UC San Diego

Exercise forces skeletal muscle to deal with severe oxygen stress, causing the muscle to have to balance oxygen demand with oxygen availability. Endurance training further challenges the muscle by repeatedly exposing it to lowered oxygen levels. The muscle's ability to cope with this oxygen stress is essential for its function in the body. The primary response pathway for hypoxia runs through the transcription factor Hypoxia Inducible Factor- 1alpha (HIF-1a), a transcription factor which upregulates glycolysis and angiogenesis in response to hypoxia. To study the role of HIF-1a in untrained and endurance- trained muscle, we have created a mouse lacking HIF-1a specifically in the skeletal muscle. Although structurally normal, loss of HIF-1a results in muscles that are unable to maintain glycolytic flux in response to exertion. As a result, the muscles undergo an adaptive compensatory response resulting in increased oxidative capacity. This response makes the HIF-1a null mice more suited for endurance exercise, as they have greater sub-maximal endurance relative to control littermates. The endurance advantage comes at a cost, though, as HIF-1a null muscles experience severe muscle damage in response to exhaustive exercise. Endurance training of the mice shows that both control and HIF-1a null mice are able to improve overall endurance due to an increase in hexokinase activity. However, only control mice can improve oxidative capacity, as HIF-1a null mice were unable to improve on already elevated levels of citrate synthase and beta-hydroxyacyl- CoA dehydrogenase, and elevated capillary to fiber ratios. Examination of HIF-1a null muscles reveals that they have constitutively active AMP-activated protein kinase (AMPK). This activation of AMPK correlates with the adaptive response of the HIF-1a null muscle, making it a likely cause of the increase in oxidative capacity. In conclusion, HIF-1a in the skeletal muscle is important for maintaining glycolytic flux, but is not essential for the muscular response to endurance training. Removal of HIF-1a from the muscle results in the muscle being more suited for endurance exercise and training