Document Detail


Negative regulation of HIF in skeletal muscle of elite endurance athletes - a tentative mechanism promoting oxidative metabolism.
MedLine Citation:
PMID:  24898836     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The transcription factor hypoxia inducible factor (HIF) has been suggested as a candidate for mediating training adaptation in skeletal muscle. However, recent evidence rather associates HIF attenuation with a trained phenotype. For example, a muscle specific HIF deletion increases endurance performance, partly through decreased levels of pyruvate dehydrogenase kinase 1 (PDK-1). HIF activity is regulated on multiple levels; modulation of protein stability, transactivation capacity and target gene availability. Prolyl hydroxylases (PHD1-3) induces HIF degradation, while Factor Inhibiting HIF (FIH) and the histone deacetylase sirtuin-6 (SIRT6) repress its transcriptional activity. Together, these negative regulators introduce a mechanism for moderating HIF activity in vivo. We hypothesized that long-term training induces their expression. Negative regulators of HIF were explored by comparing skeletal muscle tissue from moderately active individuals (MA) with elite athletes (EA). In elite athletes, expression of the negative regulators; PHD2 (MA 73.54±9.54, EA 98.03±6.58), FIH (MA 4.31±0.25, EA 30.96±7.99) and SIRT6 (MA 0.24±0.07, EA 11.42±2.22), were all significantly higher, while the response gene PDK-1 was lower (MA 0.12±0.03, EA 0.04±0.01). Similar results were observed in a separate six-week training study. In vitro, activation of HIF in human primary muscle cell culture by PHD inactivation, strongly induced PDK-1 (0.84±0.12 vs 4.70±0.63), providing evidence of a regulatory link between PHD activity and PDK-1 levels in a relevant model system. Citrate synthase activity, closely associated with aerobic exercise adaptation, increased upon PDK-1 silencing. We suggest that training-induced negative regulation of HIF mediates the attenuation of PDK-1 and contributes to skeletal muscle adaptation to exercise.
Authors:
Malene E Lindholm; Helene Fischer; Lorenz Poellinger; Randall S Johnson; Thomas Gustafsson; Carl Johan Sundberg; Helene Rundqvist
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-6-4
Journal Detail:
Title:  American journal of physiology. Regulatory, integrative and comparative physiology     Volume:  -     ISSN:  1522-1490     ISO Abbreviation:  Am. J. Physiol. Regul. Integr. Comp. Physiol.     Publication Date:  2014 Jun 
Date Detail:
Created Date:  2014-6-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901230     Medline TA:  Am J Physiol Regul Integr Comp Physiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2013, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology.
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