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

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