Regular endurance training reduces the exercise induced HIF-1α and HIF-2α mRNA expression in human skeletal muscle in normoxic conditions

Regular exercise induces a variety of adaptive responses that enhance the oxidative and metabolic capacity of human skeletal muscle. Although the physiological adjustments of regular exercise have been known for decades, the underlying mechanisms are still unclear. The hypoxia inducible factors 1 and 2 (HIFs) are clearly related heterodimeric transcription factors that consist of an oxygen-depended α-subunit and a constitutive β-subunit. With hypoxic exposure, HIF-1α and HIF-2α protein are stabilized. Upon heterodimerization, HIFs induce the transcription of a variety of genes including erythropoietin (EPO), transferrin and its receptor, as well as vascular endothelial growth factor (VEGF) and its receptor. Considering that several of these genes are also induced with exercise, we tested the hypothesis that the mRNA level of HIF-1α and HIF-2α subunits increases with a single exercise bout, and that this response is blunted with training. We obtained muscle biopsies from a trained (5 days/week during 4 weeks) and untrained leg from the same human subject before, immediately after, and during the recovery from a 3 h two-legged knee extensor exercise bout, where the two legs exercised at the same absolute workload. In the untrained leg, the exercise bout induced an increase (P<0.05) in HIF-1α fold and HIF-2α fold mRNA at 6 h of recovery. In contrast, HIF-1α and HIF-2α mRNA levels were not altered at any time point in the trained leg. Obviously, HIF-1α and HIF-2α mRNA levels are transiently increased in untrained human skeletal muscle in response to an acute exercise bout, but this response is blunted after exercise training. We propose that HIFs expression is upregulated with exercise and that it may be an important transcription factor that regulates adaptive gene responses to exercise.