Document Detail

Tricarboxylic acid cycle intermediate pool size: functional importance for oxidative metabolism in exercising human skeletal muscle.
MedLine Citation:
PMID:  18027994     Owner:  NLM     Status:  MEDLINE    
The tricarboxylic acid (TCA) cycle is the major final common pathway for oxidation of carbohydrates, lipids and some amino acids, which produces reducing equivalents in the form of nicotinamide adenine dinucleotide and flavin adenine dinucleotide that result in production of large amounts of adenosine triphosphate (ATP) via oxidative phosphorylation. Although regulated primarily by the products of ATP hydrolysis, in particular adenosine diphosphate, the rate of delivery of reducing equivalents to the electron transport chain is also a potential regulatory step of oxidative phosphorylation. The TCA cycle is responsible for the generation of approximately 67% of all reducing equivalents per molecule of glucose, hence factors that influence TCA cycle flux will be of critical importance for oxidative phosphorylation. TCA cycle flux is dependent upon the supply of acetyl units, activation of the three non-equilibrium reactions within the TCA cycle, and it has been suggested that an increase in the total concentration of the TCA cycle intermediates (TCAi) is also necessary to augment and maintain TCA cycle flux during exercise. This article reviews the evidence of the functional importance of the TCAi pool size for oxidative metabolism in exercising human skeletal muscle. In parallel with increased oxidative metabolism and TCA cycle flux during exercise, there is an exercise intensity-dependent 4- to 5-fold increase in the concentration of the TCAi. TCAi concentration reaches a peak after 10-15 minutes of exercise, and thereafter tends to decline. This seems to support the suggestion that the concentration of TCAi may be of functional importance for oxidative phosphorylation. However, researchers have been able to induce dissociations between TCAi pool size and oxidative energy provision using a variety of nutritional, pharmacological and exercise interventions. Brief periods of endurance training (5 days or 7 weeks) have been found to result in reduced TCAi pool expansion at the start of exercise (same absolute work intensity) in parallel with either equivalent or increased oxidative energy provision. Cycloserine inhibits alanine aminotransferase, which catalyses the predominant anaplerotic reaction in exercising human muscle. When infused into contracting rat hindlimb muscle, TCAi pool expansion was reduced by 25% with no significant change in oxidative energy provision or power output. Glutamine supplementation has been shown to enhance TCAi pool expansion at the start of exercise with no increase in oxidative energy provision. In summary, there is a consistent dissociation between the extent of TCAi pool expansion at the onset of exercise and oxidative energy provision. At the other end of the spectrum, the parallel loss of TCAi, glycogen and adenine nucleotides and accumulation of inosine monophosphate during prolonged exercise has led to the suggestion that there is a link between muscle glycogen depletion, reduced TCA cycle flux and the development of fatigue. However, analysis of serial biopsies during prolonged exercise demonstrated dissociation between muscle TCAi content and both muscle glycogen content and muscle oxygen uptake. In addition, the delay in fatigue development achieved through increased carbohydrate availability does not attenuate TCAi reduction during prolonged exercise. Therefore, TCAi concentration in whole muscle homogenate does not seem to be of functional importance. However, TCAi content can currently only be measured in whole muscle homogenate rather than the mitochondrial subfraction where TCA cycle reactions occur. In addition, anaplerotic flux rather than TCAi content per se is likely to be of greater importance in determining TCA cycle flux, since TCAi content is probably merely reflective of anaplerotic substrate concentration. Methodological advances are required to allow researchers to address the questions of whether oxidative phosphorylation is limited by mitochondrial TCAi content and/or anaplerotic flux.
Joanna L Bowtell; Simon Marwood; Mark Bruce; Dumitru Constantin-Teodosiu; Paul L Greenhaff
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Sports medicine (Auckland, N.Z.)     Volume:  37     ISSN:  0112-1642     ISO Abbreviation:  Sports Med     Publication Date:  2007  
Date Detail:
Created Date:  2007-11-21     Completed Date:  2008-03-05     Revised Date:  2009-11-03    
Medline Journal Info:
Nlm Unique ID:  8412297     Medline TA:  Sports Med     Country:  New Zealand    
Other Details:
Languages:  eng     Pagination:  1071-88     Citation Subset:  IM    
Academy of Sport, Physical Activity and Wellbeing, London South Bank University, London, UK.
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MeSH Terms
Citric Acid Cycle / physiology*
Exercise / physiology*
Great Britain
Muscle, Skeletal / metabolism*
Oxidative Phosphorylation*

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