Skip to main content
Log in

Acid–base balance at exercise in normoxia and in chronic hypoxia. Revisiting the "lactate paradox"

  • Review Article
  • Published:
European Journal of Applied Physiology Aims and scope Submit manuscript

Abstract

Transitions between rest and work, in either direction, and heavy exercise loads are characterized by changes of muscle pH depending on the buffer power and capacity of the tissues and on the metabolic processes involved. Among the latter, in chronological sequence: (1) aerobic glycolysis generates sizeable amounts of lactate and H+ by way of the recently described, extremely fast (20–100 ms) "glycogen shunt" and of the excess of glycolytic pyruvate supply; (2) hydrolysis of phosphocreatine, tightly coupled with that of ATP in the Lohmann reaction, is known to consume protons, a process undergoing reversal during recovery; (3) anaerobic glycolysis sustaining ATP production in supramaximal exercise as well as in conditions of hypoxia and ischemia, is responsible for the accumulation of large amounts of lactic acid (up to 1 mol for the whole body). The handling of metabolic acids, i.e., acid-base regulation, occurs both in blood and in tissues, mainly in muscles which are the main producers and consumers of lactic acid. The role of both blood and muscle bicarbonate and non-bicarbonate buffers as well as that of lactate/H+ cotransport mechanisms is analyzed in relation to acid-base homeostasis in the course of exercise. A section of the review deals with the analysis of the acid-base state of humans exposed to chronic hypoxia. Particular emphasis is put on anaerobic glycolysis. In this context, the so-called lactate paradox is revisited and interpreted on the basis of the most recent findings on exercise at altitude.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.
Fig. 7.
Fig. 8.
Fig. 9.
Fig. 10.
Fig. 11
Fig. 12.
Fig. 13.
Fig. 14.
Fig. 15.
Fig. 16.

Similar content being viewed by others

Notes

  1. It should be pointed out that changes of tissue lactate and proton concentrations in the ratio 1 to 1 lead to progressive drifts of the calculated β value because of the logarithmic nature of the latter parameter.

References

  • Bangsbo J, Gollnick PD, Graham PE, Juel C, Kiens B, Mizuno M, Saltin B (1990) Anaerobic energy production and O2 deficit-debt relationship during exhaustive exercise in humans. J Physiol (Lond) 422:539–559

    Google Scholar 

  • Bangsbo J, Juel C, Hellsten Y, Saltin B (1997) Dissociation between lactate and proton exchange in muscle during intense exercise in man. J Physiol (Lond) 504.2:489–499

    Google Scholar 

  • Bendahan D, Kemp GJ, Roussel M, Le Fur Y, Cozzone PJ (2003) ATP synthesis and proton handling in muscle during short periods of exercise and subsequent recovery. J Appl Physiol (in press)

  • Bender PR, Groves BM, McCullough RE, McCullough RG, Trad L, Young AJ, Cymerman A Reeves JT (1989) Decreased exercise muscle lactate release after high altitude acclimatization. J Appl Physiol 67:1456–1462

    CAS  PubMed  Google Scholar 

  • Bonen A, Miskovic D, Tonouchi M, Lemieux K, Wilson MC, Marette A, Halestrap AP (2000) Abundance and subcellular distribution of MCT1 and MCT4 in heart and fast-twitch skeletal muscles. Am J Physiol 278:E1067–E1077

    CAS  Google Scholar 

  • Böning D, Maassen N, Thomas A, Steinacker JM (2001) Extracellular pH defense against lactic acid in normoxia and hypoxia before and after a Himalayan expedition. Eur J Appl Physiol 84:78–86

    Article  PubMed  Google Scholar 

  • Bradwell AR, Dykes PW, Coote JH (1987) Effect of acetazolamide on exercise at altitude. Sports Med 4:157–163

    CAS  PubMed  Google Scholar 

  • Cerretelli P (1976a) Limiting factors to oxygen transport on Mount Everest. J Appl Physiol 40:658–667

    CAS  PubMed  Google Scholar 

  • Cerretelli P (1976b) Metabolismo ossidativo ed anaerobico nel soggetto acclimatato all'altitudine. Minerva Aerosp Suppl Minerva Medica 67:11–26

    Google Scholar 

  • Cerretelli P, Hoppeler H (1996) Morphologic and metabolic response to chronic hypoxia: the muscle system. In: Rowell LB, Shepherd JT (eds) Handbook of physiology. Exercise: regulation and integration of multiple systems. American Physiological Society, Bethesda, Md. and Oxford University Press, Oxford, pp 1155–1181

  • Cerretelli P, Veicsteinas A, Marconi C (1982) Anaerobic metabolism at high altitude: the lactic mechanism. In: Brendel W, Zink RA (eds) High altitude physiology and medicine. Springer-Verlag, Berling Heidelberg New York, pp 94–102

  • Conley KE, Kemper WF, Crowther GJ (2001) Limits to sustainable muscle performance: interaction between glycolysis and oxidative phosphorylation. J Exp Biol 204:3189–3194

    CAS  PubMed  Google Scholar 

  • Connett RJ, Sahlin K (1996) In: Rowell LB, Shepherd JT (eds) Exercise: regulation and integration of multiple systems. Oxford University Press, New York, pp 870–911

  • Cross HR, Clarke K, Opie LH, Radda GK (1995) Is lactate-induced myocardial ischemic injury mediated by decreased pH or by increased intracellular lactate? J Mol Cell Cardiol 27:1369–1381

    Article  CAS  PubMed  Google Scholar 

  • Edwards HT (1936) Lactic acid in rest and work at high altitude. Am J Physiol 116:367–375

    CAS  Google Scholar 

  • Gassmann M, Wenger RH (1997) HIF-1, a mediator of the molecular response to hypoxia. News Physiol Sci 12:214–218

    CAS  Google Scholar 

  • Ge R-L, Chen QH, Wang LH, Gen D, Yang P, Kubo K, Fujimoto K, Matsusawa Y, Yoshimura K, Takeoka M, Kobayashi T (1994) Higher exercise performance and lowerO2max in Tibetan than Han residents at 4700 m altitude. J Appl Physiol 77:684–691

    CAS  PubMed  Google Scholar 

  • Gladden B (1996) Lactate transport and exchange during exercise. In: Rowell LB, Shepherd JT (eds) Handbook of physiology. Exercise: regulation and integration of multiple systems. American Physiological Society, Bethesda, Md. and Oxford University Press, Oxford, pp 614–648

  • Gnaiger E, Méndez G, Hand SC (2000) High phosphorylation efficiency and depression of uncoupled respiration in mitochondria under hypoxia. Proc Natl Acad Sci USA 97:11080–11085

    Article  CAS  PubMed  Google Scholar 

  • Gore CJ, Hahn AG, Aughey RJ, Martin DT, Ashenden MJ, Clark SA, Garnham AP, Roberts AD, Slater GJ, McKenna MJ (2001) Live high: train low increases muscle buffer capacity and submaximal cycling efficiency. Acta Physiol Scand 173:275–286

    CAS  PubMed  Google Scholar 

  • Grassi B, Ferretti G, Kayser B, Marzorati M, Colombini A, Marconi C, Cerretelli P (1995) Maximal rate of blood lactate accumulation during exercise at altitude in humans. J Appl Physiol 79:331–339

    CAS  PubMed  Google Scholar 

  • Grassi B, Marzorati M, Kayser B, Bordini M, Colombini A, Conti M, Marconi C, Cerretelli P (1996) Peak blood lactate and blood lactate vs. workload during acclimatization to 5,050 m and in deacclimatization. J Appl Physiol 80:685–692

    CAS  PubMed  Google Scholar 

  • Grassi B, Mognoni P, Marzorati M, Mattiotti S, Marconi C, Cerretelli P (2001) Power and peak blood lactate at 5050 m with 10 and 30 s "all out" cycling . Acta Physiol Scand 172:189–194

    Article  CAS  PubMed  Google Scholar 

  • Heisler N (1975) Intracellular pH of isolated rat diaphragm muscle with metabolic and respiratory changes of extracellular pH. Respir Physiol 23:243–255

    Article  CAS  PubMed  Google Scholar 

  • Hermansen L, Osnes J-B (1972) Blood and muscle pH after maximal exercise in man. J Appl Physiol 32:304–308

    CAS  PubMed  Google Scholar 

  • Hochachka PW (1988) The lactate paradox: analysis of underlying mechanisms. Ann Sports Med 4:184–188

    Google Scholar 

  • Hochachka PW, Stanley C, Matheson GO, McKenzie DC, Allen PS, Parkhouse WS (1991) Metabolic and work efficiencies during exercise in Andean natives. J Appl Physiol 70:1720–1730

    CAS  PubMed  Google Scholar 

  • Hochachka PW, Stanley C, McKenzie DC, Villena A, Monge C (1992) Enzyme mechanisms for pyruvate-to-lactate flux attenuation: a study of Sherpas, Quechuas and hummingbirds. Int J Sports Med 13: S119-S122

    CAS  PubMed  Google Scholar 

  • Hochachka PW, Gunga HC, Kirsch K (1998) Our ancestral physiological phenotype: an adaptation for hypoxia tolerance and for endurance performance? Proc Natl Acad Sci USA 95:1915–1920

    Article  CAS  PubMed  Google Scholar 

  • Hochachka PW, Beatty CL, Burelle Y, Trump ME, McKenzie DC, Matheson GO (2002) The lactate paradox in human high- altitude physiological performance. News Physiol Sci 17:122–126

    CAS  PubMed  Google Scholar 

  • Hogan J, Gladden LB, Kurdak SS, Poole DC (1995) Increased lactate in working dog muscle reduces tension development independent of pH. Med Sci Sports Exerc 27:371–377.

    CAS  PubMed  Google Scholar 

  • Hoppeler H, Kleinert E, Schlegel C, Claassen H, Howald H, Kayar SR, Cerretelli P (1990) Morphological adaptations of human skeletal muscle to chronic hypoxia. Int J Sports Med 11:S3-S9

    PubMed  Google Scholar 

  • Johannsson E, Lunde PK, Heddle C, Sjaastad I, Thomas MJ, Bergersen L, Halestrap AP, Blackstad TW, Ottersen OP, Sejersted OM (2001) Upregulation of the cardiac monocarboxylate transporter MCT1 in a rat model of congestive heart failure. Circulation 104:729–734

    CAS  PubMed  Google Scholar 

  • Juel C (1997) Lactate-proton cotransport in skeletal muscle. Physiol Rev 77:321–358

    CAS  PubMed  Google Scholar 

  • Juel C (1998) Muscle pH regulation: role of training. Acta Physiol Scand 162:359–366

    CAS  PubMed  Google Scholar 

  • Juel C (2001) Current aspects of lactate exchange: lactate/H+ transport in human skeletal muscle. Eur J Appl Physiol 86:12–16

    Google Scholar 

  • Juel C, Pilegaard H (1998) Lactate/H+ transport kinetics in rat skeletal muscle related to fibre type and changes in transport capacity. Pflugers Arch 436:560–564

    Article  CAS  PubMed  Google Scholar 

  • Juel C, Bangsbo J, Graham T, Saltin B (1990) Lactate and potassium fluxes from human skeletal muscle during and after intense, dynamic, knee extensor exercise. Acta Physiol Scand 140:147–159

    CAS  PubMed  Google Scholar 

  • Juel C, Lundby C, Sander M, Calbet JA, Hall GG (2003) Human skeletal muscle and erythrocyte proteins involved in acid-base homeostasis: adaptation to chronic hypoxia. J Physiol (Lond) 548:639–648

    Google Scholar 

  • Karmazyn M (1993) Na+/H+ exchange inhibitors reverse lactate-induced depression in postischemic ventricular recovery. Br J Pharmacol 108:50–56

    CAS  PubMed  Google Scholar 

  • Kayser B, Ferretti G, Grassi B, Binzoni T, Cerretelli P (1993) Maximal lactic capacity at altitude: effect of bicarbonate loading. J Appl Physiol 75:1070–1074

    CAS  PubMed  Google Scholar 

  • Kayser B, Marconi C, Amatya T, Basnyat B, Colombini A, Broers B, Cerretelli P (1994) The metabolic and ventilatory response to exercise in Tibetans born at low altitude. Respir Physiol 98:15–26

    Article  CAS  PubMed  Google Scholar 

  • Kayser B, Favier R, Ferretti G, Desplanches D, Spielvogel H, Koubi H, Sempore B, Hoppeler H (1996) Lactate and epinephrine during exercise in altitude natives. J Appl Physiol 81:2488–2494

    CAS  PubMed  Google Scholar 

  • Keele CA, Neil E, Joels N (1982) Part III Respiration. In: Samson Wright's applied physiology. Oxford University Press, New York, pp 155–217

  • Kemp GJ, Taylor DJ, Styles P, Radda GK (1993) The production, buffering and efflux of protons in human skeletal muscle during exercise and recovery. NMR Biomed 6:73–83

    CAS  PubMed  Google Scholar 

  • Kemper WF, Lindstedt SL, Hartzler LK, Hicks JW, Conley KE (2001) Shaking up glycolysis: Sustained, high lactate flux during aerobic rattling. Proc Natl Acad Sci USA 98:723–728

    Article  CAS  PubMed  Google Scholar 

  • Lacour JR, Bouvat E, Barthélémy JC (1990) Post-competition blood lactate concentrations as indicators of anaerobic energy expenditure during 400-m and 800-m races. Eur J Appl Physiol 61:172–176

    CAS  Google Scholar 

  • Lahiri S, Edelman NH, Cherniack NS, Fishman AP (1969) Blunted hypoxic drive to ventilation in subjects with life-long hypoxemia. Fed Proc 28:1289–1295

    CAS  PubMed  Google Scholar 

  • Lundby C, Saltin B, Van Hall G (2000) The "lactate paradox", evidence for a transient change in the course of acclimatization to severe hypoxia in lowlanders. Acta Physiol Scand 170:265–269

    Article  CAS  PubMed  Google Scholar 

  • Mader A (2003) Glycolysis and oxidative phosphorylation as a function of cytosolic phosphorylation state and power output of the muscle cell. Eur J Appl Physiol 88:317–338

    CAS  PubMed  Google Scholar 

  • Mannion AF, Jakeman PM, Willan PLT (1993) Determination of human skeletal muscle buffer value by homogenate technique: methods of measurement. J Appl Physiol 75:1412–1418

    CAS  PubMed  Google Scholar 

  • Martinelli M, Winterhalder R, Cerretelli P, Howald H, Hoppeler H (1990) Muscle lipofuscin content and satellite cell volume is increased after high altitude exposure in humans. Experientia 46:672–676

    CAS  PubMed  Google Scholar 

  • Matheson GO, Allen PS, Ellinger DC, Hanstock CC, Gheorghiu D, McKenzie DC, Stanley C, Parkhouse WS, Hochachka PW (1991) Skeletal muscle metabolism and work capacity: a 31P-NMR study of Andean natives and lowlanders. J.Appl Physiol 70:1963–1976

    CAS  Google Scholar 

  • McClelland GB, Brooks GA (2002) Changes in MCT 1, MCT 4, and LDH expression are tissue specific in rats after long-term hypobaric hypoxia. J Appl Physiol 92:1573–1584

    Google Scholar 

  • Medbø JI, Sejersted OM (1985) Acid-base and electrolyte balance after exhausting exercise in endurance-trained and sprint-trained subjects. Acta Physiol Scand 125:97–109

    CAS  PubMed  Google Scholar 

  • Mizuno M, Juel C, Bro-Rasmussen T, Mygind E, Scibye B, Rasmussen B, Saltin B (1990) Limb skeletal muscle adaptation in athletes after training at altitude. J Appl Physiol 68:496–502

    Google Scholar 

  • Osnes J-B, Hermansen L (1972) Acid-base balance after maximal exercise of short duration. J Appl Physiol 32:59–63

    CAS  PubMed  Google Scholar 

  • Piiper J (1971) Buffering of lactic acid produced in exercising muscle. Proceedings of the Symposium "Onset of Exercise". In: Gibert A, Guille P (eds) Centre d'Hémotypologie C.H.U. Purpan, Toulouse, France, pp 175–185

  • Pilegaard H, Bangsbo J, Richter EA, Juel C (1994) Lactate transport studied in sarcolemmal giant vesicles form human muscle biopsies: relation to training status. J Appl Physiol 77:1858–1862

    CAS  PubMed  Google Scholar 

  • Pilegaard H, Terzis G, Halestrap AP, Juel C (1999) Distribution of the lactate/H+ transporter isoforms MCT1 and MCT4 in human skeletal muscle. Am J Physiol 276: E843–E848

    CAS  PubMed  Google Scholar 

  • Poole RC, Halestrap AP (1993) Transport of lactate and other monocarboxylates across mammalian plasma membranes. Am J Physiol 264:C761–C782

    CAS  PubMed  Google Scholar 

  • Rahn H, Otis AB (1949) Man's respiratory response during and after acclimatization to high altitude. Am J Physiol 157:445–462

    CAS  Google Scholar 

  • Sahlin K (1978) Intracellular pH and energy metabolism in skeletal muscle of man .Acta Physiol Scand Suppl 455:1–56

    CAS  PubMed  Google Scholar 

  • Sahlin K, Henriksson J (1984) Buffer capacity and lactate accumulation in skeletal muscle of trained and untrained men. Acta Physiol Scand 122:331–339

    CAS  PubMed  Google Scholar 

  • Samaja M (1997) Blood gas transport at high altitude. Respiration 64:422–428

    CAS  PubMed  Google Scholar 

  • Samaja M, Winslow RM (1979) The separate effects of H+ and 2,3-DPG on the oxygen equilibrium curve of human blood. Br J Haematol 41:373–381

    CAS  PubMed  Google Scholar 

  • Samaja M, di Prampero PE, Cerretelli P (1986) The role of 2,3-DPG in the oxygen transport at altitude. Respir Physiol 64:191–202

    Article  CAS  PubMed  Google Scholar 

  • Samaja M, Mariani C, Prestini A, Cerretelli P (1997) Acid-base balance and O2 transport at high altitude. Acta Physiol Scand 159:249–256

    CAS  PubMed  Google Scholar 

  • Samaja M, Allibardi S, Milano G, Neri G, Grassi B, Gladden LB, Hogan MC (1999) Differential depression of myocardial function and metabolism by lactate and H+. Am J Physiol 276:H3–H8

    CAS  PubMed  Google Scholar 

  • Schurr A, Payne RS, Miller JJ, Tseng MT, Rigor BM (2001) Blockade of lactate transport exacerbates delayed neuronal damage in a rat model of cerebral ischemia. Brain Res 895:268–272

    Article  CAS  PubMed  Google Scholar 

  • Semenza GL (1999) Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1.Ann Rev Cell Dev Biol 15:551–578

    Article  CAS  Google Scholar 

  • Semenza GL (2000a) Expression of hypoxia-inducible factor 1: mechanisms and consequences. Biochem Pharmacol 59:47–53

    Article  CAS  PubMed  Google Scholar 

  • Semenza GL (2000b) HIF-1 and human disease: one highly involved factor. Genes Dev 14:1983–1991

    CAS  PubMed  Google Scholar 

  • Sharp RL, Costill DL, Fink WJ, King DS (1986) Effects of eight weeks of bicycle ergometer sprint training on human muscle buffer capacity. Int J Sports Med 7:13–17

    CAS  PubMed  Google Scholar 

  • Shulman RG, Rothman DL (2001) The "glycogen shunt" in exercising muscle: A role for glycogen in muscle energetics and fatigue. Proc Natl Acad Sci USA 98:457–461

    Article  CAS  PubMed  Google Scholar 

  • Siggaard-Andersen O (1974) The acid-base status of blood. Munksgaard, Copenhagen

  • Stroka DM, Burkhardt T, Desbaillets I, Wengger RH, Neil DAH, Bauer C, Gassmann M, Candinas D (2001) HIF-1 is expressed in normoxic tissue and displays an organ-specific regulation under systemic hypoxia. FASEB J 15:2445–2453

    CAS  PubMed  Google Scholar 

  • Sutton JR, Reeves JT, Wagner PD, Groves BM, Cymerman A, Malconian MK, Rock PB, Young PM, Walter SD, Houston CS (1988) Operation Everest II: oxygen transport during exercise at extreme simulated altitude. J Appl Physiol 64:1309–1321

    CAS  PubMed  Google Scholar 

  • Van Hall G, Calbet JAL, Sondergaard H, Saltin B (2001) The re-establishment of the normal blood lactate response to exercise in humans after prolonged acclimatization to altitude. J Physiol (Lond) 563.3:963–975

    Google Scholar 

  • Van Slyke DD (1922) On the measurement of buffer value and on relationship of buffer value to the dissociation constant of the buffer and reaction of the buffer solution. J Biol Chem 52:525

    Google Scholar 

  • Wagner PD, Araoz M, Boushel R, Calbet JAL, Jessen B, Radegran G, Spielvogel H, Sondegaard H, Wagner H, Saltin B (2002) Pulmonary gas exchange and acid-base state at 5,260 m in high altitude Bolivians and acclimatized lowlanders. J Appl Physiol 92:1393–1400

    PubMed  Google Scholar 

  • Wang GL, Jiang B-H, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514

    CAS  PubMed  Google Scholar 

  • West JB (1986) Lactate during exercise at extreme altitude. Fed Proc 45:2953–2957

    CAS  PubMed  Google Scholar 

  • West JB, Hackett PH, Maret KH, Milledge JS, Peters Jr RM, Pizzo CJ, Winslow RM (1983) Pulmonary gas exchange on the summit of Mt. Everest. J Appl Physiol 55:678–687

    CAS  PubMed  Google Scholar 

  • Winslow RM, Samaja M, Winslow NJ, Rossi Bernardi L, Shrager RI (1983) Simulation of continuous blood O2 equilibrium curve over the physiologic pH, DPG and pCO2 range. J Appl Physiol 54:524–529

    Article  CAS  PubMed  Google Scholar 

  • Winslow RM, Samaja M, West JB (1984) Red cell function at extreme altitudes on Mount Everest. J Appl Physiol 56:109–116

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Paolo Cerretelli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cerretelli, P., Samaja, M. Acid–base balance at exercise in normoxia and in chronic hypoxia. Revisiting the "lactate paradox". Eur J Appl Physiol 90, 431–448 (2003). https://doi.org/10.1007/s00421-003-0928-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00421-003-0928-x

Keywords

Navigation