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.