Abstract
In comparison to cardiac tissue, relatively few data are available regarding the concentrations of tricarboxylic acid cycle intermediates (TCAI) and the potential influence of TCAI pool size on the regulation of cycle flux in mammalian skeletal muscle. However, recent human exercise studies have confirmed the fundamental observation made in electrically-stimulated rodent muscle that moderate to intense contraction results in a net accumulation of TCAI. The increase in TCAI pool size, termed “anaplerosis,” appears exponentially related to work intensity, although the relative changes in the individual cycle intermediates differ markedly. While a number of mechanisms could potentially contribute to the increase in TCAI, the reaction catalyzed by alanine aminotransferase appears primarily responsible for anaplerosis at the onset of exercise in humans. The expansion of the TCAI pool has been suggested to be important for aerobic energy provision, and various theories have been proposed which link the total concentration of TCAI with the capacity for TCA cycle flux during exercise. However, despite the recent advances which have been made with regard to the magnitude and potential source of TCAI expansion in humans, our understanding of the physiological significance of anaplerosis is limited. Indeed, it remains speculative whether the increase in TCAI pool size represents an important regulatory signal or is simply a consequence of the huge increase in metabolic flux which occurs during exercise.
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References
Aragón, J.J., and J.M. Lowenstein. The purine nucleotide cycle. Comparison of the levels of citric acid cycle intermediates with the operation of the purine nucleotide cycle in rat skeletal muscle during exercise and recovery from exercise. Eur. J. Biochem. 110: 371–377, 1980.
Armstrong, R.G., and R.O. Phelps. Muscle fibre type composition of the rat hindlimb. Am. J. Anat. 171: 259–272, 1984.
Blomstrand, E., G. Rõdegran, and B. Saltin. Maximum rate of oxygen uptake by human skeletal muscle in relation to maximal activities of enzymes in the Kreb’s cycle. J. Physiol. 501: 455–460, 1997.
Brodai, B., and K. Hjelle. Synthesis of phosphoenolpyruvate from pyruvate in rat skeletal muscle. Int. J. Biochem. 22: 752–758, 1990.
Cadefau, J., H.J. Green, R. Cusso, M. Ball-Burnett, and G. Jamieson. Coupling of muscle phosphorylation potential to glycolysis during work after short-term training. J. Appl. Physiol. 76: 2586–2593, 1994.
Crabtree, B., S.J. Higgins, and E.A. Newsholme. The activities of pyruvate carboxylase, phosphoenolpyruvate carboxylase and fructose diphosphate in muscles from vertebrates and invertebrates. Biochem. J. 130: 391–396, 1972.
Davis, E.J., Ø. Spydevold, and J. Bremer. Pyruvate carboxylase and propionyl-CoA carboxylase as anaplerotic enzymes in skeletal muscle mitochondria. Eur. J. Biochem. 110: 255–262, 1980.
Essén, B., and L. Kaijser. Regulation of glycolysis in intermittent exercise in man. J. Physiol. 281: 499–511, 1978.
Flanagan, W.F., E.W. Holmes, R.L. Sabina, and J.L. Swain. Importance of purine nucleotide cycle to energy production in skeletal muscle. Am. J. Physiol. 252 (Cell Physiol. 20): C795-C802, 1986.
Gibala, M.J. D.A. MacLean, T.E. Graham, and B. Saltin. Anaplerotic processes in human skeletal muscle during brief dynamic exercise. J. Physiol. 502: 703–713, 1997.
Gibala, M. J., D. A. MacLean, T. E. Graham, and B. Saltin. Tricarboxylic acid cycle intermediate pool size and estimated cycle flux in human muscle during exercise. Am. J. Physiol. 275 (Endocrinol. Metab.), in press, 1998.
Gibala, M.J., M.A. Tarnopolsky, and T.E. Graham. Tricarboxylic acid cycle intermediates in human muscle at rest and during prolonged cycling. Am. J. Physiol. 272 (Endocrinol. Metab. 35): E239-E244, 1997.
Graham, T.E., B. Kiens, M. Hargreaves, and E.A. Richter. Influence of fatty acids on ammonia and amino acid flux from active human muscle. Am. J. Physiol. 261 (Endocrinol. Metab. 24): E168-E176, 1991.
Graham, T.E., and B. Saltin. Estimation of the mitochondrial redox state in human skeletal muscle during exercise. J. Appl. Physiol. 66: 561–566, 1989.
Hansford, R.G. Control of mitochondrial substrate oxidation. Curr. Top. Bioenerg. 10: 217–78, 1980.
Hiltunen, J.K., and E.J. Davis. The disposition of citric acid cycle intermediates by isolated rat heart mitochondria. Biochem. Biophys. Acta. 678: 115–121, 1981.
Hiltunen, J.K., and I.E. Hassinen. Energy-linked regulation of the citric acid cycle and the pool size of the cycle intermediates in the isolated perfused rat heart. J. Biochem. 8: 505–509, 1977.
Jackman, M.L., M.J. Gibala, E. Hultman, and T.E. Graham. Nutritional status affects branched-chain oxoacid dehydrogenase activity during exercise in humans. Am. J. Physiol. 272 (Endocrinol. Metab. 35): E233-E238, 1997.
Karlsson, J. Pyruvate and lactate ratios in muscle tissue and blood during exercise in man. Acta Physiol. Scand. 81: 455–459, 1971.
Kornberg, H.L. Anaplerotic sequences and their role in metabolism. In: Essays in Biochemistry, edited by P.N. Campbell and R.D. Marshall. London: Academic Press, 1966, pp. 1–31.
Lanoue, K.F., and A.C. Schoolwerth. Metabolite transport in mammalian mitochondria. In: Bioenergetics, edited by L. Ernster. Amsterdam: Elsevier Science Publishers, 1984, pp. 221–268.
Lee, S.-H., and E.J. Davis. Carboxylationand decarboxylation reactions. Anaplerotic flux and removal of citrate cycle intermediates. J. Biol. Chem. 254: 420–430, 1979.
Lowenstein, J.M. Ammonia production in muscle and other tissues: the purine nucleotide cycle. Physiol. Rev. 52: 382–414, 1972.
Newsholme, E.A., and A.R. Leech. Biochemistry for the Medical Sciences. Toronto: Wiley, 1983.
Palmieri, F., F. Bisaccia, L. Capobianco, V. Dolce, G. Fiermonte, V. Iacobazzi, C. Indiveri, and L. Palmieri. Mitochondrial metabolite transporters. Biochim. Biophys. Acta. 1275: 127–132, 1996.
Pastoris, O., M. Dossena, R. Arnaboldi, A. Gorini, and R.F. Villa. Age-related alterations of skeletal muscle metabolism by intermittent hypoxia and TRH-analogue treatment. Pharmacological Res. 30: 171–185, 1994.
Peuhkurinen, K.J. Regulation of the tricarboxylic acid cycle pool size in heart muscle. J. Mol. Cell. Cardiol. 16: 487–495, 1984.
Putman, C.T., N.L. Jones, L.C. Lands, T.M. Bragg, M.G. Hollidge-Horvat, and G.J.F. Heigenhauser. Skeletal muscle pyruvate dehydrogenase activity during maximal exercise in humans. Am. J. Physiol. 269 (Endocrinol. Metab. 32): E458-E468, 1995.
Randle, P.J., P.J. England, and R.M. Denton. Control of the tricarboxylate cycle and its interactions with glycolysis during acetate utilization in rat heart. Biochem. J. 117: 677–695, 1970.
Randle, P.J., and P.K. Tubbs. Carbohydrate and fatty acid metabolism. In: Handbook of Physiology: The Cardiovascular System, edited by R.M. Berne. Bethesda, MD: American Physiological Society, 1979, pp. 805-844.
Sahlin, K. Muscle carnitine metabolism during incremental dynamic exercise in humans. Acta Physiol. Scand. 138: 259–262, 1990.
Sahlin, K., L. Jorfeldt, K.-G. Henriksson, S.R. Lewis, and R.G. Haller. Tricarboxylic acid cycle intermediates during incremental exercise in healthy subjects and in patients with McArdle’s disease. Clin. Sci. 88: 687–693, 1995.
Sahlin, K., A. Katz, and S. Broberg. Tricarboxylic acid cycle intermediates in human muscle during prolonged exercise. Am. J. Physiol. 259 (Cell Physiol. 28): C834-C841, 1990.
Sahlin, K., A. Katz, and J. Henrikkson. Redox state and lactate accumulation in human skeletal muscle during dynamic exercise. Biochem. J. 245: 551–556, 1987.
Spencer, M.K., and A. Katz. Role of glycogen in control of glycolysis and IMP formation in human muscle during exercise. Am. J. Physiol. 260 (Endocrinol. Metab. 23): E859-E864, 1991.
Spencer, M.K., A. Katz, and I. Raz. Epinephrine increases tricarboxylic acid cycle intermediates in human muscle. Am. J. Physiol. 260 (Endocrinol. Metab. 23): E436-E439, 1991a.
Spencer, M.K., Z. Yan, and A. Katz. Carbohydrate supplementation attenuates IMP accumulation in human muscle during prolonged exercise. Am. J. Physiol. 261 (Cell Physiol. 30): C71-C76, 1991b.
Spencer, M.K., Z. Yan, and A. Katz. Effect of low glycogen on carbohydrate and energy metabolism in human muscle during exercise. Am. J. Physiol. 262 (Cell Physiol. 31): C975-C979, 1992.
Spydevold, Ø., E.J. Davis, and J. Bremer. Replenishment and depletion of citric acid cycle intermediates in skeletal muscle. Eur. J. Biochem. 71: 155–165, 1976.
Swain, J.L., J.J. Hines, R.L. Sabina, O.L. Harbury, and E.W. Holmes. Disruption of purine nucleotide cycle by inhibition of adenylosuccinate lyase produces skeletal muscle dysfunction. J. Clin. Invest. 74: 1422–1427, 1984.
Taegtmeyer, H. On the inability of ketone bodies to serve as the only energy providing substrate for rat heart at physiological work load. Bas. Res. Cardiol. 78: 435–450, 1983.
Wagenmakers, A.J.M., J.H. Coakley, and R.H.T. Edwards. Metabolism of branched-chain amino acids and ammonia during exercise: clues from McArdle’s disease. Int. J. Sports Med. 11: S101–S113, 1990.
Wibom, R., and E. Hultman. ATP production rate in mitochondria isolated from microsamples of human muscle. Am. J. Physiol. 259 (Endocrinol. Metab. 22): E204-E209, 1990.
Williamson, J.R., and R.H. Cooper. Regulation of the citric acid cycle in mammalian systems. FEBS Lett. 117, Suppl.: K73–K85, 1980.
Wolfe, B.R., T.E. Graham, and J.K. Barclay. Hyperoxia, mitochondrial redox state, and lactate metabolism of in situ canine muscle. Am. J. Physiol. 253 (Cell Physiol. 22): C263-C268, 1987.
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Graham, T.E., Gibala, M.J. (1998). Anaplerosis of the Tricarboxylic Acid Cycle in Human Skeletal Muscle during Exercise. In: Richter, E.A., Kiens, B., Galbo, H., Saltin, B. (eds) Skeletal Muscle Metabolism in Exercise and Diabetes. Advances in Experimental Medicine and Biology, vol 441. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-1928-1_25
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DOI: https://doi.org/10.1007/978-1-4899-1928-1_25
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