The newly cloned proton-linked monocarboxylate transporter MCT3 was shown by Western blotting and immunofluorescence confocal microscopy to be expressed in all muscle fibers. In contrast, MCT1 is expressed most abundantly in oxidative fibers but is almost totally absent in fast-twitch glycolytic fibers. Thus MCT3 appears to be the major MCT isoform responsible for efflux of glycolytically derived lactic acid from white skeletal muscle. MCT3 is also expressed in several other tissues requiring rapid lactic acid efflux. The expression of both MCT3 and MCT1 was decreased by 40 -60% 3 weeks after denervation of rat hind limb muscles, whereas chronic stimulation of the muscles for 7 days increased expression of MCT1 2-3-fold but had no effect on MCT3 expression. The kinetics and substrate and inhibitor specificities of monocarboxylate transport into cell lines expressing only MCT3 or MCT1 have been determined. Differences in the properties of MCT1 and MCT3 are relatively modest, suggesting that the significance of the two isoforms may be related to their regulation rather than their intrinsic properties.Lactic acid is both a major fuel for skeletal muscle ("red" oxidative fibers) and a major metabolic end product ("white" glycolytic muscles). Even oxidative fibers become net lactic acid exporters when oxygen supply cannot meet demand, and glycolysis is stimulated to maintain ATP supplies. Fatigue occurs when lactic acid builds up within the myocyte. This causes intracellular pH (pH i ) to drop, inhibiting both glycolysis and contractile activity (1, 2). In the extreme case further muscle activity is totally prevented, a phenomenon used to advantage by anglers "playing" their fish to exhaustion. The transport of lactic acid out of skeletal muscle fibers is essential if such intracellular accumulation of lactic acid is to be prevented.Better removal of lactic acid from the muscle fibers might improve athletic performance during intense exercise and enable better muscle function and subsequent recovery under pathological conditions such as inherited mitochondrial diseases, hypoxia, and reperfusion following a period of ischemia.Transport of lactic acid into skeletal muscle fibers for oxidation is thought to be mediated by the proton-linked monocarboxylate transporter (MCT) 1 isoform MCT1 whose expression correlates with the oxidative capacity of muscle fibers and is increased following chronic muscle stimulation (3, 4). However, sarcolemmal membranes of muscle fibers that are primarily glycolytic do not contain significant amounts of MCT1 yet transport lactic acid by means of a saturable carrier that is inhibited by known inhibitors of MCT1 (3,5,6). These data imply the presence of another MCT isoform in such glycolytic fibers. MCT kinetics in heart (7-9) and liver (10) cells also imply the existence of other MCT isoforms, and this conclusion has been confirmed by cloning and sequencing studies.The first MCT isoform (MCT1) was cloned from Chinese hamster ovary cells (11) and has since been cloned and sequenced from huma...

SUMMARY1. The effect of changes in the pH of the extracellular solution on the membrane conductance of frog sartorius and toe muscle fibres was measured with intracellular micro-electrodes.2. In Ringer solution the membrane conductance was found to be highly sensitive to changes in pH between 5 0 and 9 8. In alkaline solution the conductance rose; in acid solution it fell. 3. After replacement of chloride by the relatively impermeant methylsulphate ion the membrane conductance showed little change when pH was altered. It is concluded that chloride is the ion species principally concerned in the pH sensitivity of the resting membrane conductance.4. The relation between pH and the chloride conductance was sigmoid, with the steepest part of the curve lying in the region of neutrality.5. The membrane conductance of muscles equilibrated in a 100 mm-K 216 mM-Cl solution was also sensitive to changes of extracellular pH. As in Ringer solution, the membrane conductance rose in alkaline and fell in acid solutions in a sigmoid fashion.6. Sartorius muscles in isotonic potassium methylsulphate solution showed no change in membrane conductance at different pH values.7. In chloride-free solution a fall in pH tended to cause depolarization; a rise in pH had the opposite effect.8. In Ringer solution the initial effect of a rise in pH was usually a transient depolarization. The indication is that the intracellular concentration of chloride ions may be slightly in excess of that which corresponds to the resting potential. The long-term effects of changes in pH on the membrane potential in Ringer solution were in the same direction as in the absence of chloride.9. The transient potential changes produced on addition and withdrawal of -chloride ions were found to be larger in alkaline solutions than in acid solutions. This is further evidence for a higher chloride permeability in alkaline solutions.

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