α null muscles. Additionally, HIF-1α null muscles have decreased expression of pyruvate dehydrogenase kinase I, a HIF-1α target that inhibits oxidative metabolism. These data demonstrate that removal of HIF-1α causes an adaptive response in skeletal muscle akin to endurance training and provides evidence for the suppression of mitochondrial biogenesis by HIF-1α in normal tissue.