Dissociation between muscle tricarboxylic acid cycle pool size and aerobic energy provision during prolonged exercise in humans
Open accessAbstract
It has been suggested that a decrease in the total concentration of tricarboxylic acid cycle intermediates (TCAIs)--secondary to a reduction in glycogen availability--compromises oxidative energy provision in skeletal muscle during prolonged exercise. However, no study has directly tested this hypothesis. We therefore studied six men (28 +/- 2 years) during 90 min of leg kicking exercise at an intensity equivalent to 70 % of maximum. Biopsies (vastus lateralis) were obtained at rest and after 5, 10, 15, 30, 60 and 90 min of exercise, and thigh oxygen uptake (V(O(2),thigh)) was calculated according to the Fick principle. The sum of six measured TCAIs (approximately 95 % of total pool size) was 1.30 +/- 0.15 mmol (kg dry wt)(-1) at rest and increased (P < or = 0.05) rapidly during exercise to a peak value of 3.15 +/- 0.23 mmol (kg dry wt)(-1) after 10 min. Thereafter, the [TCAI] declined to 2.14 +/- 0.23, 1.73 +/- 0.32 and 1.62 +/- 0.10 mmol (kg dry wt)(-1) after 30, 60 and 90 min, respectively (P < or = 0.05 vs.10 min). Despite the 50 % decrease in [TCAI], aerobic energy provision was not compromised, as evidenced by stable V(O(2),thigh) values throughout the entire exercise bout and little change in muscle [phosphocreatine] after 10 min. The largest decrease in [TCAI] (delta = 1.00 +/- 0.24 mmol (kg dry wt)(-1)) occurred from 10 to 30 min of exercise despite the fact that muscle [glycogen] remained relatively high at this point in exercise (approximately 274 +/- 24 mmol (kg dry wt)(-1) after 30 min; approximately 65 % of rest value). Conversely, there was little change in [TCAI] during the final 30 min of exercise (delta = 0.11 +/- 0.29 mmol (kg dry wt)(-1)) despite a decrease in [glycogen] to approximately 72 +/- 3 mmol (kg dry wt)(-1) after 90 min (approximately 13 % of rest value). We conclude that there is a progressive decrease in muscle [TCAI] during prolonged exercise in humans; however this decrease does not compromise aerobic energy provision and is not attributable to the depletion of muscle [glycogen].
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In humans, a dissociation between TCA cycle pool size and aerobic phosphorylation was demonstrated, suggesting that TCA intermediate content does not represent any functional importance to oxidative phosphorylation.
“In humans, a dissociation between TCA cycle pool size and aerobic phosphorylation was demonstrated [184,185], suggesting that TCA intermediate content does not represent any functional importance to oxidative phosphorylation [182].”
From Regulation of Energy Substrate Metabolism in Endurance Exercise (2021) · cites this paper as [184]
Cites
Maximal perfusion of skeletal muscle in man.
Andersen, P., & Saltin, B. (1985) · The Journal of Physiology · doi:10.1113/jphysiol.1985.sp015794 · Cited by 1,250 · see citing works
Self-citationBiochemistry for the Medical Sciences
Newsholme, E. A., & Leech, A. R. (1983) · Andalas University Repository (Andalas University) · Cited by 940 · see citing works
Harris, R. C., Hultman, E., & Nordesjö, L. ‐. (1974) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.3109/00365517409082477 · Cited by 857 · see citing works
Enzymatic analysis; a practical guide
(1993) · General Pharmacology The Vascular System · doi:10.1016/0306-3623(93)90404-l · Cited by 522 · see citing works
Jones, P. R., & PEARSON, J. S. (1969) · PubMed · Cited by 429 · see citing works
Harris, R. C., Hultman, E., & Nordesjö, L. O. (1974) · PubMed · Cited by 315 · see citing works
Passonneau, J. V., & Lowry, O. H. (1993) · Humana Press eBooks · doi:10.1007/978-1-60327-407-4 · Cited by 300 · see citing works
Tricarboxylic acid cycle intermediates in human muscle during prolonged exercise
Sahlin, K., Katz, A., & Broberg, S. (1990) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1990.259.5.c834 · Cited by 274 · see citing works
Interaction of factors determining oxygen uptake at the onset of exercise
Tschakovsky, M. E., & Hughson, R. L. (1999) · Journal of Applied Physiology · doi:10.1152/jappl.1999.86.4.1101 · Cited by 254 · see citing works
Fructose-1, 6-diphosphate Aldolase UV Assay, Manuel Method
Bergmeyer, H. U., & Bernt, E. (1974) · Elsevier eBooks · doi:10.1016/b978-0-12-091302-2.50109-2 · Cited by 251 · see citing works
Muscle amino acid metabolism at rest and during exercise: role in human physiology and metabolism.
Wagenmakers, A. J. M. (1998) · PubMed · Cited by 225 · see citing works
Exercise Physiology: Exercise, Performance, and Clinical Applications
Rodean, J. (1997) · Medicine & Science in Sports & Exercise · doi:10.1097/00005768-199702000-00019 · Cited by 206 · see citing works
Gibala, M. J., MacLean, D. A., Graham, T. E., & Saltin, B. (1998) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1998.275.2.e235 · Cited by 160 · see citing works
Self-citationExercise Physiology: Exercise, Performance, and Clinical Applications
Robergs, R. A., & Roberts, S. O. (1997) · Medical Entomology and Zoology · Cited by 154 · see citing works
Exercise-induced activation of the branched-chain 2-oxo acid dehydrogenase in human muscle
Wagenmakers, A. J. M., Brookes, J. H., Coakley, J. H., Reilly, T., & Edwards, R. H. T. (1989) · European Journal of Applied Physiology and Occupational Physiology · doi:10.1007/bf02386181 · Cited by 148 · see citing works
Exercise and Sports Science Reviews
Frisch, S. G. (1989) · American Journal of Physical Medicine & Rehabilitation · doi:10.1097/00002060-198904000-00017 · Cited by 144 · see citing works
Metabolism of Branched-Chain Amino Acids and Ammonia During Exercise: Clues from McArdle's Disease*
Wagenmakers, A. J. M., Coakley, J., & Edwards, R. H. T. (1990) · International Journal of Sports Medicine · doi:10.1055/s-2007-1024861 · Cited by 139 · see citing works
Muscle alanine synthesis and hepatic gluconeogenesis
Snell, K. (1980) · Biochemical Society Transactions · doi:10.1042/bst0080205 · Cited by 106 · see citing works
Carbohydrate supplementation attenuates IMP accumulation in human muscle during prolonged exercise
SPENCER, M. K., Yan, Z., & Katz, A. (1991) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1991.261.1.c71 · Cited by 98 · see citing works
Taegtmeyer, H. (1983) · Basic Research in Cardiology · doi:10.1007/bf02070167 · Cited by 88 · see citing works
Tricarboxylic acid cycle intermediates in human muscle at rest and during prolonged cycling
Gibala, M. J., Tarnopolsky, M. A., & Graham, T. E. (1997) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1997.272.2.e239 · Cited by 84 · see citing works
Self-citationEffect of low glycogen on carbohydrate and energy metabolism in human muscle during exercise
SPENCER, M. K., Yan, Z., & Katz, A. L. (1992) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1992.262.4.c975 · Cited by 84 · see citing works
Anaplerotic processes in human skeletal muscle during brief dynamic exercise
Gibala, M. J., MacLean, D. A., Graham, T. E., & Saltin, B. (1997) · The Journal of Physiology · doi:10.1111/j.1469-7793.1997.703bj.x · Cited by 83 · see citing works
Self-citationvan Hall, G., MacLean, D. A., Saltin, B., & Wagenmakers, A. J. M. (1996) · The Journal of Physiology · doi:10.1113/jphysiol.1996.sp021542 · Cited by 74 · see citing works
Self-citationFree amino acids in muscle tissue and plasma during exercise in man
Bergström, J. P., Fürst, P., & Hultman, E. (1985) · Clinical Physiology · doi:10.1111/j.1475-097x.1985.tb00591.x · Cited by 73 · see citing works
Gleeson, M. (2000) · doi:10.1002/9780470693766.ch2 · Cited by 67 · see citing works
Influence of Exercise on Protein and Amino Acid Metabolism
Rennie, M. J. (1996) · Comprehensive physiology · doi:10.1002/cphy.cp120122 · Cited by 62 · see citing works
Bruce, M., Constantin‐Teodosiu, D., Greenhaff, P. L., Boobis, L., Williams, C., & Bowtell, J. L. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.280.4.e669 · Cited by 53 · see citing works
Sahlin, K., Jorfeldt, L., Henriksson, K. G., Lewis, S. F., & Haller, R. G. (1995) · Clinical Science · doi:10.1042/cs0880687 · Cited by 52 · see citing works
Role of glycogen in control of glycolysis and IMP formation in human muscle during exercise
SPENCER, M. K., & Katz, A. (1991) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1991.260.6.e859 · Cited by 49 · see citing works
The importance of pyruvate availability to PDC activation and anaplerosis in human skeletal muscle
Constantin‐Teodosiu, D., Simpson, E. J., & Greenhaff, P. L. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.276.3.e472 · Cited by 44 · see citing works
Gibala, M. J., Peirce, N., Constantin‐Teodosiu, D., & Greenhaff, P. L. (2002) · The Journal of Physiology · doi:10.1113/jphysiol.2001.012983 · Cited by 37 · see citing works
Self-citationGibala, M. J., & Saltin, B. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.277.1.e33 · Cited by 32 · see citing works
Self-citationNutritional status affects branched-chain oxoacid dehydrogenase activity during exercise in humans
Jackman, M. L., Gibala, M. J., Hultman, E., & Graham, T. E. (1997) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1997.272.2.e233 · Cited by 29 · see citing works
Self-citationGibala, M. J., Lozej, M., Tarnopolsky, M. A., McLean, C., & Graham, T. E. (1999) · Journal of Applied Physiology · doi:10.1152/jappl.1999.87.5.1662 · Cited by 24 · see citing works
Self-citationExercise causes branched-chain oxoacid dehydrogenase dephosphorylation but not AMP deaminase binding
Rush, J. W. E., MacLean, D. A., Hultman, E., & Graham, T. E. (1995) · Journal of Applied Physiology · doi:10.1152/jappl.1995.78.6.2193 · Cited by 15 · see citing works
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Cerebral perturbations provoked by prolonged exercise
Nybo, L., & Secher, N. H. (2004) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2004.03.005 · Cited by 398 · see citing works
Light, A. R., Hughen, R. W., Zhang, J., Rainier, J. D., Liu, Z., & Lee, J. (2008) · Journal of Neurophysiology · doi:10.1152/jn.01344.2007 · Cited by 278 · see citing works
Logical limitations to the “catastrophe” models of fatigue during exercise in humans
Noakes, T. D., & Gibson, A. S. C. (2004) · British Journal of Sports Medicine · doi:10.1136/bjsm.2003.009761 · Cited by 259 · see citing works
Brachial Artery Blood Flow Responses to Different Modalities of Lower Limb Exercise
Thijssen, D. H. J., Dawson, E. A., Black, M. A., Hopman, M. T. E., Cable, N. T., & GREEN, D. J. (2009) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0b013e3181923957 · Cited by 201 · see citing works
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VAN ESSEN, M., & GIBALA, M. J. (2006) · Medicine & Science in Sports & Exercise · doi:10.1249/01.mss.0000228958.82968.0a · Cited by 118 · see citing works
Self-citationRegulation of Energy Substrate Metabolism in Endurance Exercise
Alghannam, A. F., Ghaith, M. M., & Alhussain, M. H. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18094963 · Cited by 104 · see citing works
Carbohydrate Administration and Exercise Performance: What Are the Potential Mechanisms Involved?
Karelis, A. D., Smith, J. W., Passe, D. H., & Péronnet, F. (2010) · Sports Medicine · doi:10.2165/11533080-000000000-00000 · Cited by 101 · see citing works
Alghannam, A. F., Gonzalez, J. T., & Betts, J. A. (2018) · Nutrients · doi:10.3390/nu10020253 · Cited by 99 · see citing works
Bowtell, J. L., Marwood, S., Bruce, M., Constantin-Teodosiu, D., & Greenhaff, P. L. (2007) · Sports Medicine · doi:10.2165/00007256-200737120-00005 · Cited by 81 · see citing works
de Campos‐Ferraz, P. L., Bozza, T., Nicastro, H., & Lancha, A. H. (2013) · Nutrition · doi:10.1016/j.nut.2013.05.003 · Cited by 57 · see citing works
Mourtzakis, M., Saltin, B., Graham, T. E., & Pilegaard, H. (2006) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00571.2005 · Cited by 55 · see citing works
Self-citationLi, Y., Dash, R. K., Kim, J., Saidel, G. M., & Cabrera, M. E. (2008) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00094.2008 · Cited by 46 · see citing works
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Eisner, V., Parra, V., Lavandero, S., Hidalgo, C., & Jaimovich, E. (2010) · Cell Calcium · doi:10.1016/j.ceca.2010.11.001 · Cited by 31 · see citing works
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Self-citationWalton, M., Ebert, D. J., & Haller, R. G. (2003) · The Journal of Physiology · doi:10.1111/j.1469-7793.2003.00541.x · Cited by 18 · see citing works
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Helmering, J., Juan, T., Li, C. M., Chhoa, M., Baron, W., Gyuris, T., Richards, W. G., Turk, J. R., Lawrence, J., Cosgrove, P. A., et al. (2014) · Lipids in Health and Disease · doi:10.1186/1476-511x-13-167 · Cited by 17 · see citing works
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- Authors
- Gibala, M. J., González‐Alonso, J., & Saltin, B.
- Affiliations
- Rigshospitalet (DK)
- Corresponding author
- Gibala, Martin J.
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2002-12
- Volume
- 545
- Issue
- 2
- Pages
- 705-713
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC2290699
- OpenAlex
- W1996146747
- Cited by
- 45
- References
- 36
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 1 · 2021: 1 · 2018: 1 · 2017: 1 · 2014: 1 · 2013: 2
- FWCI
- 7.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Danmarks Grundforskningsfond
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Keywords
- tricarboxylic acid cycle intermediates, prolonged exercise, skeletal muscle, muscle glycogen, phosphocreatine, oxidative metabolism, vastus lateralis, glycogen depletion, muscle energy metabolism, substrate utilization, substrate oxidation
- MeSH terms
- Adult, Aerobiosis, Alanine, Carbon Dioxide, Citric Acid Cycle, Energy Metabolism, Glycogen, Humans, Male, Oxygen Consumption, Exercise, Respiratory Mechanics, Muscle, Skeletal, Glutamic Acid
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