Exercise under acute hypoxia elicits a large increase in blood lactate ([La]b) compared to normoxic exercise. However, several studies in humans show that with the transition to chronic hypoxia, exercise [La]b returns to normoxic levels. Although extensively examined over the last decades, the muscle-specific mechanisms responsible for this phenomenon remain unknown. To assess the changes in skeletal muscle associated with a transition from acute to chronic hypoxia, CD-1 mice were exposed for 24hours (24H), 1 or 4 weeks (1WH and 4WH) to hypobaric hypoxia (equivalent to 4300m), exercised under 12% O2, and compared to normoxic mice (N) at 21% O2. As the enzyme pyruvate dehydrogenase (PDH) plays a major role in the metabolic fate of pyruvate (oxidation versus lactate production), we assessed the changes in its activity and regulation. Here we report that when run under hypoxia, 24H mice exhibited the highest blood and intramuscular lactate of all groups, while 1WH approached N values. Concomitantly, the 24H exhibited the lowest PDH activity, associated with a higher phosphorylation (inactive) state of the Ser232 residue of PDH, a site specific to PDH kinase 1 (PDK1). Furthermore, protein levels of PDK1 and its regulator, the hypoxia inducible factor-1α (HIF-1α), were both elevated in the 24H group compared to N and 1WH. Overall, our results point to a novel mechanism in muscle where the HIF-1α pathway is desensitized in the transition from acute to chronic hypoxia, leading to a reestablishment of PDH activity and a reduction in lactate production by the exercising muscles.
- Copyright © 2011, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology