Negative Regulation Of HIF-1 Through FIH And SIRT6 In Elite Athletes And With Training

Abstract

Hypoxia inducible factor 1α (HIF-1α) is a hypoxia sensitive transcription factor suggested to be involved in skeletal muscle adaptation to endurance training. HIF-1α is stabilized in response to an acute bout of exercise, but there is debate regarding the HIF-1 system in response to long-term training. HIF-1 activity is mainly regulated through hydroxylation by prolyl hydroxylases, (PHD1-3), leading to degradation. We have previously shown that PHD2 is the dominant prolyl hydroxylase in human skeletal muscle and that the levels are higher in elite athletes compared to sedentary individuals, while the response gene pyruvate dehydrogenase kinase 1 (PDK-1) is lower. PDK-1 inhibits the activity of pyruvate dehydrogenase, the limiting step for aerobic metabolism. Both factor inhibiting HIF (FIH) and SIRT6 inhibit the transcriptional activity of HIF-1, FIH through inhibition of cofactor binding and SIRT6 as a corepressor through deacetylation of histone 3 lysine 9 of several of the HIF-1 response genes. PURPOSE: To elucidate the role of HIF-1 in endurance-training adapted human skeletal muscle. METHODS: Skeletal muscle biopsies were obtained at rest from the vastus lateralis muscle of 12 males with high oxidative capacity and 9 sedentary controls, as well as from eight sedentary males before and after four weeks of one-legged bicycle training. RESULTS: In elite athletes, the mRNA and protein levels of FIH are seven and four times higher than in control subjects respectively (p<0.05). SIRT6 expression is also seven times higher (p<0.05) in elite athletes. Similar trends are seen in response to four weeks of one-legged endurance training, with 45 % and 35 % increases in expression of FIH (p=0.07) and SIRT6 (p=0.08) respectively. CONCLUSIONS: Elite athletes have significantly higher levels of FIH and SIRT6 than the sedentary control group, and the trend seen in response to only four weeks of training indicate that this is a training-induced response. In combination with previously reported data of higher PHD2 and lower PDK-1 levels in elite athletes, these data suggest an attenuated HIF-1 response with long-term training and an important switch from glycolysis in favor of increased mitochondrial activity.