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Lactate: valuable for physical performance and maintenance of brain function during exercise

Lactate: valuable for physical performance and maintenance of brain function during exercise BioscienceHorizons Volume 7 2014 10.1093/biohorizons/hzu001 Review Lactate: valuable for physical performance and maintenance of brain function during exercise Joshua J Todd* Faculty of Health and Applied Sciences, The University of the West of UK, Coldharbour Lane, Bristol BS16 1QY, UK *Corresponding author: Northern Ireland Centre for Food and Health (NICHE), University of Ulster, Cromore Road, Coleraine, Northern Ireland, BT52 1SA. Email: todd-j10@email.ulster.ac.uk Supervisor: Dr Karina Stewart, Faculty of Health and Applied Sciences, University of the West of England, Coldharbour Lane, Bristol BS16 1QY, UK. Lactate 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. Key words: lactate shuttle, skeletal muscle, neurons, astrocytes, fatigue, noxious metabolites Received 24 December 2013; revised 3 April 2014; accepted 15 April 2014 Introduction dissociation of lactic acid into lactate ions and hydrogen (H ) entering skeletal myocytes (Robergs, 2004). This process induces The traditional stance that blood lactate accumulation, dur- acidosis, disrupting the cross-bridge cycle and impairing the ing exercise, negatively impacts upon athletic performance contractile capability of such cells (Debold, 2011). Gorostiaga arouses from research undertaken in the 1920s by British et al. (2012) demonstrated that once the critical point of lactate, physiologist A.V. Hill, whose study hypothesized that a −1 10–15 mmol per kg wet muscle, had been exceeded a signifi - decrease in pH depresses cell excitability and consequent cant decrease in the number of repetitive leg-press exercises was muscular contractile force (Hill and Lupton, 1923; Bassett, observed, indicative of lactate’s involvement in muscular fatigue. 2002). However, with modern technological advances and a In addition, Bonitch-Gongora et al. (2012) reported an inverse greater understanding of the biochemical kinetics of lactate, relationship between blood lactate concentration and isometric evidence now strongly indicates that lactate is a valuable contractile force during judo bouts. Collectively, these findings energy substrate for various physiological systems, such as suggest that lactate accumulation may contribute to impaired the brain, heart and skeletal muscle (Cairns, 2006). Lactate physical performance via disruption to the acid–base balance generation has been identified as advantageous within these within skeletal muscle during exercise. systems not only during exercise, but also at rest. Noxious metabolites Lactate-induced acidosis Despite the longstanding hypothesis that lactate-induced aci- The lactate-induced acidosis theory posits that under hypoxic dosis promotes fatigue, lactate can exert a positive effect on conditions, such as anaerobic exercise, there is increased aerobic performance. Its accumulation has been attributed to © The Author 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Review Bioscience Horizons • Volume 7 2014 counteracting the negative effects of noxious metabolites 1996; Soares et al., 2013). Yet this mechanism only appears including inorganic phosphate (Pi) and potassium (K ), as relevant for exercise <1 h in duration, after which there is 2+ well as facilitating removal of muscular proton and also act- little effect of Pi on sarcoplasmic Ca (Westerblad, Allen ing synergistically with catecholamines to reduce fatigue and Lannergren, 2001). Dhalstedt et al. (2000) demon- (McKenna, Bangsbo and Renaud, 2008). strated that, in wild-type mice, Pi concentrations significantly increased from 19.8µ mol/g dry weight at rest to 54.8 µ mol/g Greater emphasis has now been placed upon these metab- dry weight following a tetanic fatiguing exercise protocol. olites as the primary physiological cause of fatigue rather Such findings indicate that Pi is likely implicated in the devel - than lactate. Lactate not only regenerates nicotinamide opment of skeletal muscle fatigue in humans and may even be adenine dinucleotide (NAD ), an essential component for a primary cause, although without doubt future studies using glycolysis and aerobic respiration but its production uses two in vivo models at physiologically relevant temperatures are electrons, promoting a positive pH change as well as provid- required to provide greater clarity. ing a chemical gradient for proton removal from anaerobi- cally respiring skeletal muscle (Robergs, 2004). Miller et al. Mitochondrial biogenesis (2002), support this claim, by demonstrating that lactate oxidation increases during moderate-intensity exercise and Fluctuations in lactate concentrations, during prolonged that this prolongs blood glucose homeostasis. exercise, have been shown to induce mitochondrial biogene- sis of rat L6 cells, directly increasing long-term oxidative Lactate is an important component in the multifactorial capacity via activation of reactive oxygen species (Hashimoto biochemical response which acts to counteract the muscular and Brooks, 2008). This promotes expression of peroxisome fatigue process. It is capable of counteracting the electro- proliferator-activated receptor gamma coactivator 1-alpha chemical imbalance induced by K accumulation during and the subsequent transcriptional pathway that is capable of exercise and as a result, lactate indirectly enhances force pro- producing monocarboxylate transporter one (MCT1) iso- duction, promoting optimal physical performance (Nielsen, forms, facilitating mitochondrial biogenesis (Wright et al., de Paoli and Overgaard, 2001; de Paoli et al., 2007). 2007). As a result, this increases the proportion of type I Lindinger et al. (2006) support this argument and accept lac- (slow-twitch) fibres within skeletal muscle composition and, tate as a biomarker of fatigue because it accumulates propor- if findings are replicated in human studies, may improve aer - tionally in relation to an increase in plasma metabolites, obic performance (Cruz et al., 2012). during high-intensity exercise, yet may not cause muscular fatigue. Hansen, Clausen and Nielsen (2005) identified that Intracellular lactate shuttle lactate is most effective in preserving type II (fast-twitch) muscle fibre function and can exert a greater effect on this Evidence that lactate may be transported via a number of pro- subtype due to their low oxidative capacity. It is plausible to posed ‘shuttle mechanisms’ emerged as early as the mid-1980′s speculate that, due to preferential activity within type II and such findings have significantly altered the way lactate is fibres, lactate may expose type I (slow-twitch) muscle fibres currently perceived within the literature (Gladden, 2004; to cellular acidosis. However, during exercise, increased cir- Brooks, 2009). The intracellular lactate shuttle hypothesis sug- culating plasma-free catecholamines exert protective effects gests that lactate molecules are transported across the mito- upon slow-twitch muscle fibres via muscular β-2 adrenocep- chondrial intermembrane space via MCT1, proteins which tors. The accumulating K is buffered by β-2 agonist action facilitate the uptake of lactate molecules into skeletal myocytes + + which consequently up-regulates sodium (Na )/K pump for oxidation (see Fig. 2; Cruz et al., 2012). This process occurs activity within the musculature, facilitating the restoration of in each individual cell, independently of other myocytes that an effective propagation pathway and optimal cell excitabil- form skeletal muscle tissue. Lactate molecules are oxidized by ity, opposing the fatigue process (Hansen, Clausen and mitochondrial lactate dehydrogenase (mLDH), which has Nielsen, 2005). Thus, lactate acts synergistically with cate- been identified within skeletal myocyte mitochondria, and cholamines to ensure that both fast-twitch and slow-twitch facilitate the formation of pyruvate, an essential molecule in muscle fibres are protected from fatigue. effective aerobic metabolism (Brooks et al., 1999). As a result, Pi is released via the breakdown of phosphocreatine (PCr) exercise promotes lactate influx into skeletal muscle mitochon - during muscular contraction and an increased Pi concentra- dria and its consequent oxidation, although this process is rate tion is recognized as a factor contributing to muscular fatigue. limited by factors such as metabolic rate and blood pH It has been suggested that highly concentrated Pi within skel- (Gladden, 2001). For many years, the existence of mLDH in 2+ etal muscle may exacerbate sarcoplasmic calcium (Ca ) vivo was highly debated; however, with modern advances in efflux, resulting in a series of high frequency impulses and a technology mLDH has been consistently identified within number of maximal contractions which induce muscular skeletal myocyte mitochondria, using gold particle immuno - fatigue (see Fig. 1; (Westerblad, Allen and Lannergren, 2001). labelling, western blotting, confocal microscopy and immuno- 2+ Furthermore, Pi may interact with sarcoplasmic Ca , impair- precipitation (Brooks and Hashimoto, 2007). mLDH stimulates 2+ ing Ca efflux and consequent excitation–contraction cou - lactate reconversion into pyruvate, directly opposing the pling, see Fig. 1(Fryer et al. 1995; Westerblad and Allen, fatigue process (Hashimoto et al., 2007). This evidence 2 Bioscience Horizons • Volume 7 2014 Review article Figure 1. Following high-intensity exercise, inorganic phosphate (Pi) enters the skeletal musculature and promotes excess calcium efflux, 2+ causing tetanic contractions which result in muscular fatigue (A). Pi interacts with sarcoplasmic calcium (Ca ), decreasing calcium efflux and inhibiting cross-bridge cycling, resulting in muscular fatigue (B). highlights that lactate is not a waste product of anaerobic promote optimal cardiac efficiency during physiological metabolism but rather a useful alternative energy source. Not stress, such as prolonged exercise, by facilitating substrate only does lactate promote restoration of optimal blood pH availability (Cruz et al., 2012). Cardiac MCT isoforms facili- but it also fuels aerobic metabolism, by enhancing pyruvate tate a lactate utilization pathway similar to that of skeletal yield, and is therefore likely to improve sports performance muscle; however, during exercise, cardiomyocyte mitochon- rather than hinder it. This perspective is supported by dria predominantly oxidize pyruvate formed via the break- Overgaard et al. (2012) who reported an 18-fold increase in down of lactate rather than pyruvate formed from glucose net lactate turnover during exercise-induced hypoxia, indica- metabolism (Passarella et al., 2008). This indicates that lac- tive of lactate utilization within the body in response to exer- tate is important in supplying cardiac tissue with ATP cise. There is also increasing evidence that lactate oxidation required for aerobic metabolism. Lactate utilization is more may occur within cardiomyocytes, due to the presence of specific, than in skeletal muscle tissue, occurring mostly in MCT isoforms located within cardiac tissue (Halestrap and the left ventricle (Ponsot et al., 2005). Glucose-derived pyru- Meredith, 2004). It is therefore plausible that lactate may vate is released into the bloodstream for utilization by other 3 Review Bioscience Horizons • Volume 7 2014 Figure 3. In both type II (fast-twitch) muscle fibres and in astrocytes, glycolysis converts glucose into pyruvate, forming lactate as a by- Figure 2. Circulating glucose and lactate enter the cell via transport product. Lactate enters the interstitial fluid via monocarboxylate proteins on its cell surface. Glycolysis then converts glucose, forming transporter 4 (MCT4). Lactate is transported into type I fibres by MCT1 pyruvate. Both pyruvate and lactate are transported into the cells’ and by MCT2 in neurons. Lactate is then converted into pyruvate, in mitochondrion by monocarboxylate transporters. Lactate is converted both cell types, by lactate dehydrogenase (LDH). Pyruvate enters the to pyruvate by mitochondrial lactate dehydrogenase (mLDH). Pyruvate cells mitochondrion, enhancing its energy yield (adapted from Draoui derived from both glucose and lactate sources then contributes to the and Feron, 2011). cells’ oxidative energy yield via the Krebs cycle and electron transport chain (ETC). to other cells within the body with the oxidative capability to metabolize lactate, such as type I (slow-twitch) muscle cells, aerobically respiring target cells and tissues and as a result, enhancing their excitability and limiting fatigue (see Fig. 3; lactate provides the heart with an additional energy sub- Robergs, 2004). Furthermore, once in circulation, lactate strate, which is especially useful in hypoxic environments attaches to red blood cells (RBCs) and is disassociated in the (Passarella et al. 2008). This process allows any remaining liver where inter-conversion via gluconeogenesis facilitates glucose in circulation to be redistributed, via the blood- glucose formation, providing an alternative aerobic energy stream, to cells that are not capable of metabolizing lactate source. However, lactate uptake by RBC is only proportional and may contribute to the maintenance of aerobic perfor- to lactate efflux during aerobic exercise. During maximal mance when the body is faced with the physiological chal- exercise, lactate efflux exceeds its uptake indicating that this lenge of low arterial oxygen concentrations (Chatham, Des process is rate limited (Gladden, 2004). Rosiers and Forder, 2001). Intercellular lactate shuttle Lactate and cognitive function Lactate is regarded as a valuable metabolite for brain function A cell-to-cell shuttle hypothesis also exists and suggests that and is a major energy substrate utilized by neurons during type II (fast-twitch) muscle fibres are predisposed to produc - exercise (Overgaard et al., 2012). In addition, lactate opti- ing larger quantities of lactate than type I (slow-twitch) fibres. mizes gamma-aminobutyric acid receptor function, ensuring Excess lactate, formed within fast-twitch fibres, is transported 4 Bioscience Horizons • Volume 7 2014 Review article that inhibitory signals from the central nervous system, caused in passive rat soleus was not replicated in its active equivalent, by a drop in cell pH, are effectively detected (Pellerin et al., suggesting that results from passive and active skeletal muscle 2007). Lactate can therefore be regarded as important to the models may not be directly comparable. maintenance of cognitive function, protecting neurons from There is growing criticism of studies investigating the damage by acidosis. effects of lactate on sports performance at sub-physiological Neuronal lactate transport is facilitated by the lactate- temperatures. When researching the effects of lactate on skel- neuron shuttle (Draoui and Feron, 2011). van Hall et al. etal muscle function, studies often use isolated single muscle (2009) demonstrated a significant increase in net neuronal fibres at sub-physiological temperatures, owing to degrada - lactate uptake from 0.06 ± 0.01 at rest to 0.28 ± 0.16 mmol/ tion of such fibres at temperatures approaching 37°C. Single- min during exercise, indicating an essential role for lactate in fibre models are highly temperature sensitive and therefore neuronal function under both physiological conditions. findings from studies performed at sub-physiological tem - Neuronal lactate influx is moderated by MCT2 and allows a peratures should be interpreted with caution as they may not maximal flux at 1 mM but blocks lactate entry into the neu- be a true representation of the human fatigue process in vivo ron at both 3 and 10 mM, protecting the brain from lactate- (Allen, Lamb and Westerblad, 2008). Debold, Dave and Fitts induced acidosis which would compromise the ability of the (2004) demonstrated a 50% increase in peak muscle fibre brain to detect fatigue (Hertz and Dienel, 2004). power when lactate was applied at a near-physiological tem- perature of 30°C. Contrastingly, Knuth et al. (2006) found Furthermore, lactate may be shuttled between astrocytes that a lactate-induced pH change at both 15°C and 30°C and neurons (Mangia et al., 2009; Draoui and Feron, 2011). caused a decrease in force and peak power. Such contrasting This mechanism is referred to as the astrocyte-neuron-lactate evidence indicates that further research is required in order to shuttle hypothesis (ANLSH). The ANLSH is responsible for clarify the interaction between lactate and temperature. 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., Conclusions 2007; Overgaard et al., 2012). Recent evidence from an ani- To conclude, for many decades lactate has been misinter- mal model demonstrated that the ANLSH supplies neurons preted as a waste product of anaerobic metabolism, which and astrocytes with a 3- and 5-fold greater yield of mitochon- reduces aerobic performance, advances in technology and drial adenosine triphosphate respectively under hypoxia, continuing research has identified lactate as a valuable meta - when compared with conditions replete in oxygen (Genc, bolic product, both at rest and during exercise, with a wide Kurnaz and Ozilgen, 2011). During exercise, astrocytes range of physiological benefits such as counteracting acidosis metabolize glucose, forming lactate as a by-product. and maintaining neuron and astrocyte function. Future Neuronal efflux of lactate is facilitated by MCT4 which studies should aim to develop an active skeletal muscle releases lactate into the interstitial fluid. Lactate is then trans - model capable of withstanding physiological temperatures ported into neurons, via MCT2, where it is enzymatically and investigate whether lactate-induced mitochondrial bio- converted into pyruvate by lactate dehydrogenase. Pyruvate genesis translates into improved aerobic sports performance. finally enters the citric acid cycle within astrocyte mitochon - Furthermore, it is not yet known if cerebral lactate concen- dria, contributing to oxidative ATP yield (see Fig. 3; Draoui trations impact upon fatigue recognition or sensory ability, and Feron, 2011). It is important to note that neurons not during exercise, warranting future research. Although varia- only source lactate directly from astrocytes but also via the tions in opinion still exist, the general consensus on lactate bloodstream (see Fig. 2; Boumezbeur et al., 2010). This com- has shifted from being detrimental to physical performance plex mechanism may allow astrocytes to switch between glu- to an essential compound that opposes the fatigue process cose and lactate shuttle mechanisms, depending upon the and supports brain function during exercise and at rest. 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 Acknowledgements and cognitive function during exercise. The author thanks Dr Karina Stewart at the University of the West of England for her advice and support throughout my Experimental limitations undergraduate degree and in submitting this review. I would also like to thank my fiancé and family for encouraging me to Studies reporting positive effects of lactate on muscle function pursue a research career in sports nutrition. 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 Brief biography skeletal muscle during physical activity and in response Kristensen et al. (2005) investigated whether similar effects Joshua is currently a PhD student at the Northern Ireland are observed in active rat soleus when bathed in a lactate- Centre for Food and Health (NICHE), University of Ulster, metabolite solution. Interestingly, enhanced force production Coleraine. He recently completed his undergraduate degree 5 Review Bioscience Horizons • Volume 7 2014 Draoui, N. and Feron, O. (2011) Lactate shuttles at a glance: from physi- in Sports Science (Nutrition), at the University of the West of ological paradigms to anti-cancer treatments, Disease Models and England, Bristol. He has a strong research interest in vitamin Mechanism, 4 (6), 727–32. D and its effects on inflammation, skeletal muscle function and upper respiratory tract infection in elite athletes. His Fryer, M. W., Owen, V. J., Lamb, G. D. et al. (1995) Effects of creatine phos - career goals are to contribute to World-leading research in 2+ phate and p on ca movements and tension development in rat the field of sports nutrition and to engage with the next skinned skeletal muscle fibres, The Journal of Physiology, 482 (1), generation of sports scientists by lecturing within a higher 123–40. education institution. Genc, S., Kurnaz, I. A. and Ozilgen, M. (2011) Astrocyte-neuron lactate shuttle may boost more ATP supply to the neuron under hypoxic References conditions—in silico study supported by in vitro expression data, BMC Systems Biology, 5 (1), 162. Allen, D. G., Lamb, G. D. and Westerblad, H. (2008) Skeletal muscle fatigue: cellular mechanisms, Physiological Reviews, 88 (1), 287–332. Gladden, L. B. (2001) Lactic acid: New Roles in A new Millennium, Proceedings of the National Academy of Sciences of the United States Bassett, D. R. (2002) Scientific contributions of A.V Hill: exercise physiol - of America, 98 (2), 395–7. ogy pioneer, Journal of Applied Physiology, 93 (5), 1567–82. Gladden, L. B. (2004) Lactate metabolism: a new paradigm for the third Bonitch-Gongora, J. G., Bonitch-Dominguez, J. G., Padial, P. et al. (2012) millennium, The Journal of Physiology, 558 (1), 5–30. The effect of lactate concentration on the handgrip strength during judo bouts, Journal of Strength and Conditioning Research, 26 (7), Gorostiaga, E. 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(2001) Evidence of sepa- Hertz, L. and Dienel, G. A. (2004) Lactate transport and transporters: rate pathways for lactate uptake and release by the perfused rat general principles and functional roles in brain cells, Journal of heart, American Journal of Physiology Endorinology Metabolism, 281 Neuroscience Research, 79 (1–2), 11–8. (4), E794–802. Hill, A. V. and Lupton, H. (1923) Muscular exercise, lactic acid, and the Cruz, R. S., de Aguair, R. A., Turnes, T. et al. (2012) Intracellular shuttle: the supply and utilization of oxygen, Quarterly Journal of Medicine, 16, lactate aerobic metabolism, The Scientific World Journal , 2012 (1), 135–71. 1–8. Knuth, S. T., Dave, H., Peters, J. R. et al. (2006) Low cell pH depresses peak Debold, E. P. (2011) Recent insights into muscle fatigue at the cross- power in rat skeletal muscle fibres at both 30 degrees C and 15 bridge level, Frontiers in Physiology, 3, 151. degrees C: implications for muscle fatigue, The Journal of Physiology, Debold, E. 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(2001) Protective effects of tions of phosphate on intracellular calcium and force in single fibres lactic acid on force production in rat skeletal muscle, The Journal of of mouse skeletal muscle, Pflugers Archiv , 431, 964–70. Physiology, 536 (1), 161–6. Westerblad, H., Allen, D. G. and Lannergren, J. (2001) Muscle Fatigue: Lactic Acid or Inorganic Phosphate the Major Cause? News in Overgaard, M., Ramussen, P., Bohm, A. M. et  al. (2012) Hypoxia and Physiological Science, 17, 17–21. Exercise provoke Both lactate Release and Lactate oxidation By the Human brain, The FASEB Journal, 26 (7), 3012–20. Wright, D. C., Han, D.-H., Garcia-Roves, P. M. et al. (2007) Exercise-induced Passarella, S., de Bari, L., Valenti, D. et  al. (2008) Mitochondria and mitochondrial biogenesis begins before the increase in muscle l lactate metabolism, FEBS Letters, 582 (25–28), 3569–76. PGC-1a expression, The Journal of Biological Chemistry, 282 (1), 194–99. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Bioscience Horizons Oxford University Press

Lactate: valuable for physical performance and maintenance of brain function during exercise

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BioscienceHorizons Volume 7 2014 10.1093/biohorizons/hzu001 Review Lactate: valuable for physical performance and maintenance of brain function during exercise Joshua J Todd* Faculty of Health and Applied Sciences, The University of the West of UK, Coldharbour Lane, Bristol BS16 1QY, UK *Corresponding author: Northern Ireland Centre for Food and Health (NICHE), University of Ulster, Cromore Road, Coleraine, Northern Ireland, BT52 1SA. Email: todd-j10@email.ulster.ac.uk Supervisor: Dr Karina Stewart, Faculty of Health and Applied Sciences, University of the West of England, Coldharbour Lane, Bristol BS16 1QY, UK. Lactate 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. Key words: lactate shuttle, skeletal muscle, neurons, astrocytes, fatigue, noxious metabolites Received 24 December 2013; revised 3 April 2014; accepted 15 April 2014 Introduction dissociation of lactic acid into lactate ions and hydrogen (H ) entering skeletal myocytes (Robergs, 2004). This process induces The traditional stance that blood lactate accumulation, dur- acidosis, disrupting the cross-bridge cycle and impairing the ing exercise, negatively impacts upon athletic performance contractile capability of such cells (Debold, 2011). Gorostiaga arouses from research undertaken in the 1920s by British et al. (2012) demonstrated that once the critical point of lactate, physiologist A.V. Hill, whose study hypothesized that a −1 10–15 mmol per kg wet muscle, had been exceeded a signifi - decrease in pH depresses cell excitability and consequent cant decrease in the number of repetitive leg-press exercises was muscular contractile force (Hill and Lupton, 1923; Bassett, observed, indicative of lactate’s involvement in muscular fatigue. 2002). However, with modern technological advances and a In addition, Bonitch-Gongora et al. (2012) reported an inverse greater understanding of the biochemical kinetics of lactate, relationship between blood lactate concentration and isometric evidence now strongly indicates that lactate is a valuable contractile force during judo bouts. Collectively, these findings energy substrate for various physiological systems, such as suggest that lactate accumulation may contribute to impaired the brain, heart and skeletal muscle (Cairns, 2006). Lactate physical performance via disruption to the acid–base balance generation has been identified as advantageous within these within skeletal muscle during exercise. systems not only during exercise, but also at rest. Noxious metabolites Lactate-induced acidosis Despite the longstanding hypothesis that lactate-induced aci- The lactate-induced acidosis theory posits that under hypoxic dosis promotes fatigue, lactate can exert a positive effect on conditions, such as anaerobic exercise, there is increased aerobic performance. Its accumulation has been attributed to © The Author 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Review Bioscience Horizons • Volume 7 2014 counteracting the negative effects of noxious metabolites 1996; Soares et al., 2013). Yet this mechanism only appears including inorganic phosphate (Pi) and potassium (K ), as relevant for exercise <1 h in duration, after which there is 2+ well as facilitating removal of muscular proton and also act- little effect of Pi on sarcoplasmic Ca (Westerblad, Allen ing synergistically with catecholamines to reduce fatigue and Lannergren, 2001). Dhalstedt et al. (2000) demon- (McKenna, Bangsbo and Renaud, 2008). strated that, in wild-type mice, Pi concentrations significantly increased from 19.8µ mol/g dry weight at rest to 54.8 µ mol/g Greater emphasis has now been placed upon these metab- dry weight following a tetanic fatiguing exercise protocol. olites as the primary physiological cause of fatigue rather Such findings indicate that Pi is likely implicated in the devel - than lactate. Lactate not only regenerates nicotinamide opment of skeletal muscle fatigue in humans and may even be adenine dinucleotide (NAD ), an essential component for a primary cause, although without doubt future studies using glycolysis and aerobic respiration but its production uses two in vivo models at physiologically relevant temperatures are electrons, promoting a positive pH change as well as provid- required to provide greater clarity. ing a chemical gradient for proton removal from anaerobi- cally respiring skeletal muscle (Robergs, 2004). Miller et al. Mitochondrial biogenesis (2002), support this claim, by demonstrating that lactate oxidation increases during moderate-intensity exercise and Fluctuations in lactate concentrations, during prolonged that this prolongs blood glucose homeostasis. exercise, have been shown to induce mitochondrial biogene- sis of rat L6 cells, directly increasing long-term oxidative Lactate is an important component in the multifactorial capacity via activation of reactive oxygen species (Hashimoto biochemical response which acts to counteract the muscular and Brooks, 2008). This promotes expression of peroxisome fatigue process. It is capable of counteracting the electro- proliferator-activated receptor gamma coactivator 1-alpha chemical imbalance induced by K accumulation during and the subsequent transcriptional pathway that is capable of exercise and as a result, lactate indirectly enhances force pro- producing monocarboxylate transporter one (MCT1) iso- duction, promoting optimal physical performance (Nielsen, forms, facilitating mitochondrial biogenesis (Wright et al., de Paoli and Overgaard, 2001; de Paoli et al., 2007). 2007). As a result, this increases the proportion of type I Lindinger et al. (2006) support this argument and accept lac- (slow-twitch) fibres within skeletal muscle composition and, tate as a biomarker of fatigue because it accumulates propor- if findings are replicated in human studies, may improve aer - tionally in relation to an increase in plasma metabolites, obic performance (Cruz et al., 2012). during high-intensity exercise, yet may not cause muscular fatigue. Hansen, Clausen and Nielsen (2005) identified that Intracellular lactate shuttle lactate is most effective in preserving type II (fast-twitch) muscle fibre function and can exert a greater effect on this Evidence that lactate may be transported via a number of pro- subtype due to their low oxidative capacity. It is plausible to posed ‘shuttle mechanisms’ emerged as early as the mid-1980′s speculate that, due to preferential activity within type II and such findings have significantly altered the way lactate is fibres, lactate may expose type I (slow-twitch) muscle fibres currently perceived within the literature (Gladden, 2004; to cellular acidosis. However, during exercise, increased cir- Brooks, 2009). The intracellular lactate shuttle hypothesis sug- culating plasma-free catecholamines exert protective effects gests that lactate molecules are transported across the mito- upon slow-twitch muscle fibres via muscular β-2 adrenocep- chondrial intermembrane space via MCT1, proteins which tors. The accumulating K is buffered by β-2 agonist action facilitate the uptake of lactate molecules into skeletal myocytes + + which consequently up-regulates sodium (Na )/K pump for oxidation (see Fig. 2; Cruz et al., 2012). This process occurs activity within the musculature, facilitating the restoration of in each individual cell, independently of other myocytes that an effective propagation pathway and optimal cell excitabil- form skeletal muscle tissue. Lactate molecules are oxidized by ity, opposing the fatigue process (Hansen, Clausen and mitochondrial lactate dehydrogenase (mLDH), which has Nielsen, 2005). Thus, lactate acts synergistically with cate- been identified within skeletal myocyte mitochondria, and cholamines to ensure that both fast-twitch and slow-twitch facilitate the formation of pyruvate, an essential molecule in muscle fibres are protected from fatigue. effective aerobic metabolism (Brooks et al., 1999). As a result, Pi is released via the breakdown of phosphocreatine (PCr) exercise promotes lactate influx into skeletal muscle mitochon - during muscular contraction and an increased Pi concentra- dria and its consequent oxidation, although this process is rate tion is recognized as a factor contributing to muscular fatigue. limited by factors such as metabolic rate and blood pH It has been suggested that highly concentrated Pi within skel- (Gladden, 2001). For many years, the existence of mLDH in 2+ etal muscle may exacerbate sarcoplasmic calcium (Ca ) vivo was highly debated; however, with modern advances in efflux, resulting in a series of high frequency impulses and a technology mLDH has been consistently identified within number of maximal contractions which induce muscular skeletal myocyte mitochondria, using gold particle immuno - fatigue (see Fig. 1; (Westerblad, Allen and Lannergren, 2001). labelling, western blotting, confocal microscopy and immuno- 2+ Furthermore, Pi may interact with sarcoplasmic Ca , impair- precipitation (Brooks and Hashimoto, 2007). mLDH stimulates 2+ ing Ca efflux and consequent excitation–contraction cou - lactate reconversion into pyruvate, directly opposing the pling, see Fig. 1(Fryer et al. 1995; Westerblad and Allen, fatigue process (Hashimoto et al., 2007). This evidence 2 Bioscience Horizons • Volume 7 2014 Review article Figure 1. Following high-intensity exercise, inorganic phosphate (Pi) enters the skeletal musculature and promotes excess calcium efflux, 2+ causing tetanic contractions which result in muscular fatigue (A). Pi interacts with sarcoplasmic calcium (Ca ), decreasing calcium efflux and inhibiting cross-bridge cycling, resulting in muscular fatigue (B). highlights that lactate is not a waste product of anaerobic promote optimal cardiac efficiency during physiological metabolism but rather a useful alternative energy source. Not stress, such as prolonged exercise, by facilitating substrate only does lactate promote restoration of optimal blood pH availability (Cruz et al., 2012). Cardiac MCT isoforms facili- but it also fuels aerobic metabolism, by enhancing pyruvate tate a lactate utilization pathway similar to that of skeletal yield, and is therefore likely to improve sports performance muscle; however, during exercise, cardiomyocyte mitochon- rather than hinder it. This perspective is supported by dria predominantly oxidize pyruvate formed via the break- Overgaard et al. (2012) who reported an 18-fold increase in down of lactate rather than pyruvate formed from glucose net lactate turnover during exercise-induced hypoxia, indica- metabolism (Passarella et al., 2008). This indicates that lac- tive of lactate utilization within the body in response to exer- tate is important in supplying cardiac tissue with ATP cise. There is also increasing evidence that lactate oxidation required for aerobic metabolism. Lactate utilization is more may occur within cardiomyocytes, due to the presence of specific, than in skeletal muscle tissue, occurring mostly in MCT isoforms located within cardiac tissue (Halestrap and the left ventricle (Ponsot et al., 2005). Glucose-derived pyru- Meredith, 2004). It is therefore plausible that lactate may vate is released into the bloodstream for utilization by other 3 Review Bioscience Horizons • Volume 7 2014 Figure 3. In both type II (fast-twitch) muscle fibres and in astrocytes, glycolysis converts glucose into pyruvate, forming lactate as a by- Figure 2. Circulating glucose and lactate enter the cell via transport product. Lactate enters the interstitial fluid via monocarboxylate proteins on its cell surface. Glycolysis then converts glucose, forming transporter 4 (MCT4). Lactate is transported into type I fibres by MCT1 pyruvate. Both pyruvate and lactate are transported into the cells’ and by MCT2 in neurons. Lactate is then converted into pyruvate, in mitochondrion by monocarboxylate transporters. Lactate is converted both cell types, by lactate dehydrogenase (LDH). Pyruvate enters the to pyruvate by mitochondrial lactate dehydrogenase (mLDH). Pyruvate cells mitochondrion, enhancing its energy yield (adapted from Draoui derived from both glucose and lactate sources then contributes to the and Feron, 2011). cells’ oxidative energy yield via the Krebs cycle and electron transport chain (ETC). to other cells within the body with the oxidative capability to metabolize lactate, such as type I (slow-twitch) muscle cells, aerobically respiring target cells and tissues and as a result, enhancing their excitability and limiting fatigue (see Fig. 3; lactate provides the heart with an additional energy sub- Robergs, 2004). Furthermore, once in circulation, lactate strate, which is especially useful in hypoxic environments attaches to red blood cells (RBCs) and is disassociated in the (Passarella et al. 2008). This process allows any remaining liver where inter-conversion via gluconeogenesis facilitates glucose in circulation to be redistributed, via the blood- glucose formation, providing an alternative aerobic energy stream, to cells that are not capable of metabolizing lactate source. However, lactate uptake by RBC is only proportional and may contribute to the maintenance of aerobic perfor- to lactate efflux during aerobic exercise. During maximal mance when the body is faced with the physiological chal- exercise, lactate efflux exceeds its uptake indicating that this lenge of low arterial oxygen concentrations (Chatham, Des process is rate limited (Gladden, 2004). Rosiers and Forder, 2001). Intercellular lactate shuttle Lactate and cognitive function Lactate is regarded as a valuable metabolite for brain function A cell-to-cell shuttle hypothesis also exists and suggests that and is a major energy substrate utilized by neurons during type II (fast-twitch) muscle fibres are predisposed to produc - exercise (Overgaard et al., 2012). In addition, lactate opti- ing larger quantities of lactate than type I (slow-twitch) fibres. mizes gamma-aminobutyric acid receptor function, ensuring Excess lactate, formed within fast-twitch fibres, is transported 4 Bioscience Horizons • Volume 7 2014 Review article that inhibitory signals from the central nervous system, caused in passive rat soleus was not replicated in its active equivalent, by a drop in cell pH, are effectively detected (Pellerin et al., suggesting that results from passive and active skeletal muscle 2007). Lactate can therefore be regarded as important to the models may not be directly comparable. maintenance of cognitive function, protecting neurons from There is growing criticism of studies investigating the damage by acidosis. effects of lactate on sports performance at sub-physiological Neuronal lactate transport is facilitated by the lactate- temperatures. When researching the effects of lactate on skel- neuron shuttle (Draoui and Feron, 2011). van Hall et al. etal muscle function, studies often use isolated single muscle (2009) demonstrated a significant increase in net neuronal fibres at sub-physiological temperatures, owing to degrada - lactate uptake from 0.06 ± 0.01 at rest to 0.28 ± 0.16 mmol/ tion of such fibres at temperatures approaching 37°C. Single- min during exercise, indicating an essential role for lactate in fibre models are highly temperature sensitive and therefore neuronal function under both physiological conditions. findings from studies performed at sub-physiological tem - Neuronal lactate influx is moderated by MCT2 and allows a peratures should be interpreted with caution as they may not maximal flux at 1 mM but blocks lactate entry into the neu- be a true representation of the human fatigue process in vivo ron at both 3 and 10 mM, protecting the brain from lactate- (Allen, Lamb and Westerblad, 2008). Debold, Dave and Fitts induced acidosis which would compromise the ability of the (2004) demonstrated a 50% increase in peak muscle fibre brain to detect fatigue (Hertz and Dienel, 2004). power when lactate was applied at a near-physiological tem- perature of 30°C. Contrastingly, Knuth et al. (2006) found Furthermore, lactate may be shuttled between astrocytes that a lactate-induced pH change at both 15°C and 30°C and neurons (Mangia et al., 2009; Draoui and Feron, 2011). caused a decrease in force and peak power. Such contrasting This mechanism is referred to as the astrocyte-neuron-lactate evidence indicates that further research is required in order to shuttle hypothesis (ANLSH). The ANLSH is responsible for clarify the interaction between lactate and temperature. 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., Conclusions 2007; Overgaard et al., 2012). Recent evidence from an ani- To conclude, for many decades lactate has been misinter- mal model demonstrated that the ANLSH supplies neurons preted as a waste product of anaerobic metabolism, which and astrocytes with a 3- and 5-fold greater yield of mitochon- reduces aerobic performance, advances in technology and drial adenosine triphosphate respectively under hypoxia, continuing research has identified lactate as a valuable meta - when compared with conditions replete in oxygen (Genc, bolic product, both at rest and during exercise, with a wide Kurnaz and Ozilgen, 2011). During exercise, astrocytes range of physiological benefits such as counteracting acidosis metabolize glucose, forming lactate as a by-product. and maintaining neuron and astrocyte function. Future Neuronal efflux of lactate is facilitated by MCT4 which studies should aim to develop an active skeletal muscle releases lactate into the interstitial fluid. Lactate is then trans - model capable of withstanding physiological temperatures ported into neurons, via MCT2, where it is enzymatically and investigate whether lactate-induced mitochondrial bio- converted into pyruvate by lactate dehydrogenase. Pyruvate genesis translates into improved aerobic sports performance. finally enters the citric acid cycle within astrocyte mitochon - Furthermore, it is not yet known if cerebral lactate concen- dria, contributing to oxidative ATP yield (see Fig. 3; Draoui trations impact upon fatigue recognition or sensory ability, and Feron, 2011). It is important to note that neurons not during exercise, warranting future research. Although varia- only source lactate directly from astrocytes but also via the tions in opinion still exist, the general consensus on lactate bloodstream (see Fig. 2; Boumezbeur et al., 2010). This com- has shifted from being detrimental to physical performance plex mechanism may allow astrocytes to switch between glu- to an essential compound that opposes the fatigue process cose and lactate shuttle mechanisms, depending upon the and supports brain function during exercise and at rest. 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 Acknowledgements and cognitive function during exercise. The author thanks Dr Karina Stewart at the University of the West of England for her advice and support throughout my Experimental limitations undergraduate degree and in submitting this review. I would also like to thank my fiancé and family for encouraging me to Studies reporting positive effects of lactate on muscle function pursue a research career in sports nutrition. 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 Brief biography skeletal muscle during physical activity and in response Kristensen et al. (2005) investigated whether similar effects Joshua is currently a PhD student at the Northern Ireland are observed in active rat soleus when bathed in a lactate- Centre for Food and Health (NICHE), University of Ulster, metabolite solution. Interestingly, enhanced force production Coleraine. He recently completed his undergraduate degree 5 Review Bioscience Horizons • Volume 7 2014 Draoui, N. and Feron, O. (2011) Lactate shuttles at a glance: from physi- in Sports Science (Nutrition), at the University of the West of ological paradigms to anti-cancer treatments, Disease Models and England, Bristol. He has a strong research interest in vitamin Mechanism, 4 (6), 727–32. D and its effects on inflammation, skeletal muscle function and upper respiratory tract infection in elite athletes. His Fryer, M. W., Owen, V. J., Lamb, G. D. et al. (1995) Effects of creatine phos - career goals are to contribute to World-leading research in 2+ phate and p on ca movements and tension development in rat the field of sports nutrition and to engage with the next skinned skeletal muscle fibres, The Journal of Physiology, 482 (1), generation of sports scientists by lecturing within a higher 123–40. education institution. Genc, S., Kurnaz, I. A. and Ozilgen, M. 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Bioscience HorizonsOxford University Press

Published: Jun 2, 2014

Keywords: lactate shuttle skeletal muscle neurons astrocytes fatigue noxious metabolites

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