Sports Medicine

, Volume 48, Issue 2, pp 467–479 | Cite as

Assessment of Metabolic Flexibility by Means of Measuring Blood Lactate, Fat, and Carbohydrate Oxidation Responses to Exercise in Professional Endurance Athletes and Less-Fit Individuals

  • Iñigo San-MillánEmail author
  • George A. Brooks
Original Research Article



Increased muscle mitochondrial mass is characteristic of elite professional endurance athletes (PAs), whereas increased blood lactate levels (lactatemia) at the same absolute submaximal exercise intensities and decreased mitochondrial oxidative capacity are characteristics of individuals with low aerobic power. In contrast to PAs, patients with metabolic syndrome (MtS) are characterized by a decreased capacity to oxidize lipids and by early transition from fat to carbohydrate oxidation (FATox/CHOox), as well as elevated blood lactate concentration [La] as exercise power output (PO) increases, a condition termed ‘metabolic inflexibility’.


The aim of this study was to assess metabolic flexibility across populations with different metabolic characteristics.


We used indirect calorimetry and [La] measurements to study the metabolic responses to exercise in PAs, moderately active individuals (MAs), and MtS individuals.


FATox was significantly higher in PAs than MAs and patients with MtS (p < 0.01), while [La] was significantly lower in PAs compared with MAs and patients with MtS. FATox and [La] were inversely correlated in all three groups (PA: r = −0.97, p < 0.01; MA: r = −0.98, p < 0.01; MtS: r = −0.92, p < 0.01). The correlation between FATox and [La] for all data points corresponding to all populations studied was r = −0.76 (p < 0.01).


Blood lactate accumulation is negatively correlated with FATox and positively correlated with CHOox during exercise across populations with widely ranging metabolic capabilities. Because both lactate and fatty acids are mitochondrial substrates, we believe that measurements of [La] and FATox rate during exercise provide an indirect method to assess metabolic flexibility and oxidative capacity across individuals of widely different metabolic capabilities.


Compliance with Ethical Standards

Conflict of interest

Iñigo San-Millán and George A. Brooks declare that they have no conflicts of interest that are directly relevant to the content of this article.


The authors declare that no financial support was received for the conduct of this study or the preparation of this article.


  1. 1.
    Messonnier LA, Emhoff C-AW, Fattor JA, Horning MA, Carlson TJ, Brooks GA. Lactate kinetics at the lactate threshold in trained and untrained men. J Appl Physiol. 2013;114:1593–602.CrossRefPubMedGoogle Scholar
  2. 2.
    Emhoff C-AW, Messonnier LA, Horning MA, Fattor JA, Carlson TJ, Brooks GA. Direct and indirect lactate oxidation in trained and untrained men. J Appl Physiol. 2013;115:829–38.CrossRefPubMedGoogle Scholar
  3. 3.
    Emhoff C-AW, Messonnier LA, Horning MA, Fattor JA, Carlson TJ, Brooks GA. Gluconeogenesis and hepatic glycogenolysis during exercise at the lactate threshold. J Appl Physiol. 2013;114:297–306.CrossRefPubMedGoogle Scholar
  4. 4.
    Bergman BC, Wolfel EE, Butterfield GE, Lopaschuk GD, Casazza GA, Horning MA, et al. Active muscle and whole body lactate kinetics after endurance training in men. J Appl Physiol. 1999;87:1684–96.CrossRefPubMedGoogle Scholar
  5. 5.
    Bergman BC, Butterfield GE, Wolfel EE, Casazza GA, Lopaschuk GD, Brooks GA. Evaluation of exercise and training on muscle lipid metabolism. Am J Appl Physiol. 1999;276:E106–17.Google Scholar
  6. 6.
    Bergman BC, Butterfield GE, Wolfel EE, Lopaschuk GD, Casazza GA, Horning MA, et al. Muscle net glucose uptake and glucose kinetics after endurance training in men. Am J Appl Physiol. 1999;277:E81–92.Google Scholar
  7. 7.
    Nogales-Gadea G, Pinós T, Ruiz JR, Marzo PF, Fiuza-Luces C, López-Gallardo E, et al. Are mitochondrial haplogroups associated with elite athletic status? A study on a Spanish cohort. Mitochondrion. 2011;11:905–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Maruszak A, Adamczyk JG, Siewierski M, Sozański H, Gajewski A, Żekanowski C. Mitochondrial DNA variation is associated with elite athletic status in the Polish population. Scand J Med Sci Sports. 2014;24:311–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Mikami E, Fuku N, Takahashi H, Ohiwa N, Pitsiladis YP, Higuchi M, et al. Polymorphisms in the control region of mitochondrial DNA associated with elite Japanese athlete status. Scand J Med Sci Sports. 2013;23:593–9.PubMedGoogle Scholar
  10. 10.
    Jacobs RA, Rasmussen P, Siebenmann C, Díaz V, Gassmann M, Pesta D, et al. Determinants of time trial performance and maximal incremental exercise in highly trained endurance athletes. J Appl Physiol. 2011;111:1422–30.CrossRefPubMedGoogle Scholar
  11. 11.
    Jacobs RA, Lundby C. Mitochondria express enhanced quality as well as quantity in association with aerobic fitness across recreationally active individuals up to elite athletes. J Appl Physiol. 2013;114:344–50.CrossRefPubMedGoogle Scholar
  12. 12.
    Hoppeler H, Lüthi P, Claassen H, Weibel ER, Howald H. The ultrastructure of the normal human skeletal muscle. Pflug Arch. 1973;344:217–32.CrossRefGoogle Scholar
  13. 13.
    Yang N, MacArthur DG, Gulbin JP, Hahn AG, Beggs AH, Easteal S, et al. ACTN3 genotype is associated with human elite athletic performance. Am J Hum Genet. 2003;73:627–31.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kim J-A, Wei Y, Sowers JR. Role of mitochondrial dysfunction in insulin resistance. Circ Res. 2008;102:401–14.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Goodpaster BH. Mitochondrial deficiency is associated with insulin resistance. Diabetes. 2013;62:1032–5.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med. 2004;350:664–71.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Toledo FGS, Goodpaster BH. The role of weight loss and exercise in correcting skeletal muscle mitochondrial abnormalities in obesity, diabetes and aging. Mol Cell Endocrinol. 2013;379:30–4.CrossRefPubMedGoogle Scholar
  18. 18.
    Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes. 2002;51:2944–50.CrossRefPubMedGoogle Scholar
  19. 19.
    Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science. 2005;307:384–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Phielix E, Meex R, Moonen-Kornips E, Hesselink MKC, Schrauwen P. Exercise training increases mitochondrial content and ex vivo mitochondrial function similarly in patients with type 2 diabetes and in control individuals. Diabetologia. 2010;53:1714–21.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Abdul-Ghani MA, DeFronzo RA. Mitochondrial dysfunction, insulin resistance, and type 2 diabetes mellitus. Curr Diabetes Rep. 2008;8:173–8.CrossRefGoogle Scholar
  22. 22.
    Thorburn AW, Gumbiner B, Bulacan F, Wallace P, Henry RR. Intracellular glucose oxidation and glycogen synthase activity are reduced in non-insulin-dependent (type II) diabetes independent of impaired glucose uptake. J Clin Investig. 1990;85:522–9.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Boden G, Chen X. Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes. J Clin Invest. 1995;96:1261–8.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Blaak EE, Wagenmakers A, Glatz J. Plasma free fatty acid utilisation and fatty acid binding protein content are diminished in forearm skeletal muscle of type 2 diabetic subjects. Am J Physiol. 2000;279:E146–54.Google Scholar
  25. 25.
    Kelley DE, Goodpaster B, Wing RR, Simoneau J-A. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am J Physiol Endocrinol Metab. 1999;277:E1130–41.CrossRefGoogle Scholar
  26. 26.
    Blaak EE, van Aggel-Leijssen DP, Wagenmakers AJ, Saris WH, van Baak MA. Impaired oxidation of plasma-derived fatty acids in type 2 diabetic subjects during moderate-intensity exercise. Diabetes. 2000;49:2102–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Kelley DE, Simoneau JA. Impaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus. J Clin Investig. 1994;94:2349–56.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    McGarry JD. Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes. 2002;51(1):7–18.CrossRefPubMedGoogle Scholar
  29. 29.
    Simoneau JA, Veerkamp JH, Turcotte LP, Kelley DE. Markers of capacity to utilize fatty acids in human skeletal muscle: relation to insulin resistance and obesity and effects of weight loss. FASEB J. 1999;13:2051–60.PubMedGoogle Scholar
  30. 30.
    Storlien L, Oakes ND, Kelley DE. Metabolic flexibility. Proc Nutr Soc. 2004;63:363–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Kelley DE. Skeletal muscle fat oxidation: timing and flexibility are everything. J Clin Investig. 2005;115:1699–702.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kelley DE, Mandarino LJ. Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes. 2000;49:677–83.CrossRefPubMedGoogle Scholar
  33. 33.
    Ritov VB, Menshikova EV, He J, Ferrell RE, Goodpaster BH, Kelley DE. Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes. 2005;54:8–14.CrossRefPubMedGoogle Scholar
  34. 34.
    Brooks GA, Mercier J. Balance of carbohydrate and lipid utilization during exercise: the “crossover” concept. J Appl Physiol. 1994;76:2253–61.CrossRefPubMedGoogle Scholar
  35. 35.
    Lopaschuk GD, Witters LA, Itoi T, Barr R, Barr A. Acetyl-CoA carboxylase involvement in the rapid maturation of fatty acid oxidation in the newborn rabbit heart. J Biol Chem. 1994;269:25871–8.PubMedGoogle Scholar
  36. 36.
    Brooks GA. Master regulator or readout: the wisdom of distributed control. Focus on “Pyruvate suppresses PGC1 expression and substrate utilization despite increased respiratory chain content in C2C12 myotubes”. Am J Physiol. 2010;299:C216–7.CrossRefGoogle Scholar
  37. 37.
    Eckel RH, Alberti K, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2010;375:181–3.CrossRefPubMedGoogle Scholar
  38. 38.
    Randle PI, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963;1:785–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Boden G. Free fatty acids, insulin resistance, and type 2 diabetes mellitus. Proc Assoc Am Physicians. 1999;111:241–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Boden G. Effects of free fatty acids (FFA) on glucose metabolism: significance for insulin resistance and type 2 diabetes. Exp Clin Endocrinol Diabetes. 2003;111:121–4.CrossRefPubMedGoogle Scholar
  41. 41.
    Cai TQ, Ren N, Jin L, Cheng K, Kash S, Chen R. Role of GPR81 in lactate-mediated reduction of adipose lipolysis. Biochem Biophys Res Commun. 2008;377:987–91.CrossRefPubMedGoogle Scholar
  42. 42.
    Liu C, Wu J, Zhu J, Kuei C, Yu J, Shelton J, et al. Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. J Biol Chem. 2009;284:2811–22.CrossRefPubMedGoogle Scholar
  43. 43.
    Ahmed K, Tunaru S, Tang C, Müller M, Gille A, Sassmann A, et al. An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81. Cell Metab. 2010;11:311–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Nikooie R, Samaneh S. Exercise-induced lactate accumulation regulates intramuscular triglyceride metabolism via transforming growth factor-β1 mediated pathways. Mol Cell Endocrinol. 2016;419:244–51.CrossRefPubMedGoogle Scholar
  45. 45.
    Holloszy JO. Biochemical adaptations in muscle. Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. J Biol Chem. 1967;242:2278–82.PubMedGoogle Scholar
  46. 46.
    Davies KJA, Packer L, Brooks GA. Biochemical adaptation of mitochondria, muscle, and whole-animal respiration to endurance training. Arch Biochem Biophys. 1981;209:539–54.CrossRefPubMedGoogle Scholar
  47. 47.
    Holloszy JO, Oscai LB, Don IJ, Mole PA. Mitochondrial citric acid cycle and related enzymes: adaptive response to exercise. Biochem Biophys Res Commun. 1970;40:1368–73.CrossRefPubMedGoogle Scholar
  48. 48.
    Gollnick PD, Armstrong RB, Saubert CW IV. Enzyme activity and fiber composition in skeletal muscle of untrained and trained men. J Appl Physiol. 1972;33:312–9.CrossRefPubMedGoogle Scholar
  49. 49.
    Gollnick PD, King DW. Effect of exercise and training on mitochondria of rat skeletal muscle. Am J Physiol. 1969;216:1502–9.PubMedGoogle Scholar
  50. 50.
    Hoppeler H, Howald H, Conley K, Lindstedt SL, Claassen H, Vock P, et al. Endurance training in humans: aerobic capacity and structure of skeletal muscle. J Appl Physiol. 1985;59:320–7.CrossRefPubMedGoogle Scholar
  51. 51.
    Turcotte LP, Richter EA, Kiens B. Increased plasma FFA uptake and oxidation during prolonged exercise in trained vs. untrained humans. Am J Physiol. 1992;262:791–9.Google Scholar
  52. 52.
    Jansson E, Kaijser L. Substrate utilization and enzymes in skeletal muscle of extremely endurance-trained men. J Appl Physiol. 1987;62:999–1005.CrossRefPubMedGoogle Scholar
  53. 53.
    Henriksson J. Training induced adaptation of skeletal muscle and metabolism during submaximal exercise. J Physiol. 1977;270:661.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Kiens B, Essen Gustavsson B, Christensen NJ, Saltin B. Skeletal muscle substrate utilization during submaximal exercise in man: effect of endurance training. J Physiol. 1993;469:459–78.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Phillips SM, Green HJ, Tarnopolsky MA, Heigenhauser GF, Hill RE, Grant SM. Effects of training duration on substrate turnover and oxidation during exercise. J Appl Physiol. 1996;81:2182–91.CrossRefPubMedGoogle Scholar
  56. 56.
    Donovan CM, Brooks GA. Endurance training affects lactate clearance, not lactate production. Am J Physiol. 1983;244:83–92.Google Scholar
  57. 57.
    Dubouchaud H, Butterfield GE, Wolfel EE, Bergman BC, Brooks GA. Endurance training, expression, and physiology of LDH, MCT1, and MCT4 in human skeletal muscle. Am J Physiol Endocrinol Metabol. 2000;278:E571–9.CrossRefGoogle Scholar
  58. 58.
    Billat V, Sirvent P, Lepretre P-M, Koralsztein JP. Training effect on performance, substrate balance and blood lactate concentration at maximal lactate steady state in master endurance-runners. Pflug Arch. 2004;447:875–83.CrossRefGoogle Scholar
  59. 59.
    Neal CM, Hunter AM, Brennan L, O’Sullivan A, Hamilton DL, DeVito G, et al. Six weeks of a polarized training-intensity distribution leads to greater physiological and performance adaptations than a threshold model in trained cyclists. J Appl Physiol. 2013;114:461–71.CrossRefPubMedGoogle Scholar
  60. 60.
    Acevedo EO, Goldfarb AH. Increased training intensity effects on plasma lactate, ventilatory threshold, and endurance. Med Sci Sports Exerc. 1989;21:563–8.CrossRefPubMedGoogle Scholar
  61. 61.
    McDermott JC, Bonen A. Endurance training increases skeletal muscle lactate transport. Acta Physiol Scand. 1993;147:323–7.CrossRefPubMedGoogle Scholar
  62. 62.
    San Millán I, González-Haro C, Sagasti M. Physiological differences between road cyclists of different categories. A new approach. Med Sci Sports Exerc. 2009;41:64–5.CrossRefGoogle Scholar
  63. 63.
    Brooks GA, Wolfel EE, Groves BM, Bender PR, Butterfield GE, Cymerman A, et al. Muscle accounts for glucose disposal but not blood lactate appearance during exercise after acclimatization to 4,300 m. J Appl Physiol. 1992;72:2435–45.CrossRefPubMedGoogle Scholar
  64. 64.
    Mazzeo RS, Brooks GA, Schoeller DA, Budinger TF. Disposal of blood [1-13C]lactate in humans during rest and exercise. J Appl Physiol. 1986;60:232–41.CrossRefPubMedGoogle Scholar
  65. 65.
    Stanley WC, Gertz EW, Wisneski JA, Neese RA, Morris DL, Brooks GA. Lactate extraction during net lactate release in legs of humans during exercise. J Appl Physiol. 1986;60:1116–20.CrossRefPubMedGoogle Scholar
  66. 66.
    Brooks GA. Lactate shuttles in nature. Biochem Soc Trans. 2002;30:258–64.CrossRefPubMedGoogle Scholar
  67. 67.
    Hashimoto T, Hussien R, Oommen S, Gohil K, Brooks GA. Lactate sensitive transcription factor network in L6 cells: activation of MCT1 and mitochondrial biogenesis. FASEB J. 2007;21:2602–12.CrossRefPubMedGoogle Scholar
  68. 68.
    Ghatak S, Banerjee A, Sikdar SK. Ischaemic concentrations of lactate increase TREK1 channel activity by interacting with a single histidine residue in the carboxy terminal domain. J Physiol. 2016;594:59–81.CrossRefPubMedGoogle Scholar
  69. 69.
    Gertz EW, Wisneski JA, Stanley WC, Neese RA. Myocardial substrate utilization during exercise in humans. Dual carbon-labeled carbohydrate isotope experiments. J Clin Investig. 1988;82:2017–25.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Miller BF, Fattor JA, Jacobs KA, Horning MA, Suh SH. Lactate–glucose interaction in men during rest and exercising using lactate clamp procedure. J Physiol. 2002;544:963–75.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Miller BF, Fattor JA, Jacobs KA, Horning MA, Suh S-H, Navazio F, et al. Metabolic and cardiorespiratory responses to “the lactate clamp”. Am J Physiol Endocrinol Metabol. 2002;283:E889–98.CrossRefGoogle Scholar
  72. 72.
    Glenn TC, Martin NA, Honing MA, McArthur DL, Hodva DA, Vespa P, et al. Lactate: brain fuel in human traumatic brain injury: a comparison with normal healthy control subjects. J Neurotrauma. 2015;32:820–32.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Hashimoto T, Hussien R, Brooks GA. Colocalization of MCT1, CD147, and LDH in mitochondrial inner membrane of L6 muscle cells: evidence of a mitochondrial lactate oxidation complex. Am J Physiol Endocrinol Metabol. 2006;290:E1237–44.CrossRefGoogle Scholar
  74. 74.
    Hashimoto T, Brooks GA. Mitochondrial lactate oxidation complex and an adaptive role for lactate production. Med Sci Sports Exerc. 2008;40:486.CrossRefPubMedGoogle Scholar
  75. 75.
    Frayn KN. Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol Respir Environ Exerc Physiol. 1983;55:628–34.PubMedGoogle Scholar
  76. 76.
    Reaven GM, Hollenbeck C, Jeng C-Y, Wu MS, Chen Y-DI. Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM. Diabetes. 1988;37:1020–4.CrossRefPubMedGoogle Scholar
  77. 77.
    Konrad T, Vicini P, Kusterer K, Höflich A, Assadkhani A, Böhles HJ, et al. alpha-Lipoic acid treatment decreases serum lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Diabetes Care. 1999;22:280–7.CrossRefPubMedGoogle Scholar
  78. 78.
    Jansson E, Kaijser L. Substrate utilization and enzymes in skeletal muscle of extremely endurance-trained men. J Appl Physiol. 1987;62:999–1005.CrossRefPubMedGoogle Scholar
  79. 79.
    Issekutz B, Miller H. Plasma free fatty acids during exercise and the effect of lactic acid. Exp Biol Med. 1962;110:237–9.CrossRefGoogle Scholar
  80. 80.
    Rodahl K, Miller HI, Issekutz B. Plasma free fatty acids in exercise. J Appl Physiol. 1964;19:489–92.CrossRefPubMedGoogle Scholar
  81. 81.
    Brooks GA. Intra-and extra-cellular lactate shuttles. Med Sci Sports Exerc. 2000;32:790–9.CrossRefPubMedGoogle Scholar
  82. 82.
    Brooks GA. Cell–cell and intracellular lactate shuttles. J Physiol. 2009;587:5591–600.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG Switzerland 2017

Authors and Affiliations

  1. 1.Department of Physical Medicine and RehabilitationUniversity of Colorado School of MedicineAuroraUSA
  2. 2.CU Sports Medicine and Performance CenterBoulderUSA
  3. 3.Exercise Physiology Laboratory, Department of Integrative BiologyUniversity of CaliforniaBerkleyUSA

Personalised recommendations