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Exogenous Ketone Supplementation and Keto-Adaptation for Endurance Performance: Disentangling the Effects of Two Distinct Metabolic States

Abstract

Ketone bodies (KB) provide an alternative energy source and uniquely modulate substrate metabolism during endurance exercise. Nutritional ketosis (blood KBs > 0.5 mM) can be achieved within minutes via exogenous ketone supplementation or days-to-weeks via conforming to a very low-carbohydrate, ketogenic diet (KD). In contrast to short-term (< 2 weeks) KD ingestion, chronic adherence (> 3 weeks) leads to a state of keto-adaptation. However, despite elevating blood KBs to similar concentrations, exogenous ketone supplementation and keto-adaptation are not similar metabolic states as they elicit diverse and distinct effects on substrate availability and metabolism during exercise; meaning that their influence on endurance exercise performance is different. In contrast to contemporary, high(er)-carbohydrate fuelling strategies, inducing nutritional ketosis is rarely ergogenic irrespective of origin and, in fact, can impair endurance performance. Nonetheless, exogenous ketone supplementation and keto-adaptation possess utility for select endurance events and individuals, thus warranting further research into their performance effects and potential strategies for their optimisation. It is critical, however, that future research considers the limitations of measuring blood KB concentrations and their utilisation, and assess the effect of nutritional ketosis on performance using exercise protocols reflective of real-world competition. Furthermore, to reliably assess the effects of keto-adaptation, rigorous dietary-training controls of sufficient duration should be prioritised.

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References

  1. Romijn JA, Coyle EF, Sidossis LS, et al. Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration. Am J Physiol. 1993;265:E380–91.

    CAS  PubMed  Google Scholar 

  2. Robinson AM, Williamson DH. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev. 1980;60:143–87.

    CAS  Article  Google Scholar 

  3. Evans M, Cogan KE, Egan B. Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. J Physiol. 2016;595:2857–71. https://doi.org/10.1113/JP273185.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Volek JS, Noakes T, Phinney SD. Rethinking fat as a fuel for endurance exercise. Eur J Sport Sci. 2015;15:13–20. https://doi.org/10.1080/17461391.2014.959564.

    Article  PubMed  Google Scholar 

  5. Pardridge WM (1991) Blood–brain barrier transport of glucose, free fatty acids, and ketone bodies. In: Fuel homeostasis and the nervous system. Advances in experimental medicine and biology. Oxygen Transport to Tissue Xxxiv, pp 43–53.

  6. Halestrap AP, Wilson MC. The monocarboxylate transporter family—role and regulation. IUBMB Life. 2012;64:109–19. https://doi.org/10.1002/iub.572.

    CAS  Article  Google Scholar 

  7. Shaw DM, Merien F, Braakhuis A, et al. Effect of a ketogenic diet on submaximal exercise capacity and efficiency in runners. Med Sci Sport Exerc. 2019. https://doi.org/10.1249/MSS.0000000000002008.

    Article  Google Scholar 

  8. Phinney SD, Bistrian BR, Evans WJ, et al. The human metabolic response to chronic ketosis without caloric restriction: preservation of submaximal exercise capability with reduced carbohydrate oxidation. Metabolism. 1983;32:769–76.

    CAS  Article  Google Scholar 

  9. Burke LM, Ross ML, Garvican-Lewis LA, et al. Low Carbohydrate, High Fat diet impairs exercise economy and negates the performance benefit from intensified training in elite race walkers. J Physiol. 2016;595:1–23. https://doi.org/10.1113/JP273230.

    CAS  Article  Google Scholar 

  10. Volek JS, Freidenreich DJ, Saenz C, Kunces LJ. Metabolic characteristics of keto-adapted ultra-endurance runners. Metabolism. 2015;65:100–10.

    Article  Google Scholar 

  11. Webster CC, Noakes TD, Chacko SK, et al. Gluconeogenesis during endurance exercise in cyclists habituated to a long-term low carbohydrate high fat diet. J Physiol. 2016;594:4389–405. https://doi.org/10.1113/JP271934.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Cahill GF. Fuel metabolism in starvation. Annu Rev Nutr. 2006;26:1–22. https://doi.org/10.1146/annurev.nutr.26.061505.111258.

    CAS  Article  PubMed  Google Scholar 

  13. Owen OE, Morgan AP, Kemp HG, et al. Brain metabolism during fasting. J Clin Invest. 1967;46:1589–95. https://doi.org/10.1172/JCI105650.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. McSwiney FT, Wardrop B, Hyde PN, et al. Keto-adaptation enhances exercise performance and body composition responses to training in endurance athletes. Metab Clin Exp. 2018;81:25–34. https://doi.org/10.1016/j.metabol.2017.10.010.

    CAS  Article  PubMed  Google Scholar 

  15. Dostal T, Plews DJ, Hofmann P, et al. Effects of a 12-week very-low carbohydrate high-fat diet on maximal aerobic capacity, high-intensity intermittent exercise, and cardiac autonomic regulation: non-randomized parallel-group study. Front Physiol. 2019;10:1–12. https://doi.org/10.3389/fphys.2019.00912.

    Article  Google Scholar 

  16. Sherrier M, Li H. The impact of keto-adaptation on exercise performance and the role of metabolic-regulating cytokines. Am J Clin Nutr. 2019;67:789-12. https://doi.org/10.1093/ajcn/nqz145.

    Article  Google Scholar 

  17. Phinney SD (2004) Ketogenic diets and physical performance. Nutr Metab.

  18. Murtaza N, Burke L, Vlahovich N, et al. The effects of dietary pattern during intensified training on stool microbiota of elite race walkers. Nutrients. 2019;11:261-14. https://doi.org/10.3390/nu11020261.

    CAS  Article  Google Scholar 

  19. Murtaza N, Burke LM, Vlahovich N, et al. Analysis of the effects of dietary pattern on the oral microbiome of elite endurance athletes. Nutrients. 2019;11:614. https://doi.org/10.3390/nu11030614.

    CAS  Article  PubMed Central  Google Scholar 

  20. McKay AKA, Peeling P, Pyne DB, et al. Chronic adherence to a ketogenic diet modifies iron metabolism in elite athletes. Med Sci Sport Exerc. 2019;51:548–55. https://doi.org/10.1249/MSS.0000000000001816.

    CAS  Article  Google Scholar 

  21. McKay AKA, Peeling P, Pyne DB, et al. Acute carbohydrate ingestion does not influence the post-exercise iron-regulatory response in elite keto-adapted race walkers. J Sci Med Sport. 2019. https://doi.org/10.1016/j.jsams.2018.12.015.

    Article  PubMed  Google Scholar 

  22. Carr A, Sharma AP, Ross ML, et al. Chronic ketogenic low carbohydrate high fat diet has minimal effects on acid-base status in elite athletes. Nutrients. 2018;10:1–13. https://doi.org/10.3390/nu10020236.

    CAS  Article  Google Scholar 

  23. McKay AKA, Pyne DB, Peeling P, et al. The impact of chronic carbohydrate manipulation on mucosal immunity in elite endurance athletes. J Sports Sci. 2018;37:553–9. https://doi.org/10.1080/02640414.2018.1521712.

    Article  PubMed  Google Scholar 

  24. Coggan AR, Coyle EF. Reversal of fatigue during prolonged exercise by carbohydrate infusion or ingestion. J Appl Physiol. 1987;63:2388–95.

    CAS  Article  Google Scholar 

  25. Gonzalez JT, Fuchs CJ, Smith FE, et al. Ingestion of glucose or sucrose prevents liver but not muscle glycogen depletion during prolonged endurance-type exercise in trained cyclists. Am J Physiol Endocrinol Metab. 2015;309:E1032–9. https://doi.org/10.1152/ajpendo.00376.2015.

    CAS  Article  PubMed  Google Scholar 

  26. Coyle EF, Coggan AR, Hemmert MK, Ivy JL. Muscle glycogen utilization during prolonged strenuous exercise when fed carbohydrate. J Appl Physiol. 1986;61:165–72.

    CAS  Article  Google Scholar 

  27. Burke LM. “Fat adaptation” for athletic performance: the nail in the coffin? J Appl Physiol. 2006;100:7–8. https://doi.org/10.1152/japplphysiol.01238.2005.

    Article  PubMed  Google Scholar 

  28. Yeo WK, Carey AL, Burke L, et al. Fat adaptation in well-trained athletes: effects on cell metabolism. Appl Physiol Nutr Metab. 2011;36:12–22. https://doi.org/10.1139/H10-089.

    CAS  Article  PubMed  Google Scholar 

  29. Spriet LL. New insights into the interaction of carbohydrate and fat metabolism during exercise. Sports Med. 2014;44:87–96. https://doi.org/10.1007/s40279-014-0154-1.

    Article  PubMed Central  Google Scholar 

  30. Burke LM. Re-examining high-fat diets for sports performance: did we call the “Nail in the Coffin” too soon? Sports Med. 2015;45(Suppl 1):S33–49. https://doi.org/10.1007/s40279-015-0393-9.

    Article  PubMed  Google Scholar 

  31. Mirtschin JG, Forbes SF, Cato LE, et al. Organisation of dietary control for nutrition-training intervention involving periodized carbohydrate (CHO) availability and ketogenic low CHO high fat (LCHF) diet. Int J Sport Nutr Exerc Metab. 2018;28:480–9. https://doi.org/10.1123/ijsnem.2017-0249.

    CAS  Article  PubMed  Google Scholar 

  32. Jeukendrup AE, Wallis GA. Measurement of substrate oxidation during exercise by means of gas exchange measurements. Int J Sports Med. 2005;26:S28–37. https://doi.org/10.1055/s-2004-830512.

    CAS  Article  PubMed  Google Scholar 

  33. Rowlands DS. Model for the behaviour of compartmental CO2 stores during incremental exercise. Eur J Appl Physiol. 2005;93:555–68. https://doi.org/10.1007/s00421-004-1217-z.

    CAS  Article  PubMed  Google Scholar 

  34. Pinckaers PJM, Churchward-Venne TA, Bailey D, van Loon LJC. Ketone bodies and exercise performance: the next magic bullet or merely hype? Sports Med. 2016;47:383–91. https://doi.org/10.1007/s40279-016-0577-y.

    Article  PubMed Central  Google Scholar 

  35. Cox PJ, Clarke K. Acute nutritional ketosis: implications for exercise performance and metabolism. Extrem Physiol Med. 2014;3:17.

    Article  Google Scholar 

  36. Margolis LM, O’Fallon KS. Utility of ketone supplementation to enhance physical performance: a systematic review. Adv Nutr. 2019;31:834–8. https://doi.org/10.1093/advances/nmz104.

    Article  Google Scholar 

  37. Evans M, Patchett E, Nally R, et al. Effect of acute ingestion of β-hydroxybutyrate salts on the response to graded exercise in trained cyclists. Eur J Sport Sci. 2018;45:1–11. https://doi.org/10.1080/17461391.2017.1421711.

    Article  Google Scholar 

  38. O’Malley T, Myette-Cote E, Durrer C, Little JP. Nutritional ketone salts increase fat oxidation but impair high-intensity exercise performance in healthy adult males. Appl Physiol Nutr Metab. 2017;42:1031–5. https://doi.org/10.1139/apnm-2016-0641.

    CAS  Article  PubMed  Google Scholar 

  39. Rodger S, Plews D, Laursen P, Driller M. Oral β-hydroxybutyrate salt fails to improve 4-minute cycling performance following submaximal exercise. J Sci Cycling. 2017;6:26–31.

    Google Scholar 

  40. Stubbs BJ, Cox PJ, Evans R, et al. On the metabolism of exogenous ketones in humans. Front Physiol. 2017;8:848. https://doi.org/10.3389/fphys.2017.00848.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Waldman HS, Basham SA, Price FG, et al. Exogenous ketone salts do not improve cognitive responses after a high-intensity exercise protocol in healthy college-aged males. Appl Physiol Nutr Metab. 2018;43:711–7. https://doi.org/10.1139/apnm-2017-0724.

    CAS  Article  PubMed  Google Scholar 

  42. Veech RL. 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. 2004;70:309–19. https://doi.org/10.1016/j.plefa.2003.09.007.

    CAS  Article  PubMed  Google Scholar 

  43. Stubbs BJ, Cox PJ, Kirk T, et al. Gastrointestinal effects of exogenous ketone drinks are infrequent, mild and vary according to ketone compound and dose. Int J Sport Nutr Exerc Metab. 2019. https://doi.org/10.1123/ijsnem.2019-0014.

    Article  PubMed  Google Scholar 

  44. Scott BE, Laursen PB, James LJ, et al. The effect of 1,3-butanediol and carbohydrate supplementation on running performance. J Sci Med Sport. 2018. https://doi.org/10.1016/j.jsams.2018.11.027.

    Article  PubMed  Google Scholar 

  45. Shaw DM, Merien F, Braakhuis A, et al. The effect of 1,3-butanediol on cycling time-trial performance. Int J Sport Nutr Exerc Metab. 2019. https://doi.org/10.1123/ijsnem.2018-0284.

    Article  PubMed  Google Scholar 

  46. Puchowicz MA, Smith CL, Bomont C, et al. Dog model of therapeutic, ketosis induced by oral administration of R, S-1,3-butanediol diacetoacetate. J Nutr Biochem. 2000;11:281–7. https://doi.org/10.1016/S0955-2863(00)00079-6.

    CAS  Article  PubMed  Google Scholar 

  47. Desrochers S, David F, Garneau M, et al. Metabolism of R- and S-1,3-butanediol in perfused livers from meal-fed and starved rats. Biochem J. 1992;285:647–53.

    CAS  Article  Google Scholar 

  48. Desrochers S, Quinze K, Dugas H, et al. R, S-1,3-butanediol acetoacetate esters, potential alternates to lipid emulsions for total parenteral nutrition. J Nutr Biochem. 1995;6:111–8. https://doi.org/10.1016/0955-2863(94)00011-A.

    CAS  Article  Google Scholar 

  49. Mehlman MA, Tobin RB, Hahn HK, et al. Metabolic fate of 1,3-butanediol in the rat: liver tissue slices metabolism. J Nutr. 1971;101:1711–8.

    CAS  Article  Google Scholar 

  50. Tate RL, Mehlman MA, Tobin RB. Metabolic fate of 1,3-butanediol in rat—conversion to beta-hydroxybutyrate. J Nutr. 1971;101:1719–26.

    CAS  Article  Google Scholar 

  51. Desrochers S, Dubreuil P, Brunet J, et al. Metabolism of (R, S)-1,3-butanediol acetoacetate esters, potential parenteral and enteral nutrients in conscious pigs. Am J Physiol. 1995;31:E660–7.

    Google Scholar 

  52. D’agostino DP, Pilla R, Held HE, et al. Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats. Am J Physiol Regul Integr Comp Physiol. 2013;304:R829–36. https://doi.org/10.1152/ajpregu.00506.2012.

    CAS  Article  PubMed  Google Scholar 

  53. Leckey JJ, Ross ML, Quod M, et al. Ketone diester ingestion impairs time-trial performance in professional cyclists. Front Physiol. 2017;8:806. https://doi.org/10.3389/fphys.2017.00806.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Clarke K, Tchabanenko K, Pawlosky R, et al. Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul Toxicol Pharmacol. 2012;63:401–8. https://doi.org/10.1016/j.yrtph.2012.04.008.

    CAS  Article  PubMed  Google Scholar 

  55. Cox PJ, Kirk T, Ashmore T, et al. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab. 2016;24:256–68. https://doi.org/10.1016/j.cmet.2016.07.010.

    CAS  Article  PubMed  Google Scholar 

  56. Clarke K, Tchabanenko K, Pawlosky R, et al. Oral 28-day and developmental toxicity studies of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. Regul Toxicol Pharmacol. 2012;63:196–208. https://doi.org/10.1016/j.yrtph.2012.04.001.

    CAS  Article  PubMed  Google Scholar 

  57. Shivva V, Cox PJ, Clarke K, et al. The population pharmacokinetics of d-β-hydroxybutyrate following administration of (R)-3-Hydroxybutyl (R)-3-hydroxybutyrate. AAPS J. 2016;18:678–88. https://doi.org/10.1208/s12248-016-9879-0.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Myette-Cote E, Neudorf H, Rafiei H, et al. Prior ingestion of exogenous ketone monoester attenuates the glycemic response to an oral glucose tolerance test in healthy young individuals. J Physiol. 2018;596:1385–95. https://doi.org/10.1113/JP275709.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Stubbs BJ, Cox PJ, Evans RD, et al. A ketone ester drink lowers human ghrelin and appetite. Obesity. 2017;26:269–73. https://doi.org/10.1002/oby.22051.

    CAS  Article  PubMed  Google Scholar 

  60. Neudorf H, Durrer C, Myette-Cote E, et al. Oral ketone supplementation acutely increases markers of NLRP3 inflammasome activation in human monocytes. Mol Nutr Food Res. 2019. https://doi.org/10.1002/mnfr.201801171.

    Article  PubMed  Google Scholar 

  61. Evans M, Egan B. Intermittent running and cognitive performance after ketone ester ingestion. Med Sci Sport Exerc. 2018;50:2330–8. https://doi.org/10.1249/MSS.0000000000001700.

    CAS  Article  Google Scholar 

  62. Faull OK. Beyond RPE: the perception of exercise under normal and ketotic conditions. Front Physiol. 2019;10:229. https://doi.org/10.3389/fphys.2019.00229.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Dearlove DJ, Faull OK, Rolls E, et al. Nutritional ketoacidosis during incremental exercise in healthy athletes. Front Physiol. 2019;10:290. https://doi.org/10.3389/fphys.2019.00290.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Vandoorne T, De Smet S, Ramaekers M, et al. Intake of a ketone ester drink during recovery from exercise promotes mTORC1 signalling but not glycogen resynthesis in human muscle. Front Physiol. 2017;8:310. https://doi.org/10.3389/fphys.2017.00310/full.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Holdsworth DA, Cox PJ, Kirk T, et al. A ketone ester drink increases postexercise muscle glycogen synthesis in humans. Med Sci Sport Exerc. 2017;49:1789–95. https://doi.org/10.1249/MSS.0000000000001292.

    CAS  Article  Google Scholar 

  66. Poffé C, Ramaekers M, Van Thienen R, Hespel P. Ketone ester supplementation blunts overreaching symptoms during endurance training overload. J Physiol. 2019. https://doi.org/10.1113/JP277831.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Van Gelder J, Shafiee M, De Clercq E, et al. Species-dependent and site-specific intestinal metabolism of ester prodrugs. Int J Pharm. 2000;205:93–100. https://doi.org/10.1016/S0378-5173(00)00507-X.

    Article  PubMed  Google Scholar 

  68. Tsai Y-C, Liao T-H, Lee J-A. Identification of L-3-hydroxybutyrate as an original ketone body in rat serum by column-switching high-performance liquid chromatography and fluorescence derivatization. Analytical Biochemistry. 2003;319:34–41. https://doi.org/10.1016/S0003-2697(03)00283-5.

    CAS  Article  PubMed  Google Scholar 

  69. Tsai Y-C, Chou Y-C, Wu A-B, et al. Stereoselective effects of 3-hydroxybutyrate on glucose utilization of rat cardiomyocytes. Life Sci. 2006;78:1385–91. https://doi.org/10.1016/j.lfs.2005.07.013.

    CAS  Article  PubMed  Google Scholar 

  70. Lincoln BC, Rosiers CD, Brunengraber H. Metabolism of S-3-hydroxybutyrate in the perfused rat liver. Arch Biochem Biophys. 1987;259:149–56. https://doi.org/10.1016/0003-9861(87)90480-2.

    CAS  Article  PubMed  Google Scholar 

  71. Webber RJ. Utilization of L(+)-3-hydroxybutyrate, D(−)-3-hydroxybutyrate, acetoacetate, and glucose for respiration and lipid synthesis in the 18-day-old rat. J Biol Chem. 1977;252:5222–6.

    CAS  PubMed  Google Scholar 

  72. Misra S, Oliver NS. Utility of ketone measurement in the prevention, diagnosis and management of diabetic ketoacidosis. Diabet Med. 2015;32:14–23. https://doi.org/10.1111/dme.12604.

    CAS  Article  PubMed  Google Scholar 

  73. Urbain P, Bertz H. Monitoring for compliance with a ketogenic diet: what is the best time of day to test for urinary ketosis? Nutr Metab. 2016;13:77. https://doi.org/10.1186/s12986-016-0136-4.

    CAS  Article  Google Scholar 

  74. Ceriotti F, Kaczmarek E, Guerra E, et al. Comparative performance assessment of point-of-care testing devices for measuring glucose and ketones at the patient bedside. J Diabetes Sci Technol. 2015;9:268–77. https://doi.org/10.1177/1932296814563351.

    Article  PubMed  Google Scholar 

  75. Guimont M-C, Desjobert H, Fonfrède M, et al. Multicentric evaluation of eight glucose and four ketone blood meters. Clin Biochem. 2015;48:1310–6. https://doi.org/10.1016/j.clinbiochem.2015.07.032.

    CAS  Article  PubMed  Google Scholar 

  76. Thomas C, Bishop DJ, Lambert K, et al. Effects of acute and chronic exercise on sarcolemmal MCT1 and MCT4 contents in human skeletal muscles: current status. Am J Physiol Regul Integr Comp Physiol. 2012;302:R1–14. https://doi.org/10.1152/ajpregu.00250.2011.

    CAS  Article  PubMed  Google Scholar 

  77. Winder WW, Holloszy JO, Baldwin KM. Enzymes involved in ketone utilization in different types of muscle: adaptation to exercise. Eur J Biochem. 1974;47:461–7. https://doi.org/10.1111/j.1432-1033.1974.tb03713.x.

    CAS  Article  PubMed  Google Scholar 

  78. Romijn JA, Coyle EF, Hibbert J, Wolfe RR. Comparison of indirect calorimetry and a new breath 13C/12C ratio method during strenuous exercise. Am J Physiol. 1992;263:E64–71.

    CAS  PubMed  Google Scholar 

  79. Frayn KN. Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol Respir Environ Exerc Physiol. 1983;55:628–34.

    CAS  PubMed  Google Scholar 

  80. Soeters MR, Serlie MJ, Sauerwein HP, et al. Characterization of D-3-hydroxybutyrylcarnitine (ketocarnitine): an identified ketosis-induced metabolite. Metab Clin Exp. 2012;61:966–73. https://doi.org/10.1016/j.metabol.2011.11.009.

    CAS  Article  PubMed  Google Scholar 

  81. Féry F, Balasse EO. Effect of exercise on the disposal of infused ketone bodies in humans. J Clin Endocrinol Metab. 1988;67:245–50. https://doi.org/10.1210/jcem-67-2-245.

    Article  PubMed  Google Scholar 

  82. Hawley JA, Leckey JJ. Carbohydrate dependence during prolonged, intense endurance exercise. Sports Med. 2015;45(Suppl 1):S5–12. https://doi.org/10.1007/s40279-015-0400-1.

    Article  PubMed  Google Scholar 

  83. Gejl KD, Thams L, Hansen M, et al. No superior adaptations to carbohydrate periodization in elite endurance athletes. Med Sci Sport Exerc. 2017;49:2486–97. https://doi.org/10.1249/MSS.0000000000001377.

    CAS  Article  Google Scholar 

  84. Krogh A, Lindhard J. The relative value of fat and carbohydrate as sources of muscular energy: with appendices on the correlation between standard metabolism and the respiratory quotient during rest and work. Biochem J. 1920;14:290–363.

    CAS  Article  Google Scholar 

  85. Ørtenblad N, Nielsen J. Muscle glycogen and cell function—location, location, location. Scand J Med Sci Sports. 2015;25:34–40. https://doi.org/10.1111/sms.12599.

    Article  PubMed  Google Scholar 

  86. Mikkelsen KH, Seifert T, Secher NH, et al. Systemic, cerebral and skeletal muscle ketone body and energy metabolism during acute hyper-D-β-hydroxybutyratemia in post-absorptive healthy males. J Clin Endocrinol Metab. 2015;100:636–43. https://doi.org/10.1210/jc.2014-2608.

    CAS  Article  PubMed  Google Scholar 

  87. Olson MS, Dennis SC, DeBuysere MS, Padma A. The regulation of pyruvate dehydrogenase in the isolated perfused rat heart. J Biol Chem. 1978;253:7369–75.

    CAS  PubMed  Google Scholar 

  88. Ashour B, Hansford RG. Effect of fatty acids and ketone on the activity of pyruvate dehydrogenase in skeletal-muscle mitochondria. Biochem J. 1983;214:725–36.

    CAS  Article  Google Scholar 

  89. Sato K, Kashiwaya Y, Keon CA, et al. Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J. 1995;9:651–8.

    CAS  Article  Google Scholar 

  90. Burgess SC, Iizuka K, Jeoung NH, et al. Carbohydrate-response element-binding protein deletion alters substrate utilization producing an energy-deficient liver. J Biol Chem. 2008;283:1670–8. https://doi.org/10.1074/jbc.M706540200.

    CAS  Article  PubMed  Google Scholar 

  91. Murray AJ, Knight NS, Cole MA, et al. Novel ketone diet enhances physical and cognitive performance. FASEB J. 2016;30:4021–32. https://doi.org/10.1096/fj.201600773R.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. Evans M, McSwiney FT, Brady AJ, Egan B. No benefit of ingestion of a ketone monoester supplement on 10-km running performance. Med Sci Sport Exerc. 2019;51:2506–15. https://doi.org/10.1249/MSS.0000000000002065.

    CAS  Article  Google Scholar 

  93. Zinn C, Wood M, Williden M, et al. Ketogenic diet benefits body composition and well-being but not performance in a pilot case study of New Zealand endurance athletes. J Int Soc Sports Nutr. 2017;14:22. https://doi.org/10.1186/s12970-017-0180-0.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. Maunder E, Kilding AE, Plews DJ. Substrate metabolism during ironman triathlon: different horses on the same courses. Sports Med. 2018;48:2219–26. https://doi.org/10.1007/s40279-018-0938-9.

    Article  PubMed  Google Scholar 

  95. Tiller NB, Roberts JD, Beasley L, et al. International Society of Sports Nutrition Position Stand: nutritional considerations for single-stage ultra-marathon training and racing. J Int Soc Sports Nutr. 2019;16:1–23. https://doi.org/10.1186/s12970-019-0312-9.

    Article  Google Scholar 

  96. Stellingwerff T, Boon H, Gijsen AP, et al. Carbohydrate supplementation during prolonged cycling exercise spares muscle glycogen but does not affect intramyocellular lipid use. Pflugers Arch. 2007;454:635–47. https://doi.org/10.1007/s00424-007-0236-0.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. Stellingwerff T, Boon H, Jonkers RAM, et al. Significant intramyocellular lipid use during prolonged cycling in endurance-trained males as assessed by three different methodologies. Am J Physiol Endocrinol Metab. 2007;292:E1715–23. https://doi.org/10.1152/ajpendo.00678.2006.

    CAS  Article  PubMed  Google Scholar 

  98. van Loon LJC, Koopman R, Stegen JHCH, et al. Intramyocellular lipids form an important substrate source during moderate intensity exercise in endurance-trained males in a fasted state. J Physiol. 2004;553:611–25. https://doi.org/10.1113/jphysiol.2003.052431.

    CAS  Article  Google Scholar 

  99. De Bock K, Richter EA, Russell AP, et al. Exercise in the fasted state facilitates fibre type-specific intramyocellular lipid breakdown and stimulates glycogen resynthesis in humans. J Physiol. 2005;564:649–60. https://doi.org/10.1113/jphysiol.2005.083170.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. Frayn KN. Fat as a fuel: emerging understanding of the adipose tissue-skeletal muscle axis. Acta Physiol (Oxf). 2010;199:509–18. https://doi.org/10.1111/j.1748-1716.2010.02128.x.

    CAS  Article  Google Scholar 

  101. Chrzanowski-Smith OJ, Piatrikova E, Betts JA, et al. Variability in exercise physiology: can capturing intra-individual variation help better understand true inter-individual responses? Eur J Sport Sci. 2019. https://doi.org/10.1080/17461391.2019.1655100.

    Article  PubMed  Google Scholar 

  102. Helge JW, Watt PW, Richter EA, et al. Fat utilization during exercise: adaptation to a fat-rich diet increases utilization of plasma fatty acids and very low density lipoprotein-triacylglycerol in humans. J Physiol. 2001;537:1009–20.

    CAS  Article  Google Scholar 

  103. Braakhuis AJ, Hopkins WG. Impact of dietary antioxidants on sport performance: a review. Sports Med. 2015;45:939–55. https://doi.org/10.1007/s40279-015-0323-x.

    Article  PubMed  Google Scholar 

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Correspondence to David M. Shaw.

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Shaw DM, Merien F, Braakhuis A, Maunder E, and Dulson D declare that they have no conflict of interest.

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Shaw, D.M., Merien, F., Braakhuis, A. et al. Exogenous Ketone Supplementation and Keto-Adaptation for Endurance Performance: Disentangling the Effects of Two Distinct Metabolic States. Sports Med 50, 641–656 (2020). https://doi.org/10.1007/s40279-019-01246-y

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