The role of HIF-1 in hypoxic response in the skeletal muscle.

During endurance training, exercising skeletal muscle experiences severe and repetitive oxygen stress, and the muscle's ability to cope with and improve its function through that stress is central to its role in the body. The primary transcriptional response factor for hypoxic adaptation 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. This data demonstrates 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.