Lactate transporters (MCT proteins) in heart and skeletal muscles


Medicine & Science in Sports & Exercise: April 2000 - Volume 32 - Issue 4 - pp 778-789
BASIC SCIENCES: Original Investigations: Symposium: The role of skeletal muscles in lactate exchange during exercise

BONEN, A. Lactate transporters (MCT proteins) in heart and skeletal muscles. Med. Sci. Sports Exerc., Vol. 32, No. 4, pp. 778–789, 2000. Lactate traverses the cell membranes of many tissues, including the heart and skeletal muscle via a facilitated monocarboxylate transport system that functions as a proton symport and is stereoselective for L-lactate. In the past few years, seven monocarboxylate transporters have been cloned. Monocarboxylate transporters are ubiquitously distributed among many tissues, and the transcripts of several monocarboxylate transporters are present within many of the same tissues. This complicates the identification of their metabolic function. There is also evidence that that there is some species specificity, with differences in MCT tissue distributions in hamsters, rats, and humans. MCT1 and MCT3-M/MCT4 are present in rat and human muscles, and MCT1 expression is highly correlated with the oxidative capacity of skeletal muscles and with their capacity to take up lactate from the circulation. MCT1 is also present in heart and is located on the plasma membrane (in subdomains), T-tubules, and in caveolae. With training, MCT1 is increased in rat and human muscle, and in rat hearts, resulting in an increased uptake of lactate from the buffers perfused through these tissues and an increase in lactate efflux out of purified vesicles. In humans, the training-induced increases in MCT1 are associated with an increased lactate efflux out of muscle. MCT3-M/MCT4 is not correlated with the muscles’ oxidative capacities but is equally abundant in Type IIa and IIb muscles, whereas it is markedly lower in slow-twitch (Type I) muscles. Clearly, we are at the threshold of a new era in understanding the regulation of lactate movement into and out of skeletal muscle and cardiac cells.

For many years it had been assumed that lactate produced by skeletal muscle was freely diffusible. However, in the past two decades, it has been shown that lactate leaves (or enters) the cell via a facilitated transport system in most tissues (see Poole and Halestrap (55) for review). In the early 1970s, several groups proposed that lactate efflux out of contracting dog muscles was limited by the sarcolemma (16,17,32). Somewhat later, it was shown that lactate efflux out of human skeletal muscle during exercise was a saturable process (22). In the past decade, studies from our laboratory (35–37,40–42) and others (23,25–31,57–59) have provided convincing kinetic evidence for the facilitated lactate transport system in muscle (several excellent reviews on this topic have appeared recently (5,15,24)). Thus, for the past 20 yr or more, there has been good evidence that lactate traverses the sarcolemmal membrane via a mechanism involving specific transport proteins.

From a physiological perspective, the important findings of the lactate transport system include the following: 1) the system functions as a proton symport, so that both La+ and H+ are cotransported in an electroneutral manner (24); 2) it is stereoselective for L-lactate (24); 3) in the cell, lactate rapidly dissociates (pKa = 3.86), and it has been shown that it is the lactate ion that is transported (41,42); 4) lactate transport is increased when muscle activity has been chronically increased (i.e., training (40,47) and chronic stimulation (37)); and 5) lactate transport is decreased with muscle inactivity (i.e., denervation (36,46) or hindlimb suspension (10)). Whether lactate transport is altered during or immediately after exercise is not clear. Two studies from our laboratory have provided contradictory evidence, with either no change in lactate transport into muscles that had been electrically stimulated for 30 min (41), or a small increase in lactate uptake (+10%) after treadmill exercise (7). In each case lactate transport measurements were delayed about 20–30 min after muscle contractions had ceased, because of the time needed to prepare the muscles for transport measurements. Whether lactate transport is altered during exercise remains to be determined. This will require studies with isolated muscles in vitro and the use of a nonmetabolizable lactate analog, which remains to be developed.

Department of Kinesiology, University of Waterloo, Waterloo, Ontario N2 L 3G1, CANADA

Submitted for publication December 1998.

Accepted for publication December 1998.

Address for correspondence: A. Bonen, Department of Kinesiology, University of Waterloo, Waterloo, Ontario N2 L 3G1, Canada. E-mail:

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Whereas kinetic studies were instrumental in characterizing a proton-coupled lactate transport system, specific gene products remained elusive. To this end, a number of laboratories in the early 1990s began to search for the lactate transporter in skeletal muscle (1,35,63), as well as in other tissues (48–51,53,54). Unexpectedly, and quite serendipitously, the first monocarboxylate transporter (MCT1) was cloned in 1994 (13), followed by the identification of six additional MCT isoforms (MCT2-MCT6) in the past 4 years (Table 1 and 2). The characteristics of the known MCT proteins are described below. At least two of them, MCT1 and MCT3-M/MCT4 are coexpressed in rat and human muscle (Fig. 1), whereas very recently more MCT transcripts have been found in these tissues (Table 2).

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Monocarboxylate transporter 1 (MCT1).

Garcia et al. (13) cloned the first monocarboxylate transporter (MCT1) in 1994 from a mutant allele in a line of Chinese hamster ovarian (CHO) cells. The mutant allele encoded a protein that transported mevalonate (Mev) an intermediate in cholesterol synthesis. On searching for the origin of Mev, they found that the Mev wild-type gene coded for a monocarboxylate transporter (MCT1), which was kinetically similar to the erythrocyte lactate transporter (13). Independently, Jackson et al. (19) have cloned MCT1 from rat skeletal muscle. MCT1 has also been cloned from rat intestine (60). Poole and Halestrap (52) have analyzed the N-terminal sequence of the rabbit erythrocyte lactate transporter and confirmed its identity with MCT1. The amino-acid sequence identities of these MCT1 transporters are quite high (Table 1). The homology among the proteins was significantly higher in the transmembrane domains than in the intervening regions (60). Importantly, when expressed in Xenopus laevis oocytes, the rat MCT1 caused a significant increase in lactate uptake, and MCT1 was found to be a stereo-selective, proton-coupled lactate transporter (60). MCT1 is ubiquitously expressed in many human, rat, and hamster tissues (Table 2), including skeletal muscle and the heart (Fig. 1).

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Monocarboxylate transporter 2 (MCT2).

In 1995, another monocarboxylate transporter isoform, MCT2, was cloned from hamster liver (12). Somewhat later, MCT2 was also cloned from rat testis (20). Compared with MCT1 (12), the kinetic characteristics for lactate transport were very similar between MCT1 and MCT 2 when expressed in Sf9 cells, but the kinetics differed considerably for pyruvate transport (Table 3). Both isoforms exhibit pH sensitivity (12). However, the role of MCT2 is not clear, because its tissue distribution in rat and hamster is quite different (Table 2). In hamsters MCT2 mRNA is present in brain, liver, testis, heart, and skeletal muscle, whereas in the rat it is present in brain, liver, and testis, but not in heart or muscle (20). Similarly, we can detect the MCT2 protein and MCT2 mRNA in great abundance in the rat liver, but we cannot detect MCT2 protein or MCT2 mRNA in rat heart or rat skeletal muscle. Thus, MCT2 is likely not a lactate transporter in heart or skeletal muscle, at least in the rat. Finally, a recent report has shown that MCT2 mRNA is not detected in a wide range of human tissues that were examined (56). If correct, this further suggests considerable species specificity of MCT isoform distribution (Table 2).

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Monocarboxylate transporter 3 (MCT3).

Two groups have independently cloned another MCT, both groups have designated this to be MCT3 (56,65). Unfortunately, the MCT3 cloned from chick retinal pigment epithelium and the newly cloned MCT3 from muscle (56) share the same designation, but they are in fact different monocarboxylate transporter proteins (56,64,65). However, a new nomenclature for MCT proteins is to be used in the future to recognize that the retinal pigment epithelium MCT3 was cloned before the muscle MCT3 (64) (see also the footnote regarding the change in the nomenclature of MCT proteins in ref. (64)). The new nomenclature is being used in the present paper with cross-referencing to the older terminology. Thus, the muscle MCT3 is designated below as MCT3-M/MCT4 to facilitate the transition in terminology, whereas the retinal pigment epithelium transporter is designated as MCT3.

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The retinal pigment epithelium of the eye expresses MCT3 (65). It has a 43% and 45% amino-acid sequence identity with MCT1 and MCT2, respectively (65) (Table 1A). Notably, MCT3 appears to be highly specialized. It is expressed only on the basal membrane of the chick (65) and rat (44) retinal pigment epithelium (Table 2). MCT3 contains multiple, potential phosphorylation sites (i.e., a) six potential sites for protein kinase C phosphorylation (four in the long cytoplasmic loop, two in the carboxy terminus); b) one potential site for cAMP/cGMP-dependent phosphorylation; and c) three possible sites for casein kinase II phosphorylation). MCT3 is not present in other tissues (muscle, heart, brain, kidney, liver, intestine) that have been examined to date (Table 2) either in chicks (65) or rodents (44).

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Halestrap and colleagues have recently cloned MCT3-M/MCT4 (56). MCT3-M/MCT4 and MCT1 transcripts are found in both human and rat muscle, and in human heart (64). Whereas the MCT3-M/MCT4 and MCT1 proteins are both readily detectable in skeletal muscle (Fig. 1), and the MCT1 protein is most abundant in the heart, the MCT3-M/MCT4 protein in heart is difficult to observe, possibly indicating that it is not expressed. Further, MCT3-M/MCT4 is much more abundantly expressed in fast-twitch oxidative and fast-twitch glycolytic muscles than in slow-twitch oxidative muscles (Fig. 1). Among rat hindlimb muscles, the content of MCT3-M/MCT4 is similar in muscles rich in Type IIa and/or Type IIb fibers, whereas the MCT3-M/MCT4 content in the soleus muscle, which consists primarily of Type I fibers, is very low (Figs. 1 and 2). Thus, MCT3-M/MCT4 content among rat muscles does not scale with the oxidative capacity of muscles, as we have observed for MCT1 (see Fig. 2). The abundance of MCT3-M/MCT4 in muscles rich in Type IIa and/or Type IIb fibers, and its lower abundance in muscles with Type I fibers suggests that MCT3-M/MCT4 may serve to transport lactate out of the tissue, as we have recently proposed (64).

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Additional monocarboxylate transporters (MCT5, MCT6, MCT7).

Three additional monocarboxylate transporters have also been cloned by Halestrap’s group (56). Using the recently revised nomenclature, these should now be designated as MCT5, MCT6, and MCT7 (instead of MCT4, MCT5, and MCT6 as these appeared in the original publication (56)). Transcripts of these monocarboxylate transporters are present in a number of tissues (Table 2). Among selected human tissues (muscle, heart, and liver), MCT5 transcripts are present only in the heart, whereas MCT6 transcripts are present in both muscle and heart, but not in the liver. And finally, MCT7 transcripts are present only in the heart. The significance of these distributions remains unclear. Whether the protein product is expressed in all these tissues has not yet been determined.

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Commentary on monocarboxylate transporters.

In the past 4 years, a family of seven MCT transporters have been identified (MCT1–MCT7). All of these transporters exhibit the characteristic 10–12 membrane-spanning helices (12,14,19,20,56,60,65) that are also found with glucose transporters (cf. (4)). However, unlike the GLUT family isoforms that exhibit considerable tissue specificity and limited coexpression within tissue, it appears that many MCT isoforms are present in the same tissue (Table 2). This will make the identification of their functional roles very difficult. Furthermore, there are already indications that the tissue distribution and/or presence of selected MCT isoforms may also be species specific as there are some differences in MCT2 distribution in rat and hamster, and apparently there is no MCT2 in humans (Table 2). It has been speculated that the individual MCT proteins may have different specificities for different monocarboxylates, or function to either import or export specifically selected monocarboxylates (56). Alternatively, the different isoforms may favor different cotransport cations (e.g., Na+ as opposed to H+, possibly in kidney where MCT5 is prevalent and there is an active Na+-linked monocarboxylate system) (56). Finally, until the functions of the various MCT proteins are delineated, we may also have to consider that these MCT proteins may be able to transport unrelated molecules that share a similar transport mechanism to that of monocarboxylates (56).

The apparent and unsuspected complexity of the MCT family indicates that there will be a considerable amount of work required to elucidate the functions and regulation of the MCT family members. Because of their involvement in lactate transport, the roles and regulation of MCT1, MCT2, and MCT3-M/MCT4 in metabolically important tissues, such as muscle, heart, and liver, may be of considerable interest to exercise physiologists. We have begun studies to explore the roles of MCT1 (3,38,39), MCT2, and MCT3-M/MCT4 in a number tissues, ranging from mammalian tissues (including humans) to Xenopus laevis oocytes (Bonen et al., in progress).

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Except for the observation that MCT1 appeared to be present only in oxidative skeletal muscles (13), nothing further was known a) about the expression of MCT1 among rat hindlimb muscles with varied muscle fiber composition, and b) whether MCT1 expression in this tissue was related to the rate of lactate movement across the sarcolemma. Therefore, we initiated studies to elucidate the role of MCT1 in heart and in muscle.

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Muscle fiber composition, MCT1 expression, and lactate uptake in rat hindlimb muscles.

In our first study, we examined the relationship a) between muscle fiber composition and MCT1 expression (39) and b) between MCT1 expression and lactate movement across the sarcolemma (38,39). These studies showed that there was a high correlation between MCT1 and the oxidative capacity of a muscle, whether this comparison was based on muscle fiber type composition or citrate synthase activities in the various muscles (Fig. 2, A and B). A good relationship was also observed between MCT1 and H-LDH in muscles (39) (Fig. 3). Collectively, these results could be interpreted to suggested that the expression of MCT1 in rat muscles was organized so as to take up lactate from the circulation, thereby facilitating the oxidation of lactate by more highly oxidative types of muscle fibers (see paper by Donovan in this symposium).

If this supposition was correct, then the uptake of lactate by different muscles should be positively correlated with their different MCT1 content. To obtain such estimates of lactate transport in a variety of rat muscles we perfused rat hindlimb muscles with lactate for a brief period of time (5 min), sufficient to equilibrate lactate but short enough to minimize its oxidation. Thus, the tissue lactate accumulation provided an index of lactate transport. The results showed a good correlation between lactate uptake and MCT1 expression in rat muscles (Fig. 4).

This, however, does not mean that we believe that the only function of MCT1 is to import lactate unidirectionally into muscle, as has been incorrectly attributed to us (24). Indeed, it is known that MCT1 functions to extrude lactate from mouse Ehrlich-Lettre tumor cells (9) that produce vast quantities of lactate. Presumably, MCT1 can also function to extrude lactate out of muscle, because transmembrane lactate movement is largely driven by the concentration gradient across the sarcolemma. However, we believe that the greater concentration of MCT1 in more oxidative muscle fibers suggests strongly that a key physiological role of MCT1 is to take up lactate from the circulation, because oxidative muscles are well suited to oxidize lactate (see paper by Donovan in this symposium). This physiological role is dictated by the quantity of MCT1 in oxidative muscles and does not require any assumptions about the possible asymmetry of MCT1’s transport capacity. Although an asymmetric transport capacity might exist, there is at present no evidence for it.

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Increasing MCT1 increases muscle lactate influx and efflux.

To further examine the role of MCT1, we attempted to increase the expression of the transporter by increasing muscle activity, a well-known means for increasing gene expression. For these purposes, we used two different approaches, chronic electrical stimulation, and exercise training.

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Chronic electrical stimulation.

In these studies, we implanted electrodes next to the peroneal nerve and exited these wires to a battery pack (approx. 5 g) worn by freely moving rats. After a 1-wk recovery from surgery the red (RTA) and white (WTA) compartments of the tibialis anterior (TA) and extensor digitorum muscle (EDL) muscles were chronically stimulated 24 h·d1 for seven days. This type of stimulation is known to increase the muscles’ oxidative capacities without altering muscle fiber composition (38,39). The contralateral, unstimulated muscles served as control muscles. At the end of the 7-d experimental period, the experimental and control muscles were perfused with lactate and they were also examined for MCT1 content. In chronically stimulated RTA, WTA, and EDL, the MCT1 content was markedly increased (1.5- to 3.0-fold increase) (Fig. 5). Concomitantly, lactate uptake in the experimental muscles was also increased (Fig. 5). There was in fact a very high correlation between MCT1 and lactate uptake when the data from control and experimental muscles were plotted (Fig. 6). The fact that the data fell on the same linear regression line suggests that lactate uptake by muscle is increased in parallel with MCT1. If there are other MCT proteins that assist MCT1 in this function, it is not evident from our studies, because in such instances a deviation from linearity would have been expected. This was not observed.

In similar studies in which we chronically stimulated rat muscles, it was possible to demonstrate that an increase in lactate efflux from giant vesicles also occurred (37) (Fig. 7). Because MCT1 is an ATP-independent transporter, it would be expected to facilitate lactate influx or lactate efflux, depending on the lactate concentration gradient across the sarcolemmal membrane. Thus, we can only surmise that in chronically stimulated muscles a) the increase in MCT1 facilitated the increased lactate extrusion out of the muscle (37) and b) the increase in MCT1 also facilitated lactate uptake by muscle (38), with the lactate concentration gradient dictating the net rate of flux.

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Effects of training on MCT1 and lactate movement in rats and humans.

Exercise training provides a more physiological situation than chronic muscle stimulation. Therefore, we trained animals with moderate (21 m·min1, 8% grade) or intense exercise (31 m·min1, 15% grade). This led to several unexpected observations. At the moderate running speeds, we failed to observe any changes in MCT1 in skeletal muscles (soleus, red and white gastrocnemius, EDL) over a 3-wk period (3) (Fig. 8). But, with more intense training, MCT1 did increase, but only in the soleus and red gastrocnemius, not in the EDL and white gastrocnemius muscles (Fig. 8) In these studies, we also found that lactate uptake by the muscle (isolated soleus preparation) was increased only when MCT1 was increased (Fig. 9). Thus, it seems that the enhanced ability to take up lactate by trained muscles is due to an increase in the MCT1 transporter.

We have also recently observed, in young men, that short-term exercise training (2 h·d1, 7 d at 65% V̇O2max) increased MCT1 (8). Although it was not possible to measure lactate movement into or out of muscle directly, we did attempt to estimate this indirectly, by comparing the relationship between muscle and femoral-venous lactate during progressively increased exercise before and after training. We observed that the femoral venous lactate concentrations were increased for a given amount of muscle lactate (8). This suggests that trained muscles, in which MCT1 is increased, have an increased ability to extrude lactate. This supports our observations in chronically stimulated rat muscles, in which transmembrane lactate movement (i.e., influx and efflux) is increased when MCT1 is increased without an increase in MCT3-M/MCT4 (6,37,38).

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MCT1 protein concentration is another factor that contributes to the reduced lactate concentrations in muscle.

Interestingly, our observations (3,8,38,39) identify an additional factor that contributes to the lower concentrations of lactate observed during exercise a) in more oxidative types of muscles and b) in trained muscles. Until now, it has been recognized that the reduced lactate accumulation in oxidative or aerobically trained muscles during muscle contraction is due to a reduced rate of glycogenolysis (11) and an increased capacity for pyruvate oxidation (18). However, the greater ability to extrude lactate from more oxidative types of muscles (29), from trained (47), and from chronically stimulated muscles (37) is associated with greater quantities of MCT1 in such muscles (3,38,39). Thus, it is proposed that the increased MCT1 concentration (and possibly other as yet undiscovered MCT proteins) in muscle can contribute to reducing intramuscular lactate concentrations during exercise by facilitating the extrusion of lactate out of muscle in relation to the available MCT1, and possibly other MCT proteins.

The ability to take up lactate more readily and to extrude lactate more readily in oxidative or in trained muscles are not in conflict. An enhanced uptake capacity of lactate is particularly useful to clear lactate from the circulation after exercise. This can in fact contribute to the restitution of muscle glycogen, as increasing oxidation of lactate diverts glucose to glycogen formation (A. Bonen, unpublished data). Conversely, an increased ability to extrude lactate from the muscle cell into the blood is particularly advantageous during exercise to minimize perturbations in pHi (intracellular pH).

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Two recent studies have examined the MCT isoform-specific responses to reduced and increased muscle activity. After 3 d of denervation, the concentrations of MCT1 and MCT3-M/MCT4 proteins were reduced in red and white muscles by 10–20%. This reduction was increased to ∼50% after 3 wk of denervation (Fig. 10) (64). In contrast, 7 d of chronic muscle stimulation increased MCT1 but failed to alter the content of MCT3-M/MCT4 (Fig. 10) (6). Thus, there is some evidence that the MCT isoforms may be regulated independently in skeletal muscle.

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It is well known that lactate can be readily oxidized by the working heart. MCT1 has been shown to be present in the heart, where it is abundantly expressed. The heart contains 2–3 times more MCT1 than the most oxidative skeletal muscle (3,39). Recently, a number of additional other MCT transcripts have been found in human hearts (56) (Table 2).

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Importance of a monocarboxylate transporter in the heart, and the subcellular distribution of MCT1.

Recently, it has been shown that the proton-coupled lactate transport system is the major route for the extrusion of H+ out of the heart, being quantitatively more important than the Na+/H+ exchanger (33,61), which is also known to assist with the extrusion of H+ (43,45). Because La and H+ are cotransported, it would seem that the rates of extrusion of La, and therefore H+, could be correlated with the available number of monocarboxylate carriers and/or their activity. This may be particularly important after an ischemic episode, when it is important to re-normalize the pHi as rapidly as possible to minimize injury to the heart (33).

Interestingly, kinetic studies using the fluorescent probe BCECF (2′,7′-bis(carboxyl)-5-(6)-carboxyfluorescein) sug-gest that La transport was asymmetric in rat cardiomyocytes (62). At 23°C, the Km and Vmax of lactate efflux were three fold higher than for influx. These data could suggest that there is one monocarboxylate transporter with asymmetric transport characteristics. But, there was also a DBDS (4,4′-dibenzamidostilbene-2,2′-disulfonate)-sensitive and DBDS-insensitive transport component in the cardiac myocytes (62), which suggested that there are separate monocarboxylate transporters. Because of the three fold difference in lactate efflux compared to influx, it also seems that the different transporters may have different characteristics facilitating the efflux or influx of La at different rates. Alternatively, a more rapid lactate efflux could also be attributable to the translocation of an MCT to enhance lactate efflux at a time of great need, such as during or after ischemic episodes. These considerations prompted us to examine a) the subcellular distribution of a recently cloned MCT transporter (MCT1) in the heart, in order to gain some insight into its physiological role, and b) to determine whether MCT1 expression could be increased with exercise training, to increase the rate of proton-coupled lactate transport.

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Subcellular distribution of MCT1 in the heart.

By using high-resolution, immunogold immunocytochemistry, we were able to observe the MCT1 transporters at various sites in the heart (21) (Table 4). Interestingly, this revealed levels of MCT1 subdomains along the plasma membrane.

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MCT1 along cardiac myocyte membrane.

MCT1 was found along the plasma membrane, where myocytes appose capillaries and other myocytes (Table 4). The highest densities of MCT1 occurred in the intercalated disks (Table 4), where they avoided desmosomes and gap junctions. MCT1 appeared to be symmetrically spaced across the sarcoplasmic membrane and particles were concentrated within 50 nm of the plasmalemma. Thus, MCT1 appears to be differentially expressed along the cardiac myocyte membrane (Table 4) avoiding gap junctions and desmosomes. This demonstrates that there are separate subdomains of the plasma membrane that may differ both biochemically and functionally.

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MCT1 in caveolae.

MCT1 was also found in plasmalemmal invaginations, i.e., in caveolae (21). It was calculated that caveolae contained 13.6% and 9% of the MCT1 present at the myocyte-myocyte and myocyte-capillary interface, respectively. This greater abundance in the myocyte-myocyte interface was largely attributable to the higher number of caveolae at these locations. However per caveolae the MCT1 content was similar (Table 4). These calculations are based on one-fourth to one-fifth of the caveolae being immunogold labeled. However, this is an underestimate of the proportion of MCT-1-containing caveolae, because the embedding procedures used makes some of the caveolae inaccessible to postembedding labeling in our studies.

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MCT1 in T-tubules.

High MCT1 concentrations also occurred in T-tubules. Although most of the labeling was associated with the T-tubules, it was not possible to distinguish whether the labeling was also associated with the adjacent sarcoplasmic reticulum (which is very closely apposed to the T-tubules), due to the spatial resolution limitations of the immunogold labeling technique. Nevertheless, the most dense MCT1 labeling occurred in T-tubules that are in close proximity to mitochondria (21). This suggests that MCT1 facilitates delivery of lactate to its site of oxidation.

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Functional significance of MCT1 subcellular distribution in the heart.

In a well-perfused myocardium, the presence of MCT1 at the intercalated disks, and in plasma membranes and T-tubules should ensure a high lactate transport capacity, i.e., net uptake such as during exercise. Additionally, MCT1 in apposing cardiac myocytes may facilitate transfer of lactate and protons between myocytes, particularly during ischemic episodes, when there is reduced or no diffusional exchange with blood. Of interest, also is the absence of MCT1 in endothelial cells in our studies (21), raising the question of how lactate is transferred across the capillary wall. It is likely that endothelial cells express another monocarboxylate transporter.

Notably, MCT1 was not associated with any internal membrane compartments. Therefore, our studies establish very clearly that the MCT1 transporter is unlikely to be translocated but that the functional capacity for lactate-proton cotransport is dependent on the number of available transporters. It is unknown whether the MCT1 in caveolae are a “reserve” supply that become available when necessary (e.g., during exercise when lactate is increased or during ischemic episodes when lactate and protons need to be extruded). Presently, it is thought that caveolae in cardiac myocytes occur predominantly in an open state (or recycle rapidly between open and closed states) (34), implying that MCT1 should be continually exposed to the interstitial fluid. However, given that caveolae are a known site for entry of ions and small molecules (2), the caveolae may well be a key site for MCT1 to facilitate proton-lactate cotransport.

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Effects of exercise training on heart MCT1 and lactate uptake.

Because exercise is well known to benefit myocardial function, it was of interest to examine whether exercise training could increase MCT1 and increase the rate of lactate movement across the cell wall. Therefore, we obtained hearts from rats in the training study above (i.e., moderate training: 21 m·min1, 8% grade; intense training: 31 m·min1, 15% grade) (3). In contrast to the lack of any change in skeletal muscle MCT1 with moderate training (Fig. 8), there was a marked and progressive increase in heart MCT1 during the 3-wk training period (Fig. 11). This was also accompanied by an increase in lactate uptake by the perfused rat heart (Fig. 9). When training was made more intense, MCT1 was increased again in the heart, but the increase was similar to that observed with the moderate training program (Fig. 11). However, heart lactate uptake was disproportionately greater than the increase in MCT1 with the more intense training program (Fig. 9). Whether this is an indication that more intense training increased another MCT isoform in the heart or whether this was associated with a more strategic placement of newly synthesized MCT1 along the plasma membrane, or intercalated disks or into caveolae is not known.

It may be of considerable practical interest that exercise training increased MCT1 in the heart at a lower training intensity than in skeletal muscle. Presumably, this increase in cardiac MCT1 may offer some beneficial protection against ischemic episodes by extruding protons and lactate more rapidly, thereby avoiding myocardial damage that may be caused by intracellular protons.

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Our work has shown that MCT1 is expressed in muscle and heart. It appears that the physiological role of MCT1 is largely to support the oxidative disposal of lactate, because 1) MCT1 is abundantly expressed in skeletal muscle oxidative fibers and the heart, 2) there is a high correlation between MCT1 and indices of muscle oxidative metabolism and lactate uptake, and 3) the increase in MCT1 is associated with a more rapid transmembrane lactate movement. However, that is not to say that MCT1 is necessarily excluded from playing a role in the efflux of lactate from the cell. This would seem to be the role of MCT1 in Ehrlich-Lettre tumor cells, and possibly in chronically stimulated muscles in which MCT1 but not MCT3-M/MCT4 has been increased. Based on studies in the heart, it appears that MCT1 translocation does not occur (preliminary studies in muscle also support this lack of translocation mechanism, A. Bonen unpublished data). Thus, the lactate flux is dependent on the number of MCT1 proteins, and possibly their strategic location along subdomains of the plasma membrane and T-tubules.

Although MCT1 is shown to be responsive to exercise training, a sufficiently high intensity of exercise is required to observe an increase in skeletal muscle MCT1. In contrast, in the heart, MCT1 is increased at a much lower training intensity than in muscle. Along with increases in MCT1 there is a concomitant increase in lactate uptake by muscle and the heart after a period of exercise training.

The very low expression of MCT1 in white muscles suggests that it is only the few oxidative fibers in these muscles that express MCT1. However, our chronic stimulation studies indicate that given a sufficient contraction stimulus, it is possible to induce MCT1 expression in white muscle fibers without altering muscle fiber composition.

MCT2 and MCT3-M/MCT4 have been found mainly in rat liver and rat fast-twitch muscles, respectively. In the soleus muscle MCT3-M/MCT4 is much less abundant. These observations suggest that MCT3-M/MCT4 may be an important transporter for the efflux of lactate. Whether this is in addition to the efflux role postulated for MCT1 above remains to be determined. Such studies are now in progress, along with studies examining the function of MCT2 in liver (A. Bonen unpublished data).

Finally, we are obviously at the threshold of a new era in understanding the regulation of lactate movement into and out of skeletal muscle, cardiac, and liver cells. The discovery of seven MCT isoforms in the past 6 years and their tissue specific expression requires us to determine the factors that regulate their expression and their physiological role in muscle and the heart, as well as in other tissues, including liver, the brain, and tumor cells. Coexpression of several MCT proteins in the same tissue will require considerable work to examine the biological reason(s) for this level of organization. Certainly, it appears that there is tissue-specific and isoform-specific regulation of these monocarboxylate transport proteins.

Studies from A. Bonen’s laboratory have been supported by grants from the Natural Sciences and Engineering Research Council of Canada and by the Heart and Stroke Foundation of Ontario grant no. NA-3572. My group gratefully acknowledges the collaborations on the MCT work with Dr. A. P. Halestrap, Department of Biochemistry, University of Bristol, Bristol, U.K.

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1. Allen, P. J., and G. A. Brooks. Partial purification and reconstitution of the sarcolemmal lactate carrier from rat skeletal muscle. Biochem. J. 303:207–212, 1994.
2. Andersen, R. G. W. Caveolae: where ingoing and outgoing messengers meet. Proc. Natl. Acad. Sci. USA 90:10909–10913, 1993.
3. Baker, S. K., K. J. A. McCullagh, and A. Bonen. Training intensity dependent and tissue specific increases in lactate uptake and MCT1 in heart and muscle. J. Appl. Physiol. 84:987–994, 1998.
4. Bell, G. I., T. Kayano, J. B. Buse, et al. Molecular biology of glucose transporters. Diabetes Care 13:198–208, 1990.
5. Bonen, A., S. K. Baker, and H. Hatta. Lactate transport and lactate transporters in skeletal muscle. Can. J. Appl. Physiol. 22:531–552, 1997.
6. Bonen, A., V. N. Jackson, K. J. A. McCullagh, and A. P. Halestrap. Effects of chronic muscle stimulation on monocarboxylate transporters (MCT1 and MCT3) in skeletal muscles (Abstract no. 59445). FASEB J. 12:A1027, 1998.
7. Bonen, A., and K. J. A. McCullagh. Effects of exercise on lactate transport into mouse skeletal muscles. Can. J. Appl. Physiol. 19:275–285, 1994.
8. Bonen, A., K. J. A. McCullagh, C. T. Putman, E. Hultman, N. L. Jones, and G. J. F. Heigenhauser. Short-term training increases human muscle MCT1 and femoral venous lactate in relation to muscle lactate. Am. J. Physiol (Endocrinol. Metab) 274:E102–E107, 1998.
9. Carpenter, L., R. C. Poole, and A. P. Halestrap. Cloning and sequencing of the monocarboxylate transporter from mouse Ehrlich-Lettre tumour cells confirms its identity as MCT1 and demonstrates that glycosylation is not required for MCT1 function. Biochim. Biophys. Acta 1279:157–163, 1996.
10. Dubouchaud, H., P. Granier, J. Mercier, C. Le Peuch, and C. Prefaut. Lactate uptake by skeletal muscle sarcolemmal vesicles decreases after 4 wk of hindlimb unweighting in rats. J. Appl. Physiol. 80:416–421, 1996.
11. Favier, R., S. Constable, M. Chen, and J. Holloszy. Endurance exercise training reduces lactate production. J. Appl. Physiol. 61:885–889, 1986.
12. Garcia, C. K., M. S. Brown, R. K. Pathak, and J. L. Goldstein. cDNA cloning of MCT2, a second monocarboxylate transporter expressed in different cells than MCT1. J. Biol Chem. 270:1843–1849, 1995.
13. Garcia, C. K., J. L. Goldstein, R. K. Pathak, G. W. Anderson, and M. S. Brown. Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: implications for the Cori cycle. Cell 76:865–873, 1994.
14. Garcia, C. K., X. Li, J. Luna, and U. Francke. cDNA cloning of the human monocarboxylate transporter 1 and chromosomal localization of the SLC16A1 Locus to 1p13.2-p12. Genomica 23:500–503, 1994.
15. Gladden, L. B. Lactate transport and exchange during exercise. In: Handbook of Physiology. Section 12: Exercise: Regulation and Integration of Multiple Systems, L. B. Rowell and J. T. Shepherd (Eds.). New York: Oxord University Press, 1996, pp. 614–648.
16. Hirche, H. H., V. Hombach, D. Langohr, U. Wacher, and J. Busse. Lactic acid permeation rate in working gastrocnemii of dogs during metabolic alkalosis and acidosis. Pfluegers Arch. 356:209–222, 1975.
17. Hirche, H. H., D. Langohr, and U. Wacher. Lactic acid permeation from skeletal muscle. Pfluegers Arch. 319:R109, 1970.
18. Holloszy, J. O., and F. W. Booth. Biochemical adaptations to endurance exercise in muscle. Ann. Rev. Physiol. 38:273–291, 1976.
19. Jackson, V. N., N. T. Price, and A. P. Halestrap. cDNA cloning of MCT1, a monocarboxylate transporter from rat skeletal muscle. Biochim. Biophys. Acta 1238:193–196, 1995.
20. Jackson, V. N., N. T. Price, and A. P. Halestrap. Cloning of the monocarboxylate transporter isoform MCT2 from rat testis provides evidence that the expression is species specific and may involve post-transcriptional regulation. Biochem. J. 324:447–453, 1997.
21. Johannsson, E., E. A. Nagelhus, K. J. A. McCullagh, et al. Cellular and subcellular expression of the monocarboxylate transporter MCT1 in rat heart: a high resolution immunogold analysis. Circ. Res. 80:400–407, 1997.
22. Jorfeldt, L., A. Juhlin-Dannfelt, and J. Karlsson. Lactate release in relation to tissue lactate in human skeletal muscle during exercise. J. Appl. Physiol. 44:350–352, 1978.
23. Juel, C. Human muscle lactate transport can be studied in sarcolemmal giant vesicles made from needle-biopsies. Acta Physiol. Scand. 142:133–134, 1991.
24. Juel, C. Lactate-proton cotransport in skeletal muscle. Physiol. Rev. 77:1–37, 1997.
25. Juel, C. Lactate/proton co-transport in skeletal muscle: regulation and importance for pH homeostasis. Acta Physiol. Scand. 156:369–374, 1996.
26. Juel, C. Muscle lactate transport studied in sarcolemmal giant vesicles. Biochim. Biophys. Acta 1065:15–20, 1991.
27. Juel, C. Regulation of cellular pH in skeletal muscle fiber types studied with sarcolemmal giant vesicles obtained from rat muscles. Biochim Biophys Acta 1265:127–132, 1995.
28. Juel, C. Symmetry and pH dependency of the lactate/proton carrier in skeletal muscle studied with rat sarcolemmal giant vesicles. Biochim. Biophys. Acta 1283:106–110, 1996.
29. Juel, C., A. Honig, and H. Pilegaard. Muscle lactate transport studied in sarcolemmal giant vesicles: dependence on fiber type and age. Acta Physiol. Scand. 143:361–365, 1991.
30. Juel, C., S. Kristiansen, H. Pilegaard, J. Wojtaszewski, and E. A. Richter. Kinetics of lactate transport in sarcolemmal giant vesicles obtained from human skeletal muscle. J. Appl. Physiol. 76:1031–1036, 1994.
31. Juel, C., and F. Wibrand. Lactate transport in isolated mouse muscles studied with a tracer technique: kinetics, stereospecificity, pH dependency, and maximal capacity. Acta Physiol. Scand. 137:33–39, 1989.
32. Karlsson, J., S. Rosell, and B. Saltin. Carbohydrate and fat metabolism in contracting canine muscle. Pfluegers Arch. 331:57–69, 1972.
33. Khandoudi, N., M. Bernard, P. Cozzone, and D. Feuvray. Mechanisms of intracellular pH regulation during post-ischemic reperfusion of diabetic rat hearts. Diabetes 44:196–202, 1995.
34. Kordylewski, L., G. E. Goings, and E. Page. Rat atrial myocyte plasmalemmal caveolae in situ: reversible experimental increases in caveolar size and in surface density of caveolar necks. Circ. Res. 73:135–146, 1993.
35. McCullagh, K. J. A., and A. Bonen. L(+)-lactate binding to a protein in rat skeletal muscle plasma membranes. Can. J. Appl. Physiol. 20:112–124, 1995.
36. McCullagh, K. J. A., and A. Bonen. Reduced lactate transport in denervated rat skeletal muscle. Am. J. Physiol. (Reg. Int. Comp. Physiol.) 268:R884–R888, 1995.
37. McCullagh, K. J. A., C. Juel, M. O’Brien, and A. Bonen. Chronic muscle stimulation increases lactate transport in rat skeletal muscle. Mol. Cell. Biochem. 156:51–57, 1996.
38. McCullagh, K. J. A., R. C. Poole, A. P. Halestrap, M. O’Brien, and A. Bonen. Chronic electrical stimulation increases MCT1 and lactate uptake in red and white skeletal muscle. Am. J. Physiol. (Endocrinol. Metab.) 273:E239–E246, 1997.
39. McCullagh, K. J. A., R. C. Poole, A. P. Halestrap, M. O’Brien, and A. Bonen. Role of the lactate transporter (MCT1) in skeletal muscles. Am. J. Physiol. (Endocrinol. Metab.) 271:E143–E150, 1996.
40. McDermott, J. C., and A. Bonen. Endurance training increases skeletal muscle lactate transport. Acta Physiol. Scand. 147:323–327, 1993.
41. McDermott, J. C., and A. Bonen. Lactate transport by skeletal muscle sarcolemmal vesicles. Mol. Cell. Biochem. 122:113–121, 1993.
42. McDermott, J. C., and A. Bonen. Lactate transport in rat sarcolemmal vesicles and intact skeletal muscle, and after muscle contraction. Acta Physiol. Scand. 151:17–28, 1994.
43. Meng, H.-P., and G. N. Pierce. Protective effects of 5-(N,N-dimethyl) amiloride on ischemia-reperfusion injury in hearts. Am. J. Physiol. (Heart Circ. Physiol. ) 258:H1615–H1619, 1990.
44. Philp, N. J., H. Yoon, and E. F. Grollman. Monocarboxylate transporter MCT1 is located in the apical membrane and MCT3 in the basal membrane of rat RPE. Am. J. Physiol. (Regul., Integr. Comp. Physiol. ) 274:R1824–R1828, 1998.
45. Pierce, G. N., R. B., N. S. Dhalla, and R. Ferrari. Na+-H+ exchange in cardiac sarcolemmal vesicles isolated from diabetic hearts. Am. J. Physiol. (Heart Circ. Physiol.) 258:H255–H261, 1990.
46. Pilegaard, H., and C. Juel. Lactate transport studied in sarcolemmal giant vesicles from rat skeletal muscle: effects of denervation. Am. J. Physiol. (Endocrinol. Metab.) 269:E679–E682, 1995.
47. Pilegaard, H., C. Juel, and F. Wibrand. Lactate transport studied in sarcolemmal giant vesicles from rats: effects of training. Am. J. Physiol. 264 (Endocrinol. Metab.):E156–E160, 1993.
48. Poole, R. C., S. L. Cranmer, A. P. Halestrap, and A. J. Levi. Substrate and inhibitor specificity of monocarboxyolate transport into heart cells and erythrocytes. Biochem. J. 269:827–829, 1990.
49. Poole, R. C., S. L. Cranmer, D. W. Holdup, and A. P. Halestrap. Inhibition of L-lactate transport and band 3-mediated anion transport in erythrocytes by the novel stilbenedisulphonate N,N,N′,N′-tetrabenzyl-4,4′-diaminostilbene-2,2′-disulphonate. Biochim. Biophys. Acta 1070:69–76, 1991.
50. Poole, R. C., and A. P. Halestrap. Identification and purification of the erythrocyte lactate transporter. Biochem. J. 283:855–862, 1992.
51. Poole, R. C., and A. P. Halestrap. Inhibition and labelling of the erythrocyte lactate transporter by stilbene disulphonates. Biochem. Soc. Trans. 18:1245–1246, 1990.
52. Poole, R. C., and A. P. Halestrap. N-terminal protein sequence analysis of the rabbit erythrocyte lactate transporter suggests identity with the cloned monocarboxylate transport protein MCT1. Biochem. J. 303:755–759, 1994.
53. Poole, R. C., and A. P. Halestrap. Reconstitution of the L-lactate carrier from rat and rabbit erythrocyte plasma membranes. Biochem. J. 254:385–390, 1988.
54. Poole, R. C., and A. P. Halestrap. Reversible and irreversible inhibition by stilbenedisulfonates of lactate transport into rat erythrocytes: identification of some new high-affinity inhibitors. Biochem. J. 275:307–312, 1991.
55. Poole, R. C., and A. P. Halestrap. Transport of lactate and other monocarboxylates across mammalian plasma membranes. Am. J. Physiol. 264 (Cell Physiol.):C761–C782, 1993.
56. Price, N. T., V. N. Jackson, and A. P. Halestrap. Cloning and sequencing of four new mammalian monocarboxylate transporter (MCT) homologues confirms the existence of a transporter family with an ancient past. Biochem. J. 329:321–328, 1998.
57. Roth, D. A. The sarcolemmal lactate transporter: transmembrane determinants of lactate flux. Med. Sci. Sports Exerc. 23:925–934, 1991.
58. Roth, D. A., and G. A. Brooks. Lactate and pyruvate transport is dominated by a pH gradient-sensitive carrier in rat skeletal muscle sarcolemmal vesicles. Arch. Biochem. Biophys. 279:386–394, 1990.
59. Roth, D. A., and G. A. Brooks. Lactate transport is mediated by a membrane-bound carrier in rat skeletal muscle sarcolemmal membranes. Arch. Biochem. Biophys. 279:377–385, 1990.
60. Takanaga, H., I. Tamai, S. Inaba, Y. Sai, H. Higashida, H. Yamamoto, and A. Tsuji. cDNA cloning and functional characterization of rat intestinal monocarboxylate transporter. Biochem. Biophys. Res. Commun. 217:370–377, 1995.
61. Vandenberg, J. I., J. C. Metcalfe, and A. A. Grace. Mechanisms of pHi recovery after global ischemia in the perfused heart. Circ. Res. 72:993–1003, 1993.
62. Wang, X., A. J. Levi, and A. P. Halestrap. Kinetics of the sarcolemmal lactate carrier in single heart cells using BCECF to measure pHi. Am. J. Physiol. (Heart Circ. Physiol.) 267:H1759–H1769, 1994.
63. Wibrand, F., and C. Juel. Reconstitution of the lactate carrier from rat skeletal muscle sarcolemma. Biochem. J. 299:533–537, 1994.
64. Wilson, M. C., V. N. Jackson, C. Hedle, N. T. Price, et al. Lactic acid efflux from white skeletal muscle is catalyzed by the monocarboxylate transporter MCT3. J. Biol. Chem. 273:15920–15926, 1998.
65. Yoon, H., A. Fanelli, E. F. Grollman, and N. J. Philp. Identification of a unique monocarboxylate transporter (MCT3) in retinal pigment epithelium. Biochem. Biophys. Res. Commun. 234:90–94, 1997.
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