Lactic Acid Efflux from White Skeletal Muscle Is Catalyzed by the Monocarboxylate Transporter Isoform MCT3

Marieangela C Wilson,Vicky N Jackson,Catherine Heddle,Nigel T Price,Henriette Pilegaard,Carsten Juel,Arend Bonen,Ian Montgomery,Otto F Hutter,Andrew P Halestrap

doi:10.1074/jbc.273.26.15920

Abstract

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.

Highlights

The newly cloned proton-linked monocarboxylate transporter MCT3 was shown by Western blotting and immunofluorescence confocal microscopy to be expressed in all muscle fibers
We found that mRNA for one of these isoforms is present in large amounts in skeletal muscle, and we termed this isoform MCT3 because of its close homology to chicken MCT3, an MCT isoform found exclusively in the chicken retinal epithelium [19, 20]
MCT3 Is a Major Route for Lactic Acid Efflux from White Skeletal Muscle and Other Cells—The correlation of MCT1 expression with the oxidative capacity of skeletal muscle fibers and its low levels in fast-twitch glycolytic fibers has led us to propose that this MCT isoform is important for the transport of lactic acid into muscle fibers for use as a respiratory fuel [3, 4]. This implies that another MCT isoform must be responsible for lactic acid efflux from fibers that are primarily glycolytic and express little MCT1

Summary

Introduction

The newly cloned proton-linked monocarboxylate transporter MCT3 was shown by Western blotting and immunofluorescence confocal microscopy to be expressed in all muscle fibers. 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). 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. We use antipeptide antibodies to confirm that mammalian MCT3 protein is strongly expressed in skeletal muscle and in several other

Methods

Results

Conclusion