Document Detail


PDH activation by dichloroacetate reduces TCA cycle intermediates at rest but not during exercise in humans.
MedLine Citation:
PMID:  10409125     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We hypothesized that dichloroacetate (DCA), which stimulates the pyruvate dehydrogenase complex (PDH), would attenuate the increase in muscle tricarboxylic acid cycle intermediates (TCAI) during exercise by increasing the oxidative disposal of pyruvate and attenuating the flux through anaplerotic pathways. Six subjects were infused with either saline (Con) or DCA (100 mg/kg body mass) and then performed a moderate leg kicking exercise for 15 min, followed immediately by intense exercise until exhaustion (Exh; approximately 4 min). Resting active fraction of PDH (PDH(a)) was markedly increased (P </= 0.05) after DCA vs. Con (2.65 +/- 0.27 vs. 0.64 +/- 0.07 mmol. min(-1). kg wet wt(-1)); however, there were no differences between trials after 1 or 15 min of exercise or at Exh. The sum of five measured TCAI (SigmaTCAI; approximately 90% of total TCAI pool) was lower (P </= 0.05) after DCA vs. Con at rest (0. 78 +/- 0.11 vs. 1.52 +/- 0.23 mmol/kg dry wt, respectively). However, the net increase in muscle TCAI during the first minute of exercise was higher (P </= 0.05) in the DCA trial vs. Con (3.05 +/- 0.45 vs. 2.44 +/- 0.55 mmol. min(-1). kg dry wt(-1), respectively), and consequently, the SigmaTCAI was not different between trials during exercise. We conclude that DCA reduced TCAI pool size at rest by increasing the flux through PDH and diverting pyruvate away from anaplerotic pathways. The reason for the similar absolute increase in TCAI during exercise is not clear but may be related to 1) an initial mismatch between glycolytic flux and PDH flux that provided sufficient pyruvate for anaplerosis in both trials; or 2) a transient inhibition of PDH flux during the DCA trial due to an elevated resting acetyl-CoA-to-CoASH ratio, which augmented the anaplerotic flux of carbon during the rest-to-work transition.
Authors:
M J Gibala; B Saltin
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Publication Detail:
Type:  Clinical Trial; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The American journal of physiology     Volume:  277     ISSN:  0002-9513     ISO Abbreviation:  Am. J. Physiol.     Publication Date:  1999 Jul 
Date Detail:
Created Date:  1999-08-18     Completed Date:  1999-08-18     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0370511     Medline TA:  Am J Physiol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  E33-8     Citation Subset:  IM    
Affiliation:
Copenhagen Muscle Research Center, Rigshospitalet, DK-2200 Copenhagen N, Denmark. gibalam@mcmaster.ca
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MeSH Terms
Descriptor/Qualifier:
Adult
Citric Acid Cycle / drug effects*
Dichloroacetate / pharmacology*
Enzyme Activation / physiology*
Exercise / physiology*
Female
Humans
Leg / physiology
Male
Pyruvate Dehydrogenase Complex / metabolism*
Rest
Chemical
Reg. No./Substance:
0/Pyruvate Dehydrogenase Complex; 13425-80-4/Dichloroacetate

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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