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. 1985 Dec 1;232(2):585–591. doi: 10.1042/bj2320585

Effects of starvation and exercise on concentrations of citrate, hexose phosphates and glycogen in skeletal muscle and heart. Evidence for selective operation of the glucose-fatty acid cycle.

A Zorzano, T W Balon, L J Brady, P Rivera, L P Garetto, J C Young, M N Goodman, N B Ruderman
PMCID: PMC1152919  PMID: 4091810

Abstract

Concentrations of citrate, hexose phosphates and glycogen were measured in skeletal muscle and heart under conditions in which plasma non-esterified fatty acids and ketone bodies were physiologically increased. The aim was to determine under what conditions the glucose-fatty acid cycle might operative in skeletal muscle in vivo. In keeping with the findings of others, starvation increased the concentrations of glycogen, citrate and the fructose 6-phosphate/fructose 1,6-bisphosphate ratio in heart, indicating that the cycle was operative. In contrast, it decreased glycogen and had no effect on the concentration of citrate or the fructose 6-phosphate/fructose 1,6-bisphosphate ratio in the soleus, a slow-twitch red muscle in which the glucose-fatty acid cycle has been demonstrated in vitro. In fed rats, exercise of moderate intensity caused glycogen depletion in the soleus and red portion of gastrocnemius muscle, but not in heart. In starved rats the same exercise had no effect on the already diminished glycogen contents in skeletal muscle, but it decreased cardiac glycogen by 25-30%. After exercise, citrate and the fructose 6-phosphate/fructose 1,6-bisphosphate ratio were increased in the soleus of the starved rat. Significant changes were not observed in fed rats. The data suggest that in the resting state the glucose-fatty acid cycle operates in the heart, but not in the soleus muscle, of a starved rat. In contrast, the metabolite profile in the soleus was consistent with activation of the glucose-fatty acid cycle in the starved rat during the recovery period after exercise. Whether the cycle operates during exercise itself is unclear.

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Selected References

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  1. Adrouny G. A. Differential patterns of glycogen metabolism in cardiac and skeletal muscles. Am J Physiol. 1969 Sep;217(3):686–693. doi: 10.1152/ajplegacy.1969.217.3.686. [DOI] [PubMed] [Google Scholar]
  2. Balasse E. O., Neef M. A. Operation of the "glucose-fatty acid cycle" during experimental elevations of plasma free fatty acid levels in man. Eur J Clin Invest. 1974 Aug;4(4):247–252. doi: 10.1111/j.1365-2362.1974.tb00400.x. [DOI] [PubMed] [Google Scholar]
  3. Baldwin K. M., Reitman J. S., Terjung R. L., Winder W. W., Holloszy J. O. Substrate depletion in different types of muscle and in liver during prolonged running. Am J Physiol. 1973 Nov;225(5):1045–1050. doi: 10.1152/ajplegacy.1973.225.5.1045. [DOI] [PubMed] [Google Scholar]
  4. Beatty C. H., Bocek R. M. Interrelation of carbohydrate and palmitate metabolism in skeletal muscle. Am J Physiol. 1971 Jun;220(6):1928–1934. doi: 10.1152/ajplegacy.1971.220.6.1928. [DOI] [PubMed] [Google Scholar]
  5. Berger M., Hagg S. A., Goodman M. N., Ruderman N. B. Glucose metabolism in perfused skeletal muscle. Effects of starvation, diabetes, fatty acids, acetoacetate, insulin and exercise on glucose uptake and disposition. Biochem J. 1976 Aug 15;158(2):191–202. doi: 10.1042/bj1580191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chen V., Ianuzzo C. D., Fong B. C., Spitzer J. J. The effects of acute and chronic diabetes on myocardial metabolism in rats. Diabetes. 1984 Nov;33(11):1078–1084. doi: 10.2337/diab.33.11.1078. [DOI] [PubMed] [Google Scholar]
  7. Conlee R. K., Hickson R. C., Winder W. W., Hagberg J. M., Holloszy J. O. Regulation of glycogen resynthesis in muscles of rats following exercise. Am J Physiol. 1978 Sep;235(3):R145–R150. doi: 10.1152/ajpregu.1978.235.3.R145. [DOI] [PubMed] [Google Scholar]
  8. Costill D. L., Coyle E., Dalsky G., Evans W., Fink W., Hoopes D. Effects of elevated plasma FFA and insulin on muscle glycogen usage during exercise. J Appl Physiol Respir Environ Exerc Physiol. 1977 Oct;43(4):695–699. doi: 10.1152/jappl.1977.43.4.695. [DOI] [PubMed] [Google Scholar]
  9. DANFORTH W. H. GLYCOGEN SYNTHETASE ACTIVITY IN SKELETAL MUSCLE. INTERCONVERSION OF TWO FORMS AND CONTROL OF GLYCOGEN SYNTHESIS. J Biol Chem. 1965 Feb;240:588–593. [PubMed] [Google Scholar]
  10. Dohm G. L., Tapscott E. B., Barakat H. A., Kasperek G. J. Influence of fasting on glycogen depletion in rats during exercise. J Appl Physiol Respir Environ Exerc Physiol. 1983 Sep;55(3):830–833. doi: 10.1152/jappl.1983.55.3.830. [DOI] [PubMed] [Google Scholar]
  11. Essén B. Intramuscular substrate utilization during prolonged exercise. Ann N Y Acad Sci. 1977;301:30–44. doi: 10.1111/j.1749-6632.1977.tb38183.x. [DOI] [PubMed] [Google Scholar]
  12. Ferrannini E., Barrett E. J., Bevilacqua S., DeFronzo R. A. Effect of fatty acids on glucose production and utilization in man. J Clin Invest. 1983 Nov;72(5):1737–1747. doi: 10.1172/JCI111133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Garetto L. P., Richter E. A., Goodman M. N., Ruderman N. B. Enhanced muscle glucose metabolism after exercise in the rat: the two phases. Am J Physiol. 1984 Jun;246(6 Pt 1):E471–E475. doi: 10.1152/ajpendo.1984.246.6.E471. [DOI] [PubMed] [Google Scholar]
  14. Goodman M. N., Berger M., Ruderman N. B. Glucose metabolism in rat skeletal muscle at rest. Effect of starvation, diabetes, ketone bodies and free fatty acids. Diabetes. 1974 Nov;23(11):881–888. doi: 10.2337/diab.23.11.881. [DOI] [PubMed] [Google Scholar]
  15. Hagg S. A., Taylor S. I., Ruberman N. B. Glucose metabolism in perfused skeletal muscle. Pyruvate dehydrogenase activity in starvation, diabetes and exercise. Biochem J. 1976 Aug 15;158(2):203–210. doi: 10.1042/bj1580203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hawkins R. A., Williamson D. H. Measurements of substrate uptake by mammary gland of the rat. Biochem J. 1972 Oct;129(5):1171–1173. doi: 10.1042/bj1291171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hickson R. C., Rennie M. J., Conlee R. K., Winder W. W., Holloszy J. O. Effects of increased plasma fatty acids on glycogen utilization and endurance. J Appl Physiol Respir Environ Exerc Physiol. 1977 Nov;43(5):829–833. doi: 10.1152/jappl.1977.43.5.829. [DOI] [PubMed] [Google Scholar]
  18. Jefferson L. S., Koehler J. O., Morgan H. E. Effect of insulin on protein synthesis in skeletal muscle of an isolated perfused preparation of rat hemicorpus. Proc Natl Acad Sci U S A. 1972 Apr;69(4):816–820. doi: 10.1073/pnas.69.4.816. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Johnson R. H., Walton J. L., Krebs H. A., Williamson D. H. Metabolic fuels during and after severe exercise in athletes and non-athletes. Lancet. 1969 Aug 30;2(7618):452–455. doi: 10.1016/s0140-6736(69)90164-0. [DOI] [PubMed] [Google Scholar]
  20. Karlsson J., Diamant B., Saltin B. Muscle metabolites during submaximal and maximal exercise in man. Scand J Clin Lab Invest. 1970 Dec;26(4):385–394. doi: 10.3109/00365517009046250. [DOI] [PubMed] [Google Scholar]
  21. Kato K., Bishop J. S. Glycogen synthetase-D phosphatase. I. Some new properties of the partially purified enzyme from rabbit skeletal muscle. J Biol Chem. 1972 Nov 25;247(22):7420–7429. [PubMed] [Google Scholar]
  22. Katz J., McGarry J. D. The glucose paradox. Is glucose a substrate for liver metabolism? J Clin Invest. 1984 Dec;74(6):1901–1909. doi: 10.1172/JCI111610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Koeslag J. H. Post-exercise ketosis and the hormone response to exercise: a review. Med Sci Sports Exerc. 1982;14(5):327–334. [PubMed] [Google Scholar]
  24. MORGAN H. E., PARMEGGIANI A. REGULATION OF GLYCOGENOLYSIS IN MUSCLE. 3. CONTROL OF MUSCLE GLYCOGEN PHOSPHORYLASE ACTIVITY. J Biol Chem. 1964 Aug;239:2440–2445. [PubMed] [Google Scholar]
  25. Maizels E. Z., Ruderman N. B., Goodman M. N., Lau D. Effect of acetoacetate on glucose metabolism in the soleus and extensor digitorum longus muscles of the rat. Biochem J. 1977 Mar 15;162(3):557–568. doi: 10.1042/bj1620557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. NESTEL P. J., CARROLL K. F., SILVERSTEIN M. S. INFLUENCE OF FREE-FATTY-ACID METABOLISM ON GLUCOSE TOLERANCE. Lancet. 1964 Jul 18;2(7351):115–117. doi: 10.1016/s0140-6736(64)90125-4. [DOI] [PubMed] [Google Scholar]
  27. NOVAK M. COLORIMETRIC ULTRAMICRO METHOD FOR THE DETERMINATION OF FREE FATTY ACIDS. J Lipid Res. 1965 Jul;6:431–433. [PubMed] [Google Scholar]
  28. Nakai C., Thomas J. A. Properties of a phosphoprotein phosphatase from bovine heart with activity on glycogen synthase, phosphorylase, and histone. J Biol Chem. 1974 Oct 25;249(20):6459–6467. [PubMed] [Google Scholar]
  29. Neely J. R., Bowman R. H., Morgan H. E. Effects of ventricular pressure development and palmitate on glucose transport. Am J Physiol. 1969 Apr;216(4):804–811. doi: 10.1152/ajplegacy.1969.216.4.804. [DOI] [PubMed] [Google Scholar]
  30. Neely J. R., Whitfield C. F., Morgan H. E. Regulation of glycogenolysis in hearts: effects of pressure development, glucose, and FFA. Am J Physiol. 1970 Oct;219(4):1083–1088. doi: 10.1152/ajplegacy.1970.219.4.1083. [DOI] [PubMed] [Google Scholar]
  31. Newsholme E. A., Randle P. J. Regulation of glucose uptake by muscle. 7. Effects of fatty acids, ketone bodies and pyruvate, and of alloxan-diabetes, starvation, hypophysectomy and adrenalectomy, on the concentrations of hexose phosphates, nucleotides and inorganic phosphate in perfused rat heart. Biochem J. 1964 Dec;93(3):641–651. doi: 10.1042/bj0930641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Pearce F. J., Connett R. J. Effect of lactate and palmitate on substrate utilization of isolated rat soleus. Am J Physiol. 1980 May;238(5):C149–C159. doi: 10.1152/ajpcell.1980.238.5.C149. [DOI] [PubMed] [Google Scholar]
  33. Pelkonen R., Miettinen T. A., Taskinen M. R., Nikkilä E. A. Effect of acute elevation of plasma glycerol, triglyceride and FFA levels on glucose utilization and plasma insulin. Diabetes. 1968 Feb;17(2):76–82. doi: 10.2337/diab.17.2.76. [DOI] [PubMed] [Google Scholar]
  34. Poland J. L., Trowbridge C., Poland J. W. Substrate repletion in rat myocardium, liver, and skeletal muscles after exercise. Can J Physiol Pharmacol. 1980 Oct;58(10):1229–1233. doi: 10.1139/y80-186. [DOI] [PubMed] [Google Scholar]
  35. RANDLE P. J., GARLAND P. B., HALES C. N., NEWSHOLME E. A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963 Apr 13;1(7285):785–789. doi: 10.1016/s0140-6736(63)91500-9. [DOI] [PubMed] [Google Scholar]
  36. Randle P. J. Carbohydrate metabolism and lipid storage and breakdown in diabetes. Diabetologia. 1966 Dec;2(4):237–247. doi: 10.1007/BF01268180. [DOI] [PubMed] [Google Scholar]
  37. Randle P. J., Newsholme E. A., Garland P. B. Regulation of glucose uptake by muscle. 8. Effects of fatty acids, ketone bodies and pyruvate, and of alloxan-diabetes and starvation, on the uptake and metabolic fate of glucose in rat heart and diaphragm muscles. Biochem J. 1964 Dec;93(3):652–665. doi: 10.1042/bj0930652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Randle P. J., Sugden P. H., Kerbey A. L., Radcliffe P. M., Hutson N. J. Regulation of pyruvate oxidation and the conservation of glucose. Biochem Soc Symp. 1978;(43):47–67. [PubMed] [Google Scholar]
  39. Reimer F., Löffler G., Hennig G., Wieland O. H. The influence of insulin on glucose and fatty acid metabolism in the isolated perfused rat hind quarter. Hoppe Seylers Z Physiol Chem. 1975 Jun;356(6):1055–1066. doi: 10.1515/bchm2.1975.356.s1.1055. [DOI] [PubMed] [Google Scholar]
  40. Rennie M. J., Holloszy J. O. Inhibition of glucose uptake and glycogenolysis by availability of oleate in well-oxygenated perfused skeletal muscle. Biochem J. 1977 Nov 15;168(2):161–170. doi: 10.1042/bj1680161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Rennie M. J., Winder W. W., Holloszy J. O. A sparing effect of increased plasma fatty acids on muscle and liver glycogen content in the exercising rat. Biochem J. 1976 Jun 15;156(3):647–655. doi: 10.1042/bj1560647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Richter E. A., Garetto L. P., Goodman M. N., Ruderman N. B. Muscle glucose metabolism following exercise in the rat: increased sensitivity to insulin. J Clin Invest. 1982 Apr;69(4):785–793. doi: 10.1172/JCI110517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Richter E. A., Ruderman N. B., Gavras H., Belur E. R., Galbo H. Muscle glycogenolysis during exercise: dual control by epinephrine and contractions. Am J Physiol. 1982 Jan;242(1):E25–E32. doi: 10.1152/ajpendo.1982.242.1.E25. [DOI] [PubMed] [Google Scholar]
  44. Rider M. H., Hue L. Activation of rat heart phosphofructokinase-2 by insulin in vivo. FEBS Lett. 1984 Oct 29;176(2):484–488. doi: 10.1016/0014-5793(84)81223-5. [DOI] [PubMed] [Google Scholar]
  45. Roach P. J. Glycogen synthase and glycogen synthase kinases. Curr Top Cell Regul. 1981;20:45–105. doi: 10.1016/b978-0-12-152820-1.50006-7. [DOI] [PubMed] [Google Scholar]
  46. Robinson A. M., Williamson D. H. Effects of acetoacetate administration on glucose metabolism in mammary gland of fed lactating rats. Biochem J. 1977 Jun 15;164(3):749–752. doi: 10.1042/bj1640749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Ruderman N. B., Houghton C. R., Hems R. Evaluation of the isolated perfused rat hindquarter for the study of muscle metabolism. Biochem J. 1971 Sep;124(3):639–651. doi: 10.1042/bj1240639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Ruderman N. B., Kemmer F. W., Goodman M. N., Berger M. Oxygen consumption in perfused skeletal muscle. Effect of perfusion with aged, fresh and aged-rejuvenated erythrocytes on oxygen consumption, tissue metabolites and inhibition of glucose utilization by acetoacetate. Biochem J. 1980 Jul 15;190(1):57–64. doi: 10.1042/bj1900057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Ruderman N. B., Ross P. S., Berger M., Goodman M. N. Regulation of glucose and ketone-body metabolism in brain of anaesthetized rats. Biochem J. 1974 Jan;138(1):1–10. doi: 10.1042/bj1380001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Ruderman N. B., Toews C. J., Shafrir E. Role of free fatty acids in glucose homeostasis. Arch Intern Med. 1969 Mar;123(3):299–313. [PubMed] [Google Scholar]
  51. Schalch D. S., Kipnis D. M. Abnormalities in carbohydrate tolerance associated with elevated plasma nonesterified fatty acids. J Clin Invest. 1965 Dec;44(12):2010–2020. doi: 10.1172/JCI105308. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Start C., Newsholme E. A. The effects of starvation and alloxan-diabetes on the contents of citrate and other metabolic intermediates in rat liver. Biochem J. 1968 Apr;107(3):411–415. doi: 10.1042/bj1070411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Thiébaud D., DeFronzo R. A., Jacot E., Golay A., Acheson K., Maeder E., Jéquier E., Felber J. P. Effect of long chain triglyceride infusion on glucose metabolism in man. Metabolism. 1982 Nov;31(11):1128–1136. doi: 10.1016/0026-0495(82)90163-9. [DOI] [PubMed] [Google Scholar]
  54. Thompson M. P., Williamson D. H. Metabolic interactions of glucose, acetoacetate and adrenaline in rat submaxillary gland in vitro. Biochem J. 1975 Mar;146(3):635–644. doi: 10.1042/bj1460635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Villar-Palasi C. Oligo- and polysaccharide inhibition of muscle transferase D phosphatase. Ann N Y Acad Sci. 1969 Oct 14;166(2):719–730. doi: 10.1111/j.1749-6632.1969.tb46429.x. [DOI] [PubMed] [Google Scholar]
  56. Wahren J., Felig P., Ahlborg G., Jorfeldt L. Glucose metabolism during leg exercise in man. J Clin Invest. 1971 Dec;50(12):2715–2725. doi: 10.1172/JCI106772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Williamson D. H., McKeown S. R., Ilic V. Interactions of glucose, acetoacetate and insulin in mammary-gland slices of lactating rats. Biochem J. 1975 Aug;150(2):145–152. doi: 10.1042/bj1500145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Winder W. W., Baldwin K. M., Holloszy J. O. Enzymes involved in ketone utilization in different types of muscle: adaptation to exercise. Eur J Biochem. 1974 Sep 16;47(3):461–467. doi: 10.1111/j.1432-1033.1974.tb03713.x. [DOI] [PubMed] [Google Scholar]

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