7680 Targeting HIF1α Enhances Exercise Benefits in High Fat Diet-Fed Mice

Abstract Disclosure: J. Yu: None. C. Cheung: None. J.E. Gunton: None. Exercise is well-established to be beneficial for obesity, type 2 diabetes (T2D) and cardiovascular health. Exercise induces hypoxia inducible factor 1α (HIF1α) in muscle. HIF1α is well-known for its role in cell survival and adaptation, particularly in states of hypoxia. Interestingly, in obesity and diabetes, HIF1α can exert either beneficial or harmful effects (1). We hypothesised that these differing outcomes may relate to different hydroxylation of HIF1α. Using CRISPR-Cas9 technology, we created a novel mouse model removing the asparagine hydroxylation site: HIF1α-N813Q mice. We explored the effects of exercise and high fat diet (HFD) feeding in N813Q mice. The hypothesis is that N813Q mice will be protected from adverse consequences of HFD, and experience greater benefits with exercise. Male HIF1α-N813Q mutant mice and their wild-type (WT) littermates underwent glucose and insulin tolerance tests (GTT and ITT), fore-limb grip strength and endurance testing. They were then fed HFD (Diet 6B; 45% digestible energy from lipids) and given access to a running wheel in their home cages, with the wheels being locked for controls. Metabolic and muscle function tests were repeated during the experiment. Baseline data did not show any significant differences between genotypes in glucose and insulin tolerance, endurance or grip strength. On HFD, weight gain and fat mass were significantly reduced in mutant mice given access to a wheel but not any of the other groups. After 3 weeks of wheel access, N813Q-exercise mice had significantly enhanced grip strength (p<0.05) and increased endurance which further increased by 6 weeks. Strikingly, the 3-week improvement in mutant-exercise mice was comparable to the improvement observed at 10 weeks in WT-exercise mice. WT mice exhibited a higher percentage of lipid between myofibers whereas, mutant mice had a significantly elevated proportion of myocellular lipid depots in small droplets. Overall, the novel HIF1α mice have enhanced improvements in muscle functionality and metabolism with exercise. This suggests that targeting HIF1α is a potential mechanism to substantially augment the beneficial effects of exercise. Reference: (1). Gunton JE. J Clin Invest. 2020 Oct 1;130(10):5063-5073. Presentation: 6/3/2024