Lactic acidosis: implications for human exercise performance

European Journal of Applied Physiology https://doi.org/10.1007/s00421-025-05750-0 INVITED REVIEW Lactic acidosis: implications for human exercise performance Simeon P. Cairns1,2 · Michael I. Lindinger3 Received: 29 November 2024 / Accepted: 22 February 2025 © The Author(s) 2025 Abstract During high-intensity exercise a lactic-acidosis occurs with raised myoplasmic and plasma concentrations of lactate− and protons ([lactate−], [H+] or pH). We critically evaluate whether this causes/contributes to fatigue during human exercise. Increases of [lactate−] per se (to 25 mM in plasma, 50 mM intracellularly) exert little detrimental effect on muscle performance while ingestion/infusion of lactate− can be ergogenic. An exercise-induced intracellular acidosis at the whole-muscle level (pHi falls from 7.1–7.0 to 6.9–6.3), incorporates small changes in slow-twitch fibres ( pHi ~ 6.9) and large changes in fast-twitch fibres ( pHi ~ 6.2). The relationship between peak force/power and acidosis during fatiguing contractions varies across exercise regimes implying that acidosis is not the sole cause of fatigue. Concomitant changes of other putative fatigue factors include phosphate metabolites, glycogen, ions and reactive oxygen species. Acidosis to p Hi 6.7–6.6 at physiological temperatures (during recovery from exercise or induced in non-fatigued muscle), has minimal effect on force/power. Acidosis to pHi ~ 6.5–6.2 per se reduces maximum force (~12%), slows shortening velocity (~5%), and lowers peak power (~22%) in non-fatigued muscles/individuals. A pre-exercise induced-acidosis with ammonium chloride impairs exercise performance in humans and accelerates the decline of force/power (15–40% initial) in animal muscles stimulated repeatedly in situ. Raised [H+]i and diprotonated inorganic phosphate ([H2PO4−]i) act on myofilament proteins to reduce maximum cross-bridge activity, C a2+-sensitivity, and myosin ATPase activity. Acidosis/[lactate−]o attenuates detrimental effects of + large K -disturbances on action potentials and force in non-fatigued muscle. We propose that depressive effects of acidosis and [H2PO4−]i on myofilament function dominate over the protective effects of acidosis/lactate− on action potentials during fatigue. Raised extracellular [ H+]/[lactate−] do not usually cause central fatigue but do contribute to elevated perceived exertion and fatigue sensations by activating group III/IV muscle afferents. Modulation of H+/lactate− regulation (via extracellular H+-buffers, monocarboxylate transporters, carbonic anhydrase, carnosine) supports a role for intracellular acidosis in fatigue. In conclusion, current evidence advocates that severe acidosis in fast-twitch fibres can contribute to force/power fatigue during intense human exercise. Keywords Lactate · Acidosis · Potassium · Inorganic phosphate · Skeletal muscle fatigue · Exercise performance Communicated by Nicolas Place. * Simeon P. Cairns 1 Sport and Recreation Research Institute New Zealand, School of Sport and Recreation, Faculty of Health and Environmental Sciences, Auckland University of Technology, Private Bag 92006, Auckland 1020, New Zealand 2 Health and Rehabilitation Research Institute, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland 1020, New Zealand 3 Research and Development, The Nutraceutical Alliance Inc, Guelph, ON L8N 3Z5, Canada Abbreviations ATP Adenosine triphosphate 9-AC 9-Anthracenecarboxylic acid CA Carbonic anhydrase cAMP Cyclic adenosine monophosphate CICR Calcium-induced calcium release ClC-1 Sarcolemmal chloride channels CNS Central nervous system DHPR Dihydropyridine receptor—Voltage-sensor of T-system membranes EDL Extensor digitorum longus muscle FDB Flexor digitorum brevis muscle GLUT4 Glucose transporter protein in skeletal muscle sarcolemma H2PO4− Diprotonated phosphate Vol.:(0123456789) European Journal of Applied Physiology HPO42− Monoprotonated phosphate KATP ATP-sensitive potassium channel [lactate−]i Intracellular lactate concentration [lactate−]o Extracellular lactate concentration MCT Monocarboxylate (lactate) transporter MVIC Maximum voluntary isometric contraction M-wave Compound extracellular muscle action potential NaV1.4 Voltage-activated sodium channel NaHCO3 Sodium bicarbonate NH4Cl Ammonium chloride NHE1 Sodium-hydrogen exchanger PCr Phosphocreatine PDH Pyruvate dehydrogenase PFK Phosphofructokinase pHi Intracellular pH pHo Extracellular pH phos Glycogen phosphorylase Pi Total inorganic phosphate 31 P-MRS Phosphorus nuclear magnetic resonance spectroscopy ROS Reactive oxygen species RPE Rating of perceived exertion RyR1 Ryanodine receptor—Ca2+ release channel of sarcoplasmic reticulum SaO2 Arterial oxygen saturation of haemoglobin SERCA Ca2+-pump of sarcoplasmic reticulum SR Sarcoplasmic reticulum TnC Troponin C TnI Troponin I T-system Transverse tubular system Vmax Maximal muscle shortening velocity Introduction It has long been postulated that lactic acid is a harmful chemical formed in working skeletal muscle that impairs exercise performance. This notion has become known as the “lactic acid hypothesis of fatigue”. During intense exercise of more than a brief duration there is an acute decline of muscle or exercise performance defined as fatigue (Allen et al. 2008; Cairns 2013; Knicker et al. 2011). The relationships between fatiguing exercise, lactic acid, and acidosis in humans were first described more than 100 years ago (Fletcher and Hopkins 1907; Hill and Lupton 1923), with the early research well summarised in Jervell’s thesis (Jervell 1928). To this day there remains a strong belief amongst exercise and sport physiologists, athletes and coaches, that lactic acidosis is the major villain underpinning fatigue. Despite this, a fundamental scientific point is that virtually no lactic acid appears in the body during exercise (Lindinger et al. 2005; Robergs et al. 2004). Rather lactic acid exists as two ionic species, namely lactate anions ( lactate−) and hydrogen ions/protons (H+). Although the latter is, in reality, hydronium (H3O+) ions, it is conventional to represent it as H+ and measure it as pH (pH = −log10[H+]). With contracting muscle, it is necessary to evaluate intra- and extracellular lactate− and H+ as potential factors in fatigue since these changes typically occur together and often when there is a decline of performance. Hence, lactic acidosis has long been touted as a mechanism of fatigue (Fletcher and Hopkins 1907; Hill and Lupton 1923; Jervell 1928). Notably, association does not mean direct cause or even indirect contribution. In fact, such associative correlations between muscle fatigue and lactic acidosis have led to erroneous cause-effect conclusions. Despite the continued entrenchment in our psyche that lactate− and acidosis are bad end-products of metabolism, it became apparent in the 1990s and early 21st Century, that there are weighty ch (...truncated)