Monocarboxylate Transporters and Lactate Metabolism in Equine Athletes: A Review
- AR Pösö1
© The Author(s) 2002
Received: 19 November 2001
Accepted: 21 November 2001
Published: 30 June 2002
Lactate is known as the end product of anaerobic glycolysis, a pathway that is of key importance during high intensity exercise. Instead of being a waste product lactate is now regarded as a valuable substrate that significantly contributes to the energy production of heart, noncontracting muscles and even brain. The recent cloning of monocarboxylate transporters, a conserved protein family that transports lactate through biological membranes, has given a new insight into the role of lactate in whole body metabolism. This paper reviews current literature on lactate and monocarboxylate transporters with special reference to horses.
Monokarboxylat transportörer och laktat metabolismen hos tävlingshästar
Mjölksyra är en känd slutprodukt av den anaeroba glykolysen, en reaktionskedja som är viktig under hårt arbete. Nyligen klonade transportproteiner för monokarboxylsyror, som formar en konserverad protein familj och som transporterar mjölksyra genom biologiska membraner, har givit en ny inblick i mjölksyrans roll i kroppsmetabolismen. Istället för att vara en värdelös slutprodukt anses mjölksyra nu vara ett värdefullt substrat som i väsentlig grad deltar i energiproduktionen i hjärtat, okontraherande muskler och även hjärnan. I den här artikeln refereras ny litteratur om mjölksyra och om monokarboxylsyra transportörer med speciell hänvisning till hästar.
Horses are superb athletes in comparison to other athletic species. Exceptionally high maximal oxygen uptake, a splenic reserve of red blood cells released into the circulation during exercise, and a high amount of energy stored as glycogen in the muscles contribute to the high performance capacity of a horse [27, 9]. Furthermore, equine muscles and blood are equipped with properties that increase their tolerance to lactic acid, the formation of which is necessary for maximal performance. The buffer capacity of muscles of trained horses is higher than in other athletic species, and red blood cells appear to function as a lactate sink, both of which phenomena may increase the anaerobic capacity [40, 51]. Because the lactic acid-induced acidification is the single most important factor causing fatigue, the regulation of its concentration in exercising muscle plays a central role in muscle function. Recent characterisation of monocarboxylate transporters, a protein family involved in the transport of lactate across biological membranes, has added a new perspective to our knowledge of lactate metabolism in exercise physiology [50, 21]. At the moment the physiological importance of these transporters is not completely understood, but the number of isoforms of monocarboxylate transporters and the conservative nature of these proteins suggest that the pathways of lactate are far more complex than generally believed.
Formation of lactate in muscle
Formation of lactic acid in muscle tissue is basically a question of the capacity of different metabolic pathways. Both at rest and during exercise, the rate of ADP rephosphorylation must meet the demand of ATP for contraction and other functions of the muscle cell. During light work, the demand for ATP lies within the limits of aerobic capacity, and ATP is produced by oxidative phosphorylation, but with increasing intensity, anaerobic pathways of energy production, i.e., substrate-level phosphorylation, become more important. It has been calculated that during a 400-m Quarter Horse race, about 60% of the energy is derived from anaerobic metabolism, and in longer races, such as in1600- to 2100-m Thoroughbred and Standardbred races, estimated values range from 10% to 30% .
Aerobic capacity varies among breeds of horses, among muscles and also among fiber types. Slow-twitch, type I, fibers usually have higher aerobic capacity than the fast-twitch, especially type IIB, fibers, which usually rely more on the anaerobic metabolism . The characteristics of type IIB fibers are species specific and also depend on training. For example, in reindeer and in well trained horses also type IIB fibers have high oxidative capacity [55, 52]. Availability of oxygen and the capacity to use it are the limiting factors for aerobic metabolism. This includes the cardio-respiratory function, hemoglobin concentration in the blood, transit time of the blood in the muscle, capillarization, myoglobin concentration in the muscle, and finally the number of mitochondria in the muscle fibers . Within the animal kingdom, horses have a high oxidative capacity, as indicated by maximal oxygen uptake of about 160 ml/kg body weight × min [15, 56], more than twice the uptake in human elite athletes. Theoretically, if it is assumed that during intense exercise 90% of oxygen is consumed by exercising muscles and that approximately 40% of the body weight is muscle, it can be calculated that with this oxygen uptake, aerobic ATP production in the equine muscle may approach 2 μmol × g-1 × s-1. This value is, however, well below the approximated maximal ATP demand, the calculated value of which for human muscle is about 3 μmol × g-1 × s-1(), and the difference indicated by these 2 figures has to be met by anaerobic glycolysis, an uneconomical but high-capacity pathway.
In human athletes, ATP production in glycolysis may be as high as 3 μmol/g body weight × s (Newsholme & Leech 1983), and although similar estimations from equine muscle are unavailable, the comparison of the activities of key glycolytic enzymes in equine muscles to those in human muscles [14, 25, 54, 8] indicates that anaerobic ATP production may be equally important in horses. Another product of glycolysis is NADH, which increases the cytosolic NADH/NAD+ ratio, which would rapidly slow down the rate of glycolysis. When the NADH/NAD+ ratio increases, glycolysis switches to the anaerobic mode. Instead of oxidation, pyruvate is reduced to lactate, and simultaneously NADH is oxidized to NAD+, which allows glycolysis to continue at the maximum rate. The need for NADH reoxidation in the cytoplasm means that the formation of lactic acid is essential for anaerobic energy production.
All muscle fibers contain the necessary enzyme lactate dehydrogenase. The activity of lactate dehydrogenase is, however, highest in those fibers that have the lowest volume density of mitochondria and the lowest number of capillaries per fiber area both in horses  as well as in other species [38, 20]. In horses these are usually the fast-twitch type IIB fibers . In addition to this, lactate dehydrogenase activity in type IIB fibers is due almost exclusively to the muscle type isoenzyme that favors the reaction towards the formation of lactate, whereas in the slow-twitch fibers the isoenzyme that favors the oxidation of lactate to pyruvate is also present [38, 20]. Recently the activity of lactate dehydrogenase has been demonstrated also in mitochondria, which allows for an intracellular lactate shuttle and suggests that some of the lactate oxidation may occur in these organelles .
Effects of lactate on muscle metabolism
Accumulation of lactate in the muscle cells initiates a cascade that eventually leads to fatigue. In horses after intermittent maximal exercise lactate concentrations of the middle gluteal muscle may increase up to 200 mmol/kg dry weight, but in other maximal exercise tests values around 100 mmol/kg dry weight have been reported [64, 60, 72]. Also in exercising human subjects muscle lactate concentrations may reach 100 mmol/kg dry weight [59, 30]. Lactic acid increases the osmotic pressure of the muscle cell, which allows the extracellular water to move into the cell and increase the cell volume . Interestingly, recent studies have suggested that cell volume is one of the major regulators of cell function. Increased volume may have a direct effect on energy metabolism, because swelling has an inhibitory effect on glycogen breakdown .
Transport of lactate from muscle
Monocarboxylate transporters form a conserved protein family, the members of which are expressed in a species- and tissue-specific manner . As indicated by their name, these proteins are not specific for lactate only, but transport other monocarboxylic acids, such as pyruvate, volatile fatty acids, and ketone bodies, as well. In all cases the transport is electroneutral; one monocarboxylate anion is transported together with a proton [49, 29]. The most extensively characterised MCT isoform is MCT1, which is expressed in most tissues. This isoform has been labeled by Halestrap and his group the "housekeeping" MCT . Two isoforms of MCTs have been identified in the muscle tissue. Isoform 1 (MCT1) is the predominant isoform in the oxidative fibers, whereas in the fast-twitch, least oxidative, fibers, isoform 4 (MCT4) plays a major role [39, 73]. Several studies have shown that the expression of MCT1 is upregulated by training [39, 1, 3, 48, 11]. Interestingly, the activity and the amount of MCT1 appears to correlate with the percentage of oxidative fibers [1, 73], and it has been speculated that in oxidative fibers the role of MCT1 is to transfer lactate into the cells for oxidation, whereas MCT4 functions in the efflux of lactate from the muscle . This notion is supported by the finding that the upregulation of MCT1 is accompanied by an increase in the activity of LDH1, the heart-type isoenzyme, indicating coexpression between the substrate transfer protein and the immediate enzyme the substrate faces in the cell [39, 11]. Since the MCT on the mitochondrial membranes is MCT1, the effect of training on the MCT1 expression may in part be due to the exercise-induced increase in the number of mitochondia . MCT4 also increases with training [48, 11], but interindividual variation in this activation is large . MCTs are activated at low pH . Another important regulatory factor is the concentration gradient across the sarcolemma; as soon as lactate concentrations in the extracellular space approach that in the muscle, the efflux of lactate is attenuated.
In human subjects at exhaustion after dynamic knee extensor exercise, large interindividual differences in muscle pH occur [30, 35], which suggests that muscle sensitivity to low pH varies individually. It has also been shown that large interindividual differences exist in the post-exercise muscle-plasma lactate gradients . Together, these results suggest that lactate transport across the sarcolemma provides a control site in lactate accumulation in the exercising muscle. It can be speculated that an individual with a high lactate transport capacity may produce more ATP from glycogen/glucose before the critical pH inside the cell is reached than an individual with a low lactate transport capacity. This is supported by two lines of evidence: First, some elite athletes have exceptionally high MCT activities, and second, human beings with a deficiency in MCT also suffer from exercise intolerance [16, 47]. More research will be needed to clarify the precise role of MCT in exercise performance and in the pH regulation of muscle.
Distribution of lactate in blood
The lactate anion as well as lactic acid is freely soluble in water and can thus be dispensed into the entire water space of the body, assuming that the necessary transport protein is available. From plasma, lactate is transported into red blood cells (RBC), liver, heart, all noncontractive muscles and other tissues (Fig 5). The direction of the lactate flow is determined mainly by the concentration gradient across the membranes of those tissues. The flow of lactate into the tissues will tend to decrease the plasma concentration of lactate and thus increase the efflux from the muscle which is determined by the muscle – plasma concentration gradient.
Elimination of lactate during exercise and recovery
Transport of lactate into RBC is only a passive means to increase the muscle-plasma concentration gradient; the oxidation of lactate is more efficient. The latter occurs in the heart, liver, type I muscle fibers, and other noncontracting tissues both during exercise and especially after it . The use of lactate differs between muscle tissue and liver. In the muscle, lactate is used for oxidation and energy production, and retains still over 90% of the energy of glucose. In liver, especially during exercise, lactate is metabolised back to glucose and circulated again to working muscles. During recovery, some lactate can be used for the synthesis of glycogen, although this matter is still under debate [65, 57]. This cell-to-cell lactate shuttle is well accepted, and recently a similar shuttle has been suggested to operate also within cell cytosol and mitochondria . It is generally accepted that light exercise during recovery increases lactate disappearance from blood both in human subjects and in horses [37, 2, 19]. During recovery, muscle tissue, which on a percentage basis is the largest tissue of the body, changes from lactate producer to lactate consumer, because lactate is a good energy substrate and readily available. During light exercise, the oxygen consumption of muscle may be twice that at rest, an increase that is small in comparison to the 20-fold increase from rest to maximal aerobic exercise. This small increase in muscle oxygen consumption will also double the utilisation of lactate in muscle, seen as faster disappearance .
Lactate as a marker of performance
Several factors affect blood lactate concentration (Fig. 7), and at least some of these factors are influenced by training. The rate of lactate production in exercising muscles is influenced by oxidative capacity, and thus training which is often accompanied with an increase in the number of mitochondria may reduce lactate production. Another factor that may regulate blood lactate concentration is the rate of efflux from the muscle, and as mentioned earlier, training increases the number of monocarboxylate transport proteins on the sarcolemma, which would have the effect of increasing blood lactate concentration. The third factor that markedly influences blood lactate concentration is its uptake by tissues that oxidize lactate. Several studies in humans have shown that lactate is taken up by the liver and inactive muscles and that lactate clearance is increased by training [10, 43, 46]. Increased clearance during and after exercise would tend to lower the lactate concentration in blood. All these factors have to be taken into account when blood lactate concentration serves as a marker of performance.
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