Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes

Cell Metabolism

Volumn 24, Issue 2, 2016, Pages 256-268

  Cox, Pete J ^a,b   Kirk, Tom ^a   Ashmore, Tom ^c   Willerton, Kristof ^a   Evans, Rhys ^a   Smith, Alan ^d   Murray, Andrew J ^e   Stubbs, Brianna ^a   West, James ^c   McLure, Stewart W ^a   King, M Todd ^f   Dodd, Michael S ^a   Holloway, Cameron ^a,b   Neubauer, Stefan ^b   Drawer, Scott ^d   Veech, Richard L ^f   Griffin, Julian L ^c   Clarke, Kieran ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b UNIVERSITY OF OXFORD   (United Kingdom)

^c UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^d UK Sport   (United Kingdom)

^e UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^f NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CARBOHYDRATE; CARNITINE; ESTER; INSULIN; KETONE; TRIACYLGLYCEROL; GLYCOGEN; KETONE BODY;

ARTICLE; ATHLETE; ATHLETIC PERFORMANCE; CALORIC RESTRICTION; ENDURANCE TRAINING; EXERCISE INTENSITY; GLYCOGEN MUSCLE LEVEL; GLYCOLYSIS; HUMAN; HUMAN TISSUE; KETOACIDOSIS; KETOGENESIS; LACTATE BLOOD LEVEL; METABOLISM; MUSCLE METABOLISM; NUTRITION; PHOSPHORYLATION; PHYSICAL PERFORMANCE; PRIORITY JOURNAL; SKELETAL MUSCLE; CONTROLLED STUDY; DIET; ENDURANCE; ENERGY METABOLISM; EXERCISE; FEMALE; MALE; OBESITY; RANDOMIZED CONTROLLED TRIAL; REST;

ADIPOSITY; ATHLETES; CARBOHYDRATES; CARNITINE; DIET; ENERGY METABOLISM; EXERCISE; FEMALE; GLYCOGEN; HUMANS; KETONE BODIES; KETOSIS; MALE; MUSCLE, SKELETAL; PHYSICAL ENDURANCE; REST;

EID: 84991080555     PISSN: 15504131     EISSN: 19327420     Source Type: Journal    
DOI: 10.1016/j.cmet.2016.07.010     Document Type: Article

References (48)

1. Balasse, E.O., Fery, F., Neef, M.A., Changes induced by exercise in rates of turnover and oxidation of ketone bodies in fasting man. J. Appl. Physiol. 44 (1978), 5–11.
2. Bergmeyer, H.U., Gawehn, K., Methods of Enzymatic Analysis, Volume 3, 1974, Academic Press.
3. Bergström, J., Hultman, E., Jorfeldt, L., Pernow, B., Wahren, J., Effect of nicotinic acid on physical working capacity and on metabolism of muscle glycogen in man. J. Appl. Physiol. 26 (1969), 170–176.
4. Cahill, G.F. Jr., Starvation in man. N. Engl. J. Med. 282 (1970), 668–675.
5. Cahill, G.F. Jr., Owen, O.E., Starvation and survival. Trans. Am. Clin. Climatol. Assoc. 79 (1968), 13–20.
6. Clarke, K., Tchabanenko, K., Pawlosky, R., Carter, E., Todd King, M., Musa-Veloso, K., Ho, M., Roberts, A., Robertson, J., Vanitallie, T.B., Veech, R.L., Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul. Toxicol. Pharmacol. 63 (2012), 401–408.
7. Cox, P.J., Clarke, K., Acute nutritional ketosis: implications for exercise performance and metabolism. Extrem. Physiol. Med., 3, 2014, 17.
8. Desrochers, S., David, F., Garneau, M., Jetté, M., Brunengraber, H., Metabolism of R- and S-1,3-butanediol in perfused livers from meal-fed and starved rats. Biochem. J. 285 (1992), 647–653.
9. Felig, P., Owen, O.E., Wahren, J., Cahill, G.F. Jr., Amino acid metabolism during prolonged starvation. J. Clin. Invest. 48 (1969), 584–594.
10. Féry, F., Balasse, E.O., Ketone body turnover during and after exercise in overnight-fasted and starved humans. Am. J. Physiol. 245 (1983), E318–E325.
11. Frayn, K.N., Calculation of substrate oxidation rates in vivo from gaseous exchange. J. Appl. Physiol. 55 (1983), 628–634.
12. Gollnick, P.D., Armstrong, R.B., Saubert, C.W. 4th, Sembrowich, W.L., Shepherd, R.E., Saltin, B., Glycogen depletion patterns in human skeletal muscle fibers during prolonged work. Pflugers Arch. 344 (1973), 1–12.
13. Hagenfeldt, L., Wahren, J., Human forearm muscle metabolism during exercise. VI. Substrate utilization in prolonged fasting. Scand. J. Clin. Lab. Invest. 27 (1971), 299–306.
14. Halestrap, A.P., Meredith, D., The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch. 447 (2004), 619–628.
15. Halkjaer-Kristensen, J., Ingemann-Hansen, T., Microphotometric determination of glycogen in single fibres of human quadriceps muscle. Histochem. J. 11 (1979), 629–638.
16. Jentjens, R.L., Achten, J., Jeukendrup, A.E., High oxidation rates from a mixture of glucose, sucrose and fructose ingested during prolonged exercise. Med. Sci. Sports Exerc. 36 (2004), S19–S20.
17. Jeukendrup, A.E., Jentjens, R., Oxidation of carbohydrate feedings during prolonged exercise: current thoughts, guidelines and directions for future research. Sports Med. 29 (2000), 407–424.
18. Johnson, R.H., Walton, J.L., The effect of exercise upon acetoacetate metabolism in athletes and non-athletes. Q. J. Exp. Physiol. Cogn. Med. Sci. 57 (1972), 73–79.
19. Kashiwaya, Y., King, M.T., Veech, R.L., Substrate signaling by insulin: a ketone bodies ratio mimics insulin action in heart. Am. J. Cardiol. 80:3A (1997), 50A–64A.
20. Keene, D.L., A systematic review of the use of the ketogenic diet in childhood epilepsy. Pediatr. Neurol. 35 (2006), 1–5.
21. Keller, U., Lustenberger, M., Stauffacher, W., Effect of insulin on ketone body clearance studied by a ketone body “clamp” technique in normal man. Diabetologia 31 (1988), 24–29.
22. Koopman, R., Schaart, G., Hesselink, M.K., Optimisation of oil red O staining permits combination with immunofluorescence and automated quantification of lipids. Histochem. Cell Biol. 116 (2001), 63–68.
23. Le Belle, J.E., Harris, N.G., Williams, S.R., Bhakoo, K.K., A comparison of cell and tissue extraction techniques using high-resolution 1H-NMR spectroscopy. NMR Biomed. 15 (2002), 37–44.
24. 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. 162 (1977), 557–568.
25. Newman, J.C., Verdin, E., Ketone bodies as signaling metabolites. Trends Endocrinol. Metab. 25 (2014), 42–52.
26. Noakes, T.D., Time to move beyond a brainless exercise physiology: the evidence for complex regulation of human exercise performance. Appl. Physiol. Nutr. Metab. 36 (2011), 23–35.
27. Phinney, S.D., Bistrian, B.R., Evans, W.J., Gervino, E., Blackburn, G.L., The human metabolic response to chronic ketosis without caloric restriction: preservation of submaximal exercise capability with reduced carbohydrate oxidation. Metabolism 32 (1983), 769–776.
28. Phinney, S.D., Bistrian, B.R., Wolfe, R.R., Blackburn, G.L., The human metabolic response to chronic ketosis without caloric restriction: physical and biochemical adaptation. Metabolism 32 (1983), 757–768.
29. Randle, P.J., Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab. Rev. 14 (1998), 263–283.
30. 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 1 (1963), 785–789.
31. Robinson, A.M., Williamson, D.H., Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol. Rev. 60 (1980), 143–187.
32. Romijn, J.A., Coyle, E.F., Sidossis, L.S., Gastaldelli, A., Horowitz, J.F., Endert, E., Wolfe, R.R., Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration. Am. J. Physiol. 265 (1993), E380–E391.
33. Ruderman, N.B., Saha, A.K., Vavvas, D., Witters, L.A., Malonyl-CoA, fuel sensing, and insulin resistance. Am. J. Physiol. 276 (1999), E1–E18.
34. Russell, R.R. 3rd, Taegtmeyer, H., Changes in citric acid cycle flux and anaplerosis antedate the functional decline in isolated rat hearts utilizing acetoacetate. J. Clin. Invest. 87 (1991), 384–390.
35. Russell, R.R. 3rd, Taegtmeyer, H., Pyruvate carboxylation prevents the decline in contractile function of rat hearts oxidizing acetoacetate. Am. J. Physiol. 261 (1991), H1756–H1762.
36. Sato, K., Kashiwaya, Y., Keon, C.A., Tsuchiya, N., King, M.T., Radda, G.K., Chance, B., Clarke, K., Veech, R.L., Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J. 9 (1995), 651–658.
37. Shivva, V., Cox, P.J., Clarke, K., Veech, R.L., Tucker, I.G., Duffull, S.B., The Population Pharmacokinetics of D-beta-hydroxybutyrate Following Administration of (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate. AAPS J. 18 (2016), 678–688.
38. Spriet, L.L., Peters, S.J., Influence of diet on the metabolic responses to exercise. Proc. Nutr. Soc. 57 (1998), 25–33.
39. Stephens, F.B., Constantin-Teodosiu, D., Greenhaff, P.L., New insights concerning the role of carnitine in the regulation of fuel metabolism in skeletal muscle. J. Physiol. 581 (2007), 431–444.
40. Taggart, A.K., Kero, J., Gan, X., Cai, T.Q., Cheng, K., Ippolito, M., Ren, N., Kaplan, R., Wu, K., Wu, T.J., et al. (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J. Biol. Chem. 280 (2005), 26649–26652.
41. Thompson, J.R., Wu, G., The effect of ketone bodies on nitrogen metabolism in skeletal muscle. Comp. Biochem. Physiol. B 100 (1991), 209–216.
42. Van Gelder, J., Shafiee, M., De Clercq, E., Penninckx, F., Van den Mooter, G., Kinget, R., Augustijns, P., Species-dependent and site-specific intestinal metabolism of ester prodrugs. Int. J. Pharm. 205 (2000), 93–100.
43. van Hall, G., van der Vusse, G.J., Söderlund, K., Wagenmakers, A.J., Deamination of amino acids as a source for ammonia production in human skeletal muscle during prolonged exercise. J. Physiol. 489 (1995), 251–261.
44. van Loon, L.J., Greenhaff, P.L., Constantin-Teodosiu, D., Saris, W.H., Wagenmakers, A.J., The effects of increasing exercise intensity on muscle fuel utilisation in humans. J. Physiol. 536 (2001), 295–304.
45. Veech, R.L., The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot. Essent. Fatty Acids 70 (2004), 309–319.
46. Wall, B.T., Stephens, F.B., Constantin-Teodosiu, D., Marimuthu, K., Macdonald, I.A., Greenhaff, P.L., Chronic oral ingestion of L-carnitine and carbohydrate increases muscle carnitine content and alters muscle fuel metabolism during exercise in humans. J. Physiol. 589 (2011), 963–973.
47. Williamson, J.R., Krebs, H.A., Acetoacetate as fuel of respiration in the perfused rat heart. Biochem. J. 80 (1961), 540–547.
48. 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. 47 (1974), 461–467.