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Changes in HIF-1α protein, pyruvate dehydrogenase phosphorylation, and activity with exercise in acute and chronic hypoxia

Citation

le Moine, CMR and Morash, AJ and McClelland, GB, Changes in HIF-1α protein, pyruvate dehydrogenase phosphorylation, and activity with exercise in acute and chronic hypoxia, American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 301, (4) pp. R1098-R1104. ISSN 0363-6119 (2011) [Refereed Article]

Copyright Statement

Copyright 2011 the American Physiological Society

DOI: doi:10.1152/ajpregu.00070.2011

Abstract

Exercise under acute hypoxia elicits a large increase in blood lactate concentration ([La]b) compared with 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 24 h (24H), 1 wk (1WH), or 4 wk (4WH) to hypobaric hypoxia (equivalent to 4,300 m), exercised under 12% O2, and compared with normoxic mice (N) at 21% O2. Since the enzyme pyruvate dehydrogenase (PDH) plays a major role in the metabolic fate of pyruvate (oxidation vs. 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 the 1WH group approached N group values. Concomitantly, the 24H group 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 with N and 1WH groups. 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.

Item Details

Item Type:Refereed Article
Keywords:acclimation, hypobaria, lactate, mice
Research Division:Biological Sciences
Research Group:Biochemistry and Cell Biology
Research Field:Cell Metabolism
Objective Division:Expanding Knowledge
Objective Group:Expanding Knowledge
Objective Field:Expanding Knowledge in the Medical and Health Sciences
Author:Morash, AJ (Dr Andrea Morash)
ID Code:95043
Year Published:2011
Web of Science® Times Cited:16
Deposited By:Research Division
Deposited On:2014-09-23
Last Modified:2014-10-09
Downloads:0

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