Supervisor: Dr Karina Stewart, Faculty of Health and Applied Sciences, University of the West of England, Coldharbour Lane, Bristol BS16 1QY, UK.
Bioscience Horizons: The International Journal of Student Research, Volume 7, 2014, hzu001, https://doi.org/10.1093/biohorizons/hzu001
02 June 2014 24 December 2013 Revision received: 03 April 2014 15 April 2014 02 June 2014Joshua J Todd, Lactate: valuable for physical performance and maintenance of brain function during exercise, Bioscience Horizons: The International Journal of Student Research, Volume 7, 2014, hzu001, https://doi.org/10.1093/biohorizons/hzu001
Navbar Search Filter Mobile Enter search term Search Navbar Search Filter Enter search term SearchLactate accumulation has long been associated with impaired sports performance, with many supporting the lactate acidosis hypothesis. However, due to advances in experimental design and research, numerous beneficial roles of lactate have been established that may impact upon sports performance. Recent studies highlight lactate as a biomarker of fatigue rather than as a direct cause. The lactate-shuttle mechanism facilitates the utilization of lactate as an energy substrate in both type I and type II skeletal muscle fibres, promoting energy sufficiency during exercise. Recent literature also supports a role for lactate in enhancing human oxidative capacity by up-regulating skeletal muscle mitochondrial biogenesis. In addition, lactate-neuron and lactate-astrocyte shuttles enable lactate to supply energy to support cognitive function, during periods of low blood glucose such as prolonged aerobic exercise. This review aims to clarify the role of lactate in modulating aerobic performance and critically investigates the mechanisms responsible.
The traditional stance that blood lactate accumulation, during exercise, negatively impacts upon athletic performance arouses from research undertaken in the 1920s by British physiologist A.V. Hill, whose study hypothesized that a decrease in pH depresses cell excitability and consequent muscular contractile force ( Hill and Lupton, 1923; Bassett, 2002). However, with modern technological advances and a greater understanding of the biochemical kinetics of lactate, evidence now strongly indicates that lactate is a valuable energy substrate for various physiological systems, such as the brain, heart and skeletal muscle ( Cairns, 2006). Lactate generation has been identified as advantageous within these systems not only during exercise, but also at rest.
The lactate-induced acidosis theory posits that under hypoxic conditions, such as anaerobic exercise, there is increased dissociation of lactic acid into lactate ions and hydrogen (H + ) entering skeletal myocytes ( Robergs, 2004). This process induces acidosis, disrupting the cross-bridge cycle and impairing the contractile capability of such cells ( Debold, 2011). Gorostiaga et al. (2012) demonstrated that once the critical point of lactate, 10–15 mmol per kg −1 wet muscle, had been exceeded a significant decrease in the number of repetitive leg-press exercises was observed, indicative of lactate's involvement in muscular fatigue. In addition, Bonitch-Gongora et al. (2012) reported an inverse relationship between blood lactate concentration and isometric contractile force during judo bouts. Collectively, these findings suggest that lactate accumulation may contribute to impaired physical performance via disruption to the acid–base balance within skeletal muscle during exercise.
Despite the longstanding hypothesis that lactate-induced acidosis promotes fatigue, lactate can exert a positive effect on aerobic performance. Its accumulation has been attributed to counteracting the negative effects of noxious metabolites including inorganic phosphate (Pi) and potassium (K + ), as well as facilitating removal of muscular proton and also acting synergistically with catecholamines to reduce fatigue ( McKenna, Bangsbo and Renaud, 2008).
Greater emphasis has now been placed upon these metabolites as the primary physiological cause of fatigue rather than lactate. Lactate not only regenerates nicotinamide adenine dinucleotide (NAD + ), an essential component for glycolysis and aerobic respiration but its production uses two electrons, promoting a positive pH change as well as providing a chemical gradient for proton removal from anaerobically respiring skeletal muscle ( Robergs, 2004). Miller et al. (2002), support this claim, by demonstrating that lactate oxidation increases during moderate-intensity exercise and that this prolongs blood glucose homeostasis.
Lactate is an important component in the multifactorial biochemical response which acts to counteract the muscular fatigue process. It is capable of counteracting the electrochemical imbalance induced by K + accumulation during exercise and as a result, lactate indirectly enhances force production, promoting optimal physical performance ( Nielsen, de Paoli and Overgaard, 2001; de Paoli et al., 2007). Lindinger et al. (2006) support this argument and accept lactate as a biomarker of fatigue because it accumulates proportionally in relation to an increase in plasma metabolites, during high-intensity exercise, yet may not cause muscular fatigue. Hansen, Clausen and Nielsen (2005) identified that lactate is most effective in preserving type II (fast-twitch) muscle fibre function and can exert a greater effect on this subtype due to their low oxidative capacity. It is plausible to speculate that, due to preferential activity within type II fibres, lactate may expose type I (slow-twitch) muscle fibres to cellular acidosis. However, during exercise, increased circulating plasma-free catecholamines exert protective effects upon slow-twitch muscle fibres via muscular β-2 adrenoceptors. The accumulating K + is buffered by β-2 agonist action which consequently up-regulates sodium (Na + )/K + pump activity within the musculature, facilitating the restoration of an effective propagation pathway and optimal cell excitability, opposing the fatigue process ( Hansen, Clausen and Nielsen, 2005). Thus, lactate acts synergistically with catecholamines to ensure that both fast-twitch and slow-twitch muscle fibres are protected from fatigue.
Pi is released via the breakdown of phosphocreatine (PCr) during muscular contraction and an increased Pi concentration is recognized as a factor contributing to muscular fatigue. It has been suggested that highly concentrated Pi within skeletal muscle may exacerbate sarcoplasmic calcium (Ca 2+ ) efflux, resulting in a series of high frequency impulses and a number of maximal contractions which induce muscular fatigue (see Fig. 1; ( Westerblad, Allen and Lannergren, 2001). Furthermore, Pi may interact with sarcoplasmic Ca 2+ , impairing Ca 2+ efflux and consequent excitation–contraction coupling, see Fig. 1( Fryer et al. 1995; Westerblad and Allen, 1996; Soares et al., 2013). Yet this mechanism only appears relevant for exercise et al. (2000) demonstrated that, in wild-type mice, Pi concentrations significantly increased from 19.8μmol/g dry weight at rest to 54.8 μmol/g dry weight following a tetanic fatiguing exercise protocol. Such findings indicate that Pi is likely implicated in the development of skeletal muscle fatigue in humans and may even be a primary cause, although without doubt future studies using in vivo models at physiologically relevant temperatures are required to provide greater clarity.
Following high-intensity exercise, inorganic phosphate (Pi) enters the skeletal musculature and promotes excess calcium efflux, causing tetanic contractions which result in muscular fatigue (A). Pi interacts with sarcoplasmic calcium (Ca 2+ ), decreasing calcium efflux and inhibiting cross-bridge cycling, resulting in muscular fatigue (B).
Fluctuations in lactate concentrations, during prolonged exercise, have been shown to induce mitochondrial biogenesis of rat L6 cells, directly increasing long-term oxidative capacity via activation of reactive oxygen species ( Hashimoto and Brooks, 2008). This promotes expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and the subsequent transcriptional pathway that is capable of producing monocarboxylate transporter one (MCT1) isoforms, facilitating mitochondrial biogenesis ( Wright et al., 2007). As a result, this increases the proportion of type I (slow-twitch) fibres within skeletal muscle composition and, if findings are replicated in human studies, may improve aerobic performance ( Cruz et al., 2012).
Evidence that lactate may be transported via a number of proposed ‘shuttle mechanisms’ emerged as early as the mid-1980's and such findings have significantly altered the way lactate is currently perceived within the literature ( Gladden, 2004; Brooks, 2009). The intracellular lactate shuttle hypothesis suggests that lactate molecules are transported across the mitochondrial intermembrane space via MCT1, proteins which facilitate the uptake of lactate molecules into skeletal myocytes for oxidation (see Fig. 2; Cruz et al., 2012). This process occurs in each individual cell, independently of other myocytes that form skeletal muscle tissue. Lactate molecules are oxidized by mitochondrial lactate dehydrogenase (mLDH), which has been identified within skeletal myocyte mitochondria, and facilitate the formation of pyruvate, an essential molecule in effective aerobic metabolism ( Brooks et al., 1999). As a result, exercise promotes lactate influx into skeletal muscle mitochondria and its consequent oxidation, although this process is rate limited by factors such as metabolic rate and blood pH ( Gladden, 2001). For many years, the existence of mLDH in vivo was highly debated; however, with modern advances in technology mLDH has been consistently identified within skeletal myocyte mitochondria, using gold particle immunolabelling, western blotting, confocal microscopy and immunoprecipitation ( Brooks and Hashimoto, 2007). mLDH stimulates lactate reconversion into pyruvate, directly opposing the fatigue process ( Hashimoto et al., 2007). This evidence highlights that lactate is not a waste product of anaerobic metabolism but rather a useful alternative energy source. Not only does lactate promote restoration of optimal blood pH but it also fuels aerobic metabolism, by enhancing pyruvate yield, and is therefore likely to improve sports performance rather than hinder it. This perspective is supported by Overgaard et al. (2012) who reported an 18-fold increase in net lactate turnover during exercise-induced hypoxia, indicative of lactate utilization within the body in response to exercise. There is also increasing evidence that lactate oxidation may occur within cardiomyocytes, due to the presence of MCT isoforms located within cardiac tissue ( Halestrap and Meredith, 2004). It is therefore plausible that lactate may promote optimal cardiac efficiency during physiological stress, such as prolonged exercise, by facilitating substrate availability ( Cruz et al., 2012). Cardiac MCT isoforms facilitate a lactate utilization pathway similar to that of skeletal muscle; however, during exercise, cardiomyocyte mitochondria predominantly oxidize pyruvate formed via the breakdown of lactate rather than pyruvate formed from glucose metabolism ( Passarella et al., 2008). This indicates that lactate is important in supplying cardiac tissue with ATP required for aerobic metabolism. Lactate utilization is more specific, than in skeletal muscle tissue, occurring mostly in the left ventricle ( Ponsot et al., 2005). Glucose-derived pyruvate is released into the bloodstream for utilization by other aerobically respiring target cells and tissues and as a result, lactate provides the heart with an additional energy substrate, which is especially useful in hypoxic environments ( Passarella et al. 2008). This process allows any remaining glucose in circulation to be redistributed, via the bloodstream, to cells that are not capable of metabolizing lactate and may contribute to the maintenance of aerobic performance when the body is faced with the physiological challenge of low arterial oxygen concentrations ( Chatham, Des Rosiers and Forder, 2001).
Circulating glucose and lactate enter the cell via transport proteins on its cell surface. Glycolysis then converts glucose, forming pyruvate. Both pyruvate and lactate are transported into the cells' mitochondrion by monocarboxylate transporters. Lactate is converted to pyruvate by mitochondrial lactate dehydrogenase (mLDH). Pyruvate derived from both glucose and lactate sources then contributes to the cells' oxidative energy yield via the Krebs cycle and electron transport chain (ETC).
A cell-to-cell shuttle hypothesis also exists and suggests that type II (fast-twitch) muscle fibres are predisposed to producing larger quantities of lactate than type I (slow-twitch) fibres. Excess lactate, formed within fast-twitch fibres, is transported to other cells within the body with the oxidative capability to metabolize lactate, such as type I (slow-twitch) muscle cells, enhancing their excitability and limiting fatigue (see Fig. 3; Robergs, 2004). Furthermore, once in circulation, lactate attaches to red blood cells (RBCs) and is disassociated in the liver where inter-conversion via gluconeogenesis facilitates glucose formation, providing an alternative aerobic energy source. However, lactate uptake by RBC is only proportional to lactate efflux during aerobic exercise. During maximal exercise, lactate efflux exceeds its uptake indicating that this process is rate limited ( Gladden, 2004).
In both type II (fast-twitch) muscle fibres and in astrocytes, glycolysis converts glucose into pyruvate, forming lactate as a by-product. Lactate enters the interstitial fluid via monocarboxylate transporter 4 (MCT4). Lactate is transported into type I fibres by MCT1 and by MCT2 in neurons. Lactate is then converted into pyruvate, in both cell types, by lactate dehydrogenase (LDH). Pyruvate enters the cells mitochondrion, enhancing its energy yield (adapted from Draoui and Feron, 2011).
Lactate is regarded as a valuable metabolite for brain function and is a major energy substrate utilized by neurons during exercise ( Overgaard et al., 2012). In addition, lactate optimizes gamma-aminobutyric acid receptor function, ensuring that inhibitory signals from the central nervous system, caused by a drop in cell pH, are effectively detected ( Pellerin et al., 2007). Lactate can therefore be regarded as important to the maintenance of cognitive function, protecting neurons from damage by acidosis.
Neuronal lactate transport is facilitated by the lactate-neuron shuttle ( Draoui and Feron, 2011). van Hall et al. (2009) demonstrated a significant increase in net neuronal lactate uptake from 0.06 ± 0.01 at rest to 0.28 ± 0.16 mmol/min during exercise, indicating an essential role for lactate in neuronal function under both physiological conditions. Neuronal lactate influx is moderated by MCT2 and allows a maximal flux at 1 mM but blocks lactate entry into the neuron at both 3 and 10 mM, protecting the brain from lactate-induced acidosis which would compromise the ability of the brain to detect fatigue ( Hertz and Dienel, 2004).
Furthermore, lactate may be shuttled between astrocytes and neurons ( Mangia et al., 2009; Draoui and Feron, 2011). This mechanism is referred to as the astrocyte-neuron-lactate shuttle hypothesis (ANLSH). The ANLSH is responsible for contributing up to 33% of total energy substrate utilized by the brain during exercise, with both astrocytes and neurons demonstrating an ability to metabolize lactate ( Pellerin et al., 2007; Overgaard et al., 2012). Recent evidence from an animal model demonstrated that the ANLSH supplies neurons and astrocytes with a 3- and 5-fold greater yield of mitochondrial adenosine triphosphate respectively under hypoxia, when compared with conditions replete in oxygen ( Genc, Kurnaz and Ozilgen, 2011). During exercise, astrocytes metabolize glucose, forming lactate as a by-product. Neuronal efflux of lactate is facilitated by MCT4 which releases lactate into the interstitial fluid. Lactate is then transported into neurons, via MCT2, where it is enzymatically converted into pyruvate by lactate dehydrogenase. Pyruvate finally enters the citric acid cycle within astrocyte mitochondria, contributing to oxidative ATP yield (see Fig. 3; Draoui and Feron, 2011). It is important to note that neurons not only source lactate directly from astrocytes but also via the bloodstream (see Fig. 2; Boumezbeur et al., 2010). This complex mechanism may allow astrocytes to switch between glucose and lactate shuttle mechanisms, depending upon the metabolic demands placed upon neurons ( Genc, Kurnaz and Ozilgen, 2011). The ANLSH can therefore be regarded as an effective pathway that maintains optimal neuronal, astrocyte and cognitive function during exercise.
Studies reporting positive effects of lactate on muscle function often use passive skeletal muscle bathed in a lactate-metabolite solution ( Nagesser, van der Laarse and Elzinga, 1994). This physiological condition is unrepresentative of contracting skeletal muscle during physical activity and in response Kristensen et al. (2005) investigated whether similar effects are observed in active rat soleus when bathed in a lactate-metabolite solution. Interestingly, enhanced force production in passive rat soleus was not replicated in its active equivalent, suggesting that results from passive and active skeletal muscle models may not be directly comparable.
There is growing criticism of studies investigating the effects of lactate on sports performance at sub-physiological temperatures. When researching the effects of lactate on skeletal muscle function, studies often use isolated single muscle fibres at sub-physiological temperatures, owing to degradation of such fibres at temperatures approaching 37°C. Single-fibre models are highly temperature sensitive and therefore findings from studies performed at sub-physiological temperatures should be interpreted with caution as they may not be a true representation of the human fatigue process in vivo ( Allen, Lamb and Westerblad, 2008). Debold, Dave and Fitts (2004) demonstrated a 50% increase in peak muscle fibre power when lactate was applied at a near-physiological temperature of 30°C. Contrastingly, Knuth et al. (2006) found that a lactate-induced pH change at both 15°C and 30°C caused a decrease in force and peak power. Such contrasting evidence indicates that further research is required in order to clarify the interaction between lactate and temperature.
To conclude, for many decades lactate has been misinterpreted as a waste product of anaerobic metabolism, which reduces aerobic performance, advances in technology and continuing research has identified lactate as a valuable metabolic product, both at rest and during exercise, with a wide range of physiological benefits such as counteracting acidosis and maintaining neuron and astrocyte function. Future studies should aim to develop an active skeletal muscle model capable of withstanding physiological temperatures and investigate whether lactate-induced mitochondrial biogenesis translates into improved aerobic sports performance. Furthermore, it is not yet known if cerebral lactate concentrations impact upon fatigue recognition or sensory ability, during exercise, warranting future research. Although variations in opinion still exist, the general consensus on lactate has shifted from being detrimental to physical performance to an essential compound that opposes the fatigue process and supports brain function during exercise and at rest.
Joshua is currently a PhD student at the Northern Ireland Centre for Food and Health (NICHE), University of Ulster, Coleraine. He recently completed his undergraduate degree in Sports Science (Nutrition), at the University of the West of England, Bristol. He has a strong research interest in vitamin D and its effects on inflammation, skeletal muscle function and upper respiratory tract infection in elite athletes. His career goals are to contribute to World-leading research in the field of sports nutrition and to engage with the next generation of sports scientists by lecturing within a higher education institution.
The author thanks Dr Karina Stewart at the University of the West of England for her advice and support throughout my undergraduate degree and in submitting this review. I would also like to thank my fiancé and family for encouraging me to pursue a research career in sports nutrition.
