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Abstract
Since its discovery, the lactate molecule has always aroused interest and curiosity in academia. Over the years and scientific discoveries, lactate has only been approached in human physiology as a waste product of anaerobic metabolism. To better understand lactate, researchers have also identified and devised the concept of the anaerobic threshold. However, lactate is rediscovering a new life, as it also appears to be a metabolite of the aerobic system. In addition, it also appears to have a decisive role in neuroplasticity, as well as first and second messenger activity. The aim of the understanding is to deal with an examination of lactate from its beginnings up to the most recent discoveries, passing from the concept of the anaerobic threshold.
Keywords
- lactate
- anaerobic metabolism
- physical activity
- anaerobic threshold
- metabolism
- BDNF
1. Introduction
This chapter aims to reassess the role of lactate in physical exercise.
Within the chapter, we will analyse the historical controversy surrounding lactate, seen in the early days only as a waste metabolite produced in the absence or reduction of oxygen, to the present day, where lactate plays an active role in determining performance improvement.
There will be a focus on the concept of the anaerobic threshold and how it is modulated by exercise.
The term lactate is almost always associated with anaerobic metabolism, but as we will see in this chapter, new scientific evidence is finding that lactate can also be associated with aerobic metabolism [1].
The goal of the metabolic system during exercise is to maintain a constant ATP concentration so that the effort can continue over time. In order to achieve this, the human body has three types of metabolism at its disposal: phosphocreatine system (alactacidic anaerobic), aerobic and lactacidic anaerobic [2]. These three systems alternate with each other in relation to the duration and intensity of exercise in order to sustain the demand for ATP in the unit of time. In biochemical terms, we could call these metabolisms oxidative (O2-dependent) and substrate phosphorylation (O2-non-dependent). When physical activity is below 75% of VO2max, the predominant metabolism is oxidative; for parameters above 75% of VO2max, the metabolic activity of the skeletal muscle is supported by the anaerobic system with a high production of lactate [3]. Lactate, once produced, can be used as an energy substrate or transported to adjacent muscle fibres via lactate shuttles [4, 5]. Due to these characteristics in various metabolisms, lactate is also defined as a possible link between the glycolytic pathway and oxidative metabolism [6].
In this chapter, we will therefore illustrate how lactate once produced, can be a decisive substrate in energy production and not merely a product of fatigue induction. In addition, we will highlight developments in studies on the anaerobic threshold and how its correct interpretation can influence sports performance.
2. A brief history of lactate
The lactate molecule was first discovered in 1780 by the Swedish scholar Scheele (1742–1786) in sour milk, but it was only later, around the early 1800s, that we were able to observe the relationship between lactate and skeletal muscle [7]. This was made possible by the study conducted by Berzelius (1779–1784), in which the researcher observed how the amount of lactate was proportional to the effort exerted by skeletal muscle [8]. Through the work of many researchers, it has been possible to distinguish muscle lactate from milk lactate. Indeed, muscle lactate is described with the l(+)-lactate isoform, in contrast to that produced by microorganisms described with the d(−)-lactate isoform or a racemic mixture of d(−) and l(+) [9].
At the same time, in 1861, Louis Pasteur (a French chemist and microbiologist) noted how the presence of oxygen-induced more yeast growth than its absence per gram of sugar. Later, it was found that in yeast, there was a decrease in sugar consumption in relation to the amount of oxygen, with a simultaneous decrease in alcohol produced [10, 11]. This phenomenon was also demonstrated in muscle. Less lactate production was found under aerobic conditions than in the absence of oxygen, this condition was termed the “Pasteur effect” [12].
Continuing down the path through history, in 1890, it was shown that the interruption of oxygen supply to muscles in mammals and birds induced an increase in lactate concentration [13]. Following this, A.V. Hill, Long and Lupton [14, 15] and Krogh and Lindhard established the increase in blood lactate concentration in humans following intense exercise [16].
Early researchers believed that lactate formation was necessarily an anaerobic process. In fact, it was assumed that oxygen would play a role in “burning” the lactate produced during activity and where this was not possible, the [La-] would increase. One of the most active researchers in the early 1900s on Jervell [17]. In his studies in which he investigated the concentration of lactic acid, he came to the conclusion that the increase or decrease in lactate was closely related to the presence or absence of oxygen. The real application in understanding lactate in sports we owe to the studies done by Owlen, Wasserman and Kinderman. These researchers, along with many others, have helped us both to understand the next step, namely the interaction between the physiology of lactate metabolism under stress and to and cardiopulmonary response (VCO2/VO2) [18]. This interaction gave rise to the concept of the anaerobic threshold.
As we will see in the following paragraphs, to say today that “lactate is produced in the absence of oxygen” is an inaccuracy as lactate is a metabolite that is constantly formed during exercise and only under certain conditions, unrelated to the absence of oxygen, does it increase in muscle and blood.
3. Metabolism during exercise
The main objective of muscle tissue during exercise is to defend the ATP concentration, even when the demand for ATP is very high. Within muscle, ATP concentration is between 20 and 27 mmol/kg of dry muscle and could be totally consumed during very high-intensity activity within 15 seconds [19, 20]. In order to maintain a constant ATP concentration, metabolism has three possible solutions at its disposal:
Phosphocreatine (PCR) system
Aerobic metabolism
Anaerobic metabolism [3]
These metabolisms work so well that in the course of a sprinting activity, or in several sprint repetitions, there is only a decrease of between 20 and 40% compared to the resting condition [2].
These metabolisms are activated simultaneously in order to maintain a constant ATP concentration in the unit of time.
3.1 Phosphocreatine (PCr) system (anaerobic alactacid metabolism)
The phosphocreatine system is also referred to as the alactacid anaerobic system as it is oxygen-independent without lactate production. Through the activity of the enzyme creatine kinase, ATP is recharged from ADP by the release of a phosphate group from phosphocreatine. Not only that, in the course of this (reversible) reaction, a proton (H+) is consumed, which is essential for keeping the cellular pH under control [3].
The concentration of creatine in dry muscle is between 75 and 90 mmol/kg and is essential for maintaining ATP concentration during high-intensity exercise.
The PCr system is the fastest metabolism to activate and has a shorter half-life than the other two, around 10–15 seconds [3]. Note that the restoration of consumed PCr is very rapid at rest. In fact, phosphocreatine can be resentitised due to the reverse reaction involving ATP. The store of PCr is concluded in approximately 60–90s, thus making it ready to be reused [19].
From the dual role played by ATP in terms of both energetics and restoring, it is possible to imagine and understand how the three metabolisms must necessarily work as a unicum so that the ATP concentration remains constant in the unit of time.
3.2 Aerobic metabolism
The term aerobic metabolism is used to classify those oxygen-dependent metabolic reactions. These reactions have both carbohydrates (1) and lipids (2) as energy substrates. Both energy substrates play a key role in muscular metabolism under stress, as already characterised by Christensen’s [21] very early studies. The reference metabolic pathways of the aerobic system are, therefore, the glycolytic pathway and the beta-oxidation of fatty acids [22].
Glycolytic pathway:
Beta-oxidation pathway:
First of all, it is good to note that from the above reactions, it is possible to derive a parameter that will also be very useful in the analysis of lactate and anaerobic threshold, namely the respiratory quotient (RER). This represents a molar ratio between the CO2 produced and the O2 consumed. With a value of RER = 1, we will define the utilisation of carbohydrates for energy, with a value of 0.7, we will define fatty acids [3]. The value of RER is very important during the cardiopulmonary exercise test; in fact, during the test, we will observe the change from values of 0.7 and 0.8 to values of 1.0 and higher. When this happens, it means that we are in a condition of using carbohydrates for energy which will correspond to the anaerobic threshold (we will see this concept later).
The glycolytic pathway is a process in which glucose is converted into two smaller molecules: pyruvate. Subsequently, the two pyruvate molecules enter the tricarboxylic acid (TCA) cycle after conversion to acetyl-CoA and are oxidised into CO2 + H2O. Within the TCA cycle, acetyl-CoA binds to an oxaloacetate molecule, and following a series of transformations, 3 NADH, 1 FADH2 and 1 ATP molecule are produced. The two enzyme cofactors produced (NADH and FADH2) then serve as electron transporters within the electron transport chain located on the mitochondrial matrix, with the ultimate goal being the production of energy in the form of ATP [23].
In contrast, the lipolytic pathway involves the breakdown of triglycerides into glycerol and fatty acids. Fatty acids enter the mitochondrial matrix via carnitine transporters (CPT1-CPT2) and undergo beta-oxidation. At the end of this process, acetyl-CoA molecules are also formed, which subsequently enter the TCA cycle [24].
3.3 Anaerobic metabolism and lactate production
The process of energy formation using the lactacid anaerobic pathway is characterised by the glycolysis and glycogenolysis pathway with the final formation of lactate.
From the reference reaction, it can be seen that one molecule of glycogen is required to produce two molecules of lactate with the formation of three molecules of ATP:
Immediately noticeable is the release of 2H+ ions; indeed, the increase in their concentration, in association also with the increase in lactate anion is associated with an inability of the muscle to sustain contraction due to the inability to produce ATP [25]. How both lactate and H+ ions are handled and buffered by muscle metabolism will be discussed later.
The enzymes involved in these two reactions (anaerobic glycolysis and glycogenolysis) are phosphofructokinase (PFK), glycogen phosphorylase (PHOS), and lactate dehydrogenase (LDH). The ability of these two metabolic pathways to generate ATP during exercise is approximately four times greater than that of the PCr system [26]. In reactions of anaerobic metabolism, lactate is the final product of the reaction. As we have previously seen, lactate has, since its discovery, been associated with the concept of fatigue as described by Hogan et al. [27]. Indeed, it is now safe to assume that lactate is the real link between aerobic and anaerobic metabolism [1] and that it is not just a product for muscle fatigue but can be a valuable metabolic resource, if not “an universal” resource as reported by Rabinowitz et al. [28].
Before going any further, it is good to provide that lactic acid, which is formed by anaerobic glycolysis or glycogenolysis, has a dissociation constant (pKa) of 3.8. This characteristic means that at physiological pH (~7) it is in the form of lactate anion (La–) [29]. This consideration is very important because from now on, whenever the concept of lactate is introduced, we will refer to the anionic form (La-).
Lactate produced by the glycolytic pathway is obtained by reducing pyruvate. Pyruvate is the end product of the glycolytic pathway, but when the rate of pyruvate production is such that it cannot follow the concentration gradient that would lead it into the mitochondrion, lactate dehydrogenase (LDH) converts it into lactate [30]. On the other hand, glycogenolysis involves the formation of 6-p glucose from glycogen. The 6-P glucose immediately enters the anaerobic glycolytic pathway and the formation of lactate also occurs [3].
It should be emphasised that lactate production is always active but with low activity for physical activity below 50 per cent of maximum oxygen consumption (VO2max) [22]. In fact, for intensity values between 0 and 70%VO2max there is a decreasing utilisation of lipids and therefore of the aerobic pathway (glycolysis and beta-oxidation), with an increase in the utilisation of anabolic substrates (anaerobic glycolysis and glycogenolysis). Above the 70% value and even higher values, there is a sudden increase in the utilisation of carbohydrates as the sole source of energy in the form of anaerobic metabolism, with clear and high lactate production [22].
This ability of lactate to allow shifts between the various metabolisms during physical activity is referred to as metabolic flexibility [31, 32]. It would, therefore, seem that the lactate that is produced in the course of normal physiological functions, but even more so during physical activity, can act as a real link between the various metabolisms, leading to an activation of some metabolic pathways and an inhibition of others [33].
Analysing the role of lactate in this respect, we can divide the activity of this molecule within human metabolism into three categories:
In terms of energy source, the study carried out by Hui et al. [35] shows a very interesting key. In fact, in their mouse model, the authors, through the infusion of 13C-labelled lactate, were able to ascertain that it is one of the main fuels in the tricarboxylic acid cycle (TCA). Not only that, at the tissue level (excluding the brain), lactate is found to be more valuable than glucose as a fuel for TCA. This scientific evidence m0ight therefore suggest that despite what has always been assumed, lactate may be a more universal energy fuel than glucose [28]. Conversely, we might speculate on the concept of glucose as an ad hoc energy substrate for the brain and that the plurality of lactate interactions means that the share of glucose can be saved for the brain.
The major gluconeogenic precursor [36, 37];
As reported by Jenssen et al. [38] and later confirmed by Gerich et al. [39], lactate is the major gluconeogenic precursor. This is described through the well-known “Cori cycle.” This metabolic pathway interconnects the muscle with the liver and enables blood glucose to be sustained by using lactate conversion as the first substrate to induce gluconeogenesis [38, 40].
Signal molecule with autocrine, paracrine and endocrine activities, in the latter characteristic, lactate would act with hormone-like functions [41, 42].
The characteristic of the lactate molecule to act as a signal molecule is very important as it can act both as a first and second messenger in relation to the metabolic state, energy demands and adaptations induced by physical activity.
Lactate can perform its action as a “lactormone” through the use of transporters called monocarboxylate transporter isoforms (MCT) [43] (shuttle theory of lactate) that allow its cell-cell, tissue-tissue, organ-organ interaction [44]. As described by Brooks [45], lactate is able to modulate the utilisation of glucose and fatty acids as the primary energy source. Down-regulation of fatty acid utilisation is possible through lactate binding to G-protein receptors (GPR81). This interaction, which occurs in adipocytes, causes an inhibition of the lipolytic pathway [46]. In addition to the modulation of energy substrates, lactate studies would also seem to confirm a role for lactate in modulating gene expression, such as that of its MCT receptors [42]. In a study by Hashimoto et al. [42], incubation with 20 mM lactate was found to induce gene activation with an increase in peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α) expression. This response is very interesting and also sheds fundamental light on the interaction between lactate and aerobic metabolism. In fact, PGC1α is the promoter of mitochondrial biogenesis, and we know how an increased number of mitochondria leads to an improved aerobic response with an increase in VO2max [47]. Backing up these considerations are numerous studies in which it is observed that any type of physical activity is capable of increasing the number of mitochondria. The various types of physical activity also include high-intensity interval training (HIIT), probably the type of exercise that, due to its fluctuations in terms of VO2max (<70% and >90% VO2max) and thus metabolism, is able to produce the greatest amount of lactate [48, 49].
3.4 Shuttle theory of lactate
As described above, the lactate produced is capable of exerting a hormonal function, resulting in its activity as a “lactormone” [45].
Garcia et al. [43] highlighted how lactate is capable of triggering a gene response, with the ultimate goal being the production of its own transporters: the monocarboxylate transporter isoforms (MCT). These transporters have the task of enabling the movement of lactate, according to a concentration gradient, between cell to cell, tissue to tissue, and organ to organ [45].
MCTs belong to the solute transporter family 16 (SLC16) gene and are characterised by a symport, in which lactate and 1 proton are co-transported, and has a stereoselectivity, in fact, it can transport the L-lactate isoform but not D-lactate [50]. In addition, they can transport many other substrates such as pyruvate, short-chain fatty acids (acetate, propionate, butyrate), and ketone bodies (acetoacetate and β-hydroxybutyrate) [51]. As many as 14 MCTs are highlighted in the scientific literature. Each one is well localised in cells, fibres, tissues, and organs in a highly tissue- and transport-kinetic-specific manner [43, 52, 53]. On the plasma (sarcolemmal) membranes of skeletal muscle, there are MCT1 and MCT4 transporters [45]. MCT1 appears to be more highly expressed in high aerobic muscle fibres, whereas MCT4 does not appear to correlate with muscle fibre type [54]. These differentiations, however, highlight a ubiquitous role for lactate, emphasising its interaction with other organs and its activity as a “lactormone.”
Studies have related the amount of lactate transporters to the degree and type of physical activity [55, 56, 57]. As reported by Thomas et al. [57], constant low-intensity exercise causes an acute increase in MCT in humans. In sedentary subjects, increases in MCT1 and MCT4 were observed 2–6 days after a 5–6 h cycling training session at 60% of VO2 max in untrained humans [58]. During 16 hours of heavy, intermittent cycling exercise (6 minutes of exercise at 90% VO2 max per hour for 16 h) in untrained subjects, a rapid increase in MCT4 content (24%) was reported, with no change in MCT1 [58].
In contrast, however, no increases in MCT4 and MCT1 were found in moderately trained endurance runners subjected to a time-to-fatigue test performed at 110% VO2 max [59] lasting 2 h. This is probably induced by the fact that in sedentary subjects, the acute response is more rapid and significant than in moderately trained subjects.
The increase in lactate transporters is most evident when athletes and moderately active subjects are compared. Indeed, Thomas et al. observed a higher amount of MCT in endurance athletes than in less active subjects [60].
The role of the lactate transporters located at the muscle level is to decrease its concentration in the muscle fibres that are producing it. In this way, the fibre that is working can release both lactate and H+ ions and thus maintain its activity. The efflux would take place in the extracellular fluid adjacent to the fibre. Conversely, thanks to another MCT transporter, an adjacent fibre can utilise the lactate and by introducing it into the mitochondrial level can reoxidise it, thus supporting mitochondrial respiration. This scenario was called the intracellular lactate shuttle hypothesis [61].
When the “intracellular lactate shuttle hypothesis” was postulated by Brooks et al. [62], it was not unanimously accepted by the scientific world due to the difficulty of demonstration [63, 64]. Through numerous subsequent studies, researchers have come to postulate the presence of the Mitochondrial Lactate Oxidation Complex (mLOC) capable of utilising lactate for aerobic purposes [65]. This is possible because mLOC is characterised by a lactate transporter (MCT), its membrane chaperone basigin (BSG or CD147), LDH and cytochrome oxidase (COx) [66]. In addition to the lactate transporter, at the mitochondrial level, the pyruvate transporter (mPC) could also be identified through laboratory analysis [65]. This discovery makes the concept that lactate is reoxidised at the mitochondrial level even more plausible.
Questions still remain as to the location of mPC, as there are many conflicting studies [67, 68, 69, 70, 71]. Further studies are therefore needed to better describe the lactate and pyruvate complexes; what is certain is the presence of mechanisms at the level of the mitochondrial reticulum to oxidise both lactate and pyruvate.
4. Lactate and muscular fatigue
The term muscle fatigue identifies a decrease in muscle strength to complete an action under constant load [72].
Muscle fatigue can have two components and undergo specific physiological responses depending on the component involved. The two components are central and peripheral fatigue. Central fatigue involves the central nervous system, with the alpha-motoneuron, the spinal cord. Conversely, peripheral fatigue is at the muscular level [73].
In terms of muscle fatigue, we can identify temporary and chronic muscle fatigue.
During physical activity, in relation to the amount and type of effort required, there is a more or less marked production of lactate. The greater the production of lactate, the more rapidly the phenomenon of muscle fatigue may arise in the absence of adequate buffering systems or sufficient lactate transporters to discharge lactate. Not only that, the theory of acidosis-induced muscle fatigue postulates that the phenomenon of fatigue begins to occur due to the concentration of H+ ions, resulting in decrease in cellular pH [74]. The decrease in pH is accompanied by the exercise-induced increase in lattemia.
Subsequently, however, further and more in-depth studies [65] showed that it could not be lactate accumulation or a decrease in pH alone that induces muscle fatigue, but rather a combination of acidosis, phosphate ion accumulation and low Ca2+ [75] interaction with the theory of thread sliding, thus altering muscle contraction.
From a review of the literature, it would appear that the concomitant increase in lactate and decrease in muscle pH lead to metabolic and acid/base imbalance, resulting in the cessation of muscular contraction [76].
4.1 The definition of the anaerobic threshold
Lactate has a very dynamic metabolism during physical activity. In fact, it can undergo rapid changes in concentration both at the muscle level and in the bloodstream, depending on the type and duration of the effort. For example, during high-intensity exercise, lactate concentrations of 40 mmol/L and 25 mmol/L can be found in muscle fibres and the bloodstream, respectively [77].
The ability of the human metabolism under stress to be able to switch between aerobic and anaerobic metabolism with high lactate production has been widely discussed throughout history [18], since as we shall see, the ability to anticipate or stay longer at the anaerobic threshold could represent a fundamental turning point in performance prediction.
The concept of the anaerobic threshold closest to what we have today was postulated by Owles in 1930. In his study, he observed how the lactate concentration increased above a certain level during physical activity, calling this point: Owles’ point [78].
This evidence proved to be very useful and differed from previous authors in that, whereas previously an increase in lactate was observed in conditions of oxygen absence, with Owles, the decrease in the binding of CO2 by haemoglobin also began to be related to the increase in lactate concentration. This consideration laid the foundations for future studies and especially for what we might consider the study par excellence on the concept of the anaerobic threshold (AT): that set out by Wasserman and McIlroy [79]. In fact, in his postulate in the early 1960s, they highlighted the terminology of anaerobic threshold by merging the aspect of increased lactate concentration with the physiological response. This was possible because the buffering of lactate by bicarbonate would produce an excess of CO2, so by analysing respiratory volumes (VCO2 and VO2) it would be possible to identify the anaerobic threshold [80]. The innovation proposed by Wasserman and later developed by the same, involved a direct interaction between respiratory physiology and lactate biochemistry (breath-by-breath), whereas Hollmann, Kindermann, Keul focused exclusively on lactate concentration [18]. This test is called cardiopulmonary exercise testing (CPET). By relating the cardiopulmonary response to lactate biochemistry, it is therefore possible to indicate that the anaerobic threshold is that point on the graph where the amount of VCO2 exceeds the amount of VO2, thus leading to a decrease in available oxygen. In this condition, there is a high accumulation of lactate in the muscles and arteries, resulting in the anaerobic threshold condition [22]. The other fundamental characteristic for understanding the physiology of lactate under stress and its possible application in sports is the evaluation of the heart rate under stress. In fact, by cross-referencing the data of the VCO2/VO2 ratio and the curve that is created during exertion, it is possible to identify the metabolic shifting between the aerobic system and the lactacid anaerobic (AT) system at what power is established and at what heart rate. This concept is very important because it then defines a cardiac threshold value below which we are fairly sure we can work with a predominant aerobic metabolism and above which the anaerobic metabolism has predominance [22]. Without forgetting, however, that both metabolisms work in the first and second case; they just do not take absolute precedence.
Based on many studies and scientific evidence, many synonyms of anaerobic threshold have been described [80, 81, 82]. In fact, according to studies and various degrees of interpretation, two phenomena can be defined as anaerobic threshold or aerobic lactate threshold or “onset of blood lactate accumulation” (OBLA). These definitions refer to a point in the course of exercise at which metabolic shifting occurs, but this may not be definitive, in fact according to Kindermann et al. [81], the point that Wasserman identifies as the anaerobic threshold may actually be the maximum point of utilisation of the aerobic system. The second phenomenon refers to a moment when, during exertion, the accumulation of lactate is unavoidable. This condition is described by the term maximal lactate steady state (MLSS) [83].
In relation to the above, training can interfere with the former phenomenon as opposed to the latter. In fact, thanks to the increase in MCTs and PCr stores and the ability to buffer both H+ ion and lactate, typical of muscular adaptation to exercise, it will be possible to modulate either anaerobic threshold entry or cause MLSS to occur with much delay.
The differentiations between OBLA and MLSS seem like abstract concepts; in reality, they have a real application. Indeed, in a recent study [84], a double anaerobic threshold was observed in healthy subjects. The authors evaluated cardiopulmonary exercise tests performed over the previous 9 years. They found that 11% of the subjects evaluated had a double anaerobic threshold. The presence of the double anaerobic threshold did not lead to a differentiation in terms of CPET; however, subjects with the double threshold had lower VCO2 production, resulting in a lower respiratory exchange ratio. The authors suggest that subjects with a double anaerobic threshold actually had an earlier onset of anaerobic threshold entry but were able to remain in this state for longer than other subjects until inexorable lactate production occurred.
However, it is important to remember, as by the authors’ own admission, the lactate concentration was not measured, so it might make the study not very precise.
4.2 Anaerobic threshold as predictor of performance
Based on what has been described, an active role in the prediction of performance could be assumed to be played by the anaerobic threshold. Again, as in others previously described, the literature data is conflicting and confusing [83, 84].
Haverty et al. pointed out that in runners, maximum oxygen consumption (VO2max) is not a reliable predictor of performance, but VO2 value at MLSS speed, on the other hand, has a fundamental weight in understanding performance [85].
A similar concept was also highlighted by the work of Gregory et al. [86]. The author’s aim was to use cardiopulmonary exercise testing and anaerobic threshold analysis to describe the best type of training for cross-country mountain bikers. The data again showed that VO2max should not be the focus of the training, but rather power at the lactate threshold, and VO2 at the lactate threshold.
Ji et al. [87] through their study were able to observe how the anaerobic lactate threshold could be used to predict performance during a race. Although the data provided by the authors are very interesting, the sample size suggests that a much larger study would be needed to better understand the use of this parameter.
This consideration comes in the face of many contradictory studies on the true use of the anaerobic threshold as a predictor of performance [82]. Major contradictions also lie in the fact that the cardio-metabolic response may be sport-specific and that it may therefore be difficult to use only one absolute parameter to understand and anticipate performance [88].
The anaerobic threshold, like any other physiological parameter, can be trained, but unlike the other parameters, where even low to moderate intensity can induce an improvement, the anaerobic threshold needs high-intensity exercise to be improved [89].
From this point of view, high-intensity interval training is an excellent method for improving the utilisation of lactate for energy purposes and thus staying much more in that shadow zone between OBLA and MLSS [90].
5. Discussion and future prospective for lactate
Some 150 years have passed since the discovery of lactate, and even today, there are still considerable doubts and misunderstandings as to the real role of this molecule in the human body.
In fact, at first, it was assumed that lactate was only a waste product of metabolism and that during physical exertion, together with the concomitant release of H+ ions, it caused muscle fatigue.
We now know with certainty that lactate is produced approximately 65% by glucose metabolism and 16–20% by alanine metabolism [51]. Its production occurs at a low intensity during normal physiological functions but can abruptly increase in relation to an increased energy demand in a short unit of time. Once lactate is produced, it can undergo detoxification processes (e.g. Cori cycle), buffering, or via specific transporters (MCTS and SMCT), it can pass from the muscle fibre that is producing it to an adjacent one that is not “working.” This characteristic is very important as it has led to the hypothesis, and then to the demonstration, of the presence of a mitochondrial complex capable of reoxidising lactate so that it can be reused for energy purposes.
Moreover, the role of lactate has recently been rehabilitated, making it a true messenger, with hormonal activity, capable of interacting with other tissues and organs by determining gene suppression or activation. In addition, lactate can also modulate neurotrophic factors such as brain-derived neurotrophic factor (BDNF) [91].
This new observation opens the door to a new lactate frontier.
From a biochemical point of view, lactate can cross the blood-brain barrier [92] reaching neurons via MCTs [93, 94]. In this case, the main player is MCT 2 [95], whereas MCT 4 is only expressed in astrocytes [96]. As lactate can be used for energetic purposes, the transport of lactate from astrocytes to neurons plays a crucial role in memory formation [97, 98] and thus could be a link between exercise and neuroplasticity [92]. Indeed, exercise can increase levels of BDNF and insulin-like growth factor 1 (IGF-1) [91] and vascular endothelial growth factor (VEGF) [99].
In contrast, according to Yang et al. [100], lactate could promote neuroplasticity by enhancing NMDA glutamate receptor activity in neurons.
Morland et al. evaluated the role of hydroxycarboxylic acid receptor 1 (HCAR1) on increase VEGF expression and angiogenesis, activated by lactate binding. In this study, the authors observed a direct interaction between a molecule released from muscle during physical activity such as lactate and the central nervous system in a murine model [101]. To achieve this result, the authors divided the animals into three groups: High-intensity interval exercise 5 days weekly for 7 weeks of treadmill training, a group treated with sodium L-lactate injections and a control group with saline injections. The use of sodium L-lactate resulted in an increase in lactate concentration like that obtained with physical activity. The results showed that both the rats treated with training and those with sodium L-lactate expressed an increase in VEGFA in the brain. These data underline the direct relationship between increased blood lactate related to physical activity and increased brain neurotrophic factor.
In a recent work [102], the possible metabolic and biochemical link between physical activity, increased lactate and improved neuronal plasticity and memory was investigated.
In the mouse model proposed by El Hayek et al. [102], it was shown that lactate produced during regular physical activity can induce not only increased BDNF expression but also the NAD + -dependent histone deacetylase SIRT1. The increase in SIRT1 expression could also lead to an increase in antioxidant defences [103] in the brain, posing a possible further explanation for the improvement in neuronal plasticity.
6. Conclusions
Over the years, since its discovery, lactate has always been compared to the phenomenon of muscle fatigue and as a waste product of metabolism. The study of the possible role of lactate in muscle fatigue has led to the discovery and development of the concept of anaerobic threshold to the present day.
With the succession of studies, the role of lactate has been rehabilitated, in fact, it can be a first fuel during physical activity, and its formation prevents the accumulation of pyruvate. Not only that, more and more recent studies have also identified signalling roles. In fact, in physiological conditions or induced by physical activity, it can act either as a first signalling, for example with hormonal activity (lacthormone) or act as a second messenger. Not only that, by means of specific interactions, it would seem implicated with angiogenesis and the increase of the neurotrophic and plastic factors at the brain level. Such interactions always seem to be dependent on an active role of exercise.
Based on this latest scientific evidence, it is legitimate to hypothesise motor programmes designed to increase lactate concentration in a controlled manner to exploit the “lactormone”” capacity, especially in the brain in the most severe physiopathological conditions. More scientific evidence will certainly be needed both to redefine the concept of the anaerobic threshold and the role of lactate in human physiology.
Acknowledgments
Jonathan Fusi has conceived and written the work, has found the bibliography of reference, Giorgia Scarfò has rechecked the bibliography and the grammar, Ferdinando Franzoni has supervised the manuscript.
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