Subsequently, trans-stimulation (-acceleration) of lactate transport by sarcolemmal vesicles was demonstrated by Brown and Brooks (22). The latter result is significant as it indicates that the transporter is bi-directional, that is, transporters can facilitate lactate flux along concentration and proton gradients, either into or out of muscle cells. Importantly, results of Brooks and associates were soon replicated by others on rodent (73) and human tissue preparations (64).
The field of study of cell membrane lactate transport proteins received a tremendous boost when, in extending their earlier work on the mevalonate (Mev) transporter (66) with Chinese hamster ovary (CHO) cells, Garcia et al. (39) cloned and sequenced a monocarboxylate transporter, which they termed MCT1. MCT1 differed from Mev by only one amino acid substitution (Cys for Phe), and the amino acid structures of MCT1 and MEV predicted a membrane-bound protein with 12 membrane-spanning regions. Transfection of a breast cancer cell line lacking MCT1 with a plasmid containing cDNA encoding for MCT1 conferred properties reported for the erythrocyte transporter including increased pyruvate uptake, proton symport, trans-stimulation, partial inhibition by other monocarboxylates (including lactate), and sensitivity to CIN. With an interest to describe a role for MCT isoforms in the Cori cycle, Garcia et al. (38,40) subsequently described isolation of a second isoform (MCT2) by screening of a Syrian hamster liver library; MCT2 was found in liver and testes.
Notwithstanding that little is published on regulation of MCT expression in diverse tissues, it is probable that expression can be affected by chronic activity level. For example, with studies on sarcolemmal vesicles isolated from rat hind limb skeletal muscles of tail-suspended and control rats, Dubouchaud et al. (32) observed inactivity to decrease lactate transport activity. Conversely, working with an antibody to MCT1, McCullagh et al. (72) observed that chronic electrical stimulation increased MCT1 content in red and white rat skeletal muscles.
Although the level of physical activity can affect long-term expression of sarcolemmal lactate transporters (32,72), they are apparently not translocated as the result of acute bouts of muscle contraction (31a). Further, there are no known phosphorylation sites on MCT isoforms, and, other than H+, there are no known allosteric binding agents to MCT isoforms. Thus, rates of lactate flux, which can change 100-fold in working mammalian muscle, are not likely to be regulated over the short term by translocation or synthesis of cell membrane MCT proteins. Consistent with predictions of the classic cell-cell lactate shuttle (Fig. 1), tracer studies of glucose (36) and lactate (16) fluxes in resting and exercising humans show that the most lactate is removed through oxidation in skeletal and cardiac muscle cells with high mitochondrial densities. Further, much of the remainder is removed through gluconeogenesis, a process requiring mitochondrial function in the liver and kidneys. Thus, rather than by recruitment or activation of sarcolemmal lactate transport proteins (i.e., MCTs), lactate clearance is most likely controlled by mitochondrial uptake and oxidation in vivo.
At present, the progress in elaborating and understanding the various facets of the “lactate shuttle hypothesis” (Fig. 1) is so rapid that new results are appearing before previous results are widely appreciated. With current data, it is clear that lactate plays a key role in the distribution of carbohydrate potential energy between muscle and other cells. The role of lactate in serving as a gluconeogenic precursor dates to work of Cori (26). More recent interest has been on the role of lactate as a precursor in the synthesis of liver glycogen (35) and a fuel for muscle contraction (11,12). In general, cell-cell lactate flux appears to occur by means of facilitated exchange along pH and concentration gradients involving a family of lactate transport proteins (78,86,87), now called MCTs (38,39,105). Current emphasis is on cell membrane monocarboxylate transporters, but mitochondrial forms likely exist as well. For this reason, the “lactate shuttle” hypothesis has been modified to include a new, intracellular component involving mitochondrial lactate transporters and dehydrogenases (13) (Fig. 8). Indeed, if borne out by results of studies now in progress, the hypothesis of an intracellular lactate shuttle may likely lead to new understanding of the interrelationships among glycolytic and oxidative metabolism.
This work was supported by NIH grants DK19577 and AR42906.
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Chair: L. Bruce Gladden