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.
In addition to current evidence supporting presence of mitochondrial MCT isoforms, there exists solid evidence for an intra-mitochondrial pool of lactic dehydrogenase (mLDH). This mLDH pool, rather than cytosolic LDH, is essential in mitochondrial lactate uptake and oxidation. Depending on the tissue, this mitochondrial mLDH pool is distinct in isoenzyme pattern from that in the cytosol, and mLDH appears to consist mainly of the heart (H4, LDH-1) isoform (3,8,13,14). Location of mLDH may include the periplasmic space (8,13), or the matrix as well (3,14). Moreover, the oxidation of lactate by isolated rat heart, liver, or skeletal muscle mitochondria is oxamate sensitive, oxamate being a known inhibitor of LDH (14).
Given the presence of mMCT and mLDH, it is not surprising that isolated mitochondria consume and oxidize lactate at a rate equal to or greater than that of pyruvate (8,13a,14). Similarly, it is not surprising that data obtained with 13C-NMR spectroscopy and injection of 13C-lactate into working dog coronary circulation indicate uptake and oxidation of the tracer without labeling of the cytosolic pyruvate pool (68).
At the tissue and organism levels, the model of an “intracellular lactate shuttle” (Fig. 8) (13) makes seemingly divergent observations consistent. For instance, the model takes advantage of the finding (Fig. 6) that the Vmax and Km of sarcolemmal lactate transport are very high (86) and that trans-stimulation is a characteristic of sarcolemmal lactate transport (22). Thus, the sarcolemmal MCT population can hardly be predicted to limit or control lactate release, uptake, or oxidation under most conditions. Despite current emphasis on discovery of sarcolemmal lactate transport (MCT) isoforms (60), it needs to be remembered that lactate removal is accomplished mainly through oxidation within mitochondria of active, well-oxygenated red muscle and heart. Thus, mitochondrial respiration, not cell membrane lactate transport, reemerges as the key step in control of lactate homeostasis.
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.
1. Ahlborg, G. Mechanism of glycogenolysis in nonexercising human muscle during and after exercise. Am. J. Physiol. 248:E540–E545, 1985.
2. Allen, P. J., and G. A. Brooks. Partial purification and reconstitution of the sarcolemmal L-lactate carrier from rat skeletal muscle. Biochem. J. 303:207–212, 1994.
3. Baba, N., and H. M. Sharma. Histochemistry of lactic dehydrogenase in heart and pectoralis muscles of rat. J. Cell. Biol. 51:621–635, 1971.
4. Baldwin, K. M., P. J. Campbell, and D. A. Cooke. Glycogen, lactate and alanine changes in muscle during graded exercise. J. Appl. Physiol. 43:288–291, 1977.
5. Barnard, R., V. R. Edgerton, T. Furukawa, and J. B. Peter. Histochemical, biochemical and contractile properties of red, white, and intermediate fibers. Am. J. Physiol. 220:410–414, 1971.
6. Bartels, H., B. Vogt, and K. Jungerman. Glycogen synthesis via the indirect pathway in periportal and via the direct glucose utilizing pathway in the perivenous zone of perfused rat liver. Histochemistry 89:253–260, 1988.
7. Bolli, R., K. A. Nalecz, and A. Azzi. Monocarboxylate and a-ketoglutarate carriers in bovine heart mitochondria. Purification by affinity chromatography on immobilized 2-cyano-4-hydroxycinnamate. J. Biol. Chem. 264:18024–18030, 1989.
8. Brandt, R. B., J. E. Laux, S. E. Spainhour, and E. S. Kline. Lactate dehydrogenase in mitochondria. Arch. Biochem. Biophys. 259:412–422, 1987.
9. Brooks, G. A. Lactate: glycolytic product and oxidative substrate during sustained exercise in mammals—the “lactate shuttle.” In:Comparative Physiology and Biochemistry: Current Topics and Trends
, Volume A, Respiration-Metabolism-Circulation, R. Gilles (Ed.). Berlin: Springer-Verlag, 1985, pp. 208–218.
10. Brooks, G. A. Lactate production under fully aerobic conditions: the Lactate Shuttle during rest and exercise. Fed. Proc. 45:2924–2929, 1986.
11. Brooks, G. A. The lactate shuttle during exercise and recovery. Med. Sci. Sports Exerc. 18:360–368, 1986.
12. Brooks, G. A. Current concepts in lactate exchange. Med. Sci. Sports Exerc. 23:895–906, 1991.
13. Brooks, G. A. Mammalian fuel utilization during sustained exercise. Comp. Biochem. Physiol. 120:89–107, 1998.
13A. Brooks, G. A., M. A. Brown, C. E. Butz, J. P. Sicurello, and H. Dubouchaud. Cardiac and skeletal muscle mitochondria have a monocarboxylate transporter MCT1. J. Appl. Physiol. 87:1713–1718, 1999.
14. Brooks, G. A., H. Dubouchaud, M. Brown, J. P. Sicurello, and C. E. Butz. Role of mitochondrial lactate dehydrogenase and lactate oxidation in the intracellular lactate shuttle. Proc. Natl. Acad. Sci USA 96:1129–1134, 1999.
15. Brooks, G. A., G. E. Butterfield, R. R. Wolfe, et al. Increased dependence on blood glucose after acclimatization to 4,300 m. J. Appl. Physiol. 70:919–927, 1991.
16. Brooks, G. A., G. E. Butterfield, R. R. Wolfe, et al. Decreased reliance on lactate during exercise after acclimatization to 4,300 m. J. Appl. Physiol. 71:333–341, 1991.
17. Brooks, G. A., and C. M. Donovan. Effect of training on glucose kinetics during exercise. Am. J. Physiol. 244 (Endocrinol. Metab. 7):E505–E512, 1983.
18. Brooks, G. A., C. M. Donovan, and T. P. White. Estimation of anaerobic energy production and efficiency in rats during exercise. J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 56:520–525, 1984.
19. Brooks, G. A., and G. A. Gaesser. End points of lactate and glucose metabolism after exhausting exercise. J. Appl. Physiol.: Respir. Environ. Exerc. Physiol. 49:1057–1069, 1980.
20. Brooks, G. A., E. E. Wolfel, G. E. Butterfield, et al. Poor relationship between arterial [lactate] and leg net release during steady-rate exercise at 4,300 m altitude. J. Appl. Physiol. 275:R1192–R1201, 1998.
21. Brooks, G. A., E. E. Wolfel, B. M. Groves, et al. Muscle accounts for glucose disposal but not blood lactate appearance during exercise after acclimatization to 4,300 m. J. Appl. Physiol. 72:2435–2445, 1992.
22. Brown, M. A., and G. A. Brooks. Trans-stimulation of lactate transport from rat sarcolemmal vesicles. Arch. Biochem. Biophys. 313:22–28, 1994.
23. Bunger, R., and R. T. Mallet. Mitochondrial pyruvate transport in working guinea pig heart. Work-related vs. carrier-mediated control of pyruvate oxidation. Biochim. Biophys. Acta. 1151:223–236, 1993.
24. Connett, R. J., T. E. J. Gayeski, and C. R. Honig. Lactate accumulation in fully aerobic, working, dog gracilis muscle. Am. J. Physiol. 246:H120–H128, 1984.
25. Connett, R. J., C. R. Honig, T. E. J. Gayeski, and G. A. Brooks. Defining hypoxia: a systems view of VO2
, glycolysis, energetics and intracellular PO2
. J. Appl. Physiol. 68:833–842, 1990.
26. Cori, C. F. Mammalian carbohydrate metabolism. Physiol. Rev. 11:143–275, 1931.
27. Davis, M. A., P. E. Williams, and A. D. Cherrington. Effect of glucagon on hepatic lactate metabolism in the conscious dog. Am. J. Physiol. 248:E463–E470, 1985.
28. Depocas, F., Y. Minaire, and J. Chatonnet. Rates of formation and oxidation of lactic acid in dogs at rest and during moderate exercise. Can. J. Physiol. Pharmacol. 47:603–610, 1969.
29. Deuticke, B, E. Beyer, and B. Forst. Discrimination of three parallel pathways of lactate transport in the human erythrocyte membrane by inhibitors and kinetic properties. Biochim. Biophys. Acta 684:96–110, 1982.
30. Donovan, C. M., and G. A. Brooks. Endurance training affects lactate clearance, not lactate production. Am. J. Physiol. (Endocrinol. Metab. 7) 244:E8–E92, 1983.
31. Donovan, C. M., and M. J. Pagliassotti. Endurance training enhances lactate clearance during hyperlactatemia. Am. J. Physiol. 257:E78–E789, 1989.
31A. Dubouchaud, H., G. E. Butterfield, E. E. Wolfel, B. C. Bergman, and G. A. Brooks. Endurance training, expression and physiology of LDH, MCT1 and MCT4 in human skeletal muscle. Am. J. Physiol. 278:E571–579, 2000.
32. 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.
33. Edwards, H. T. Lactic acid at rest and work at high altitudes. Am. J. Physiol. 116:367–375, 1936.
34. Faintrenie, G., and A. Géloën. Alpha-1 adrenergic regulation of lactate production in white adipocytes. J. Pharmacol. Exp. Ther. 277:235–238, 1995.
35. Foster, D. W. From glycogen to ketones—and back. Diabetes 33:1188–1199, 1984.
36. Friedlander, A. L., G. A. Casazza, M. A. Horning, M. Huie, and G. A. Brooks. Endurance training alters glucose kinetics in response to the same absolute, but not the same relative workload. J. Appl. Physiol. 82:1360–1369, 1997.
37. Gaesser, G. A., and G. A. Brooks. Glycogen depletion following continuous and intermittent exercise to exhaustion. J. Appl. Physiol: Respir. Environ. Exerc. Physiol. 49:722–728, 1980.
38. 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.
39. Garcia, C. K., J. L. Goldstein, R. K. Pathak, R. G. 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.
40. Garcia, C. K., X. Lie, J. Ulna, and U. France. cDNA cloning of the human monocarboxylate transporter 1 and chromosomal localization of the SLC16A1 locus to 1p13.2-p12. Genomics 23:500–503, 1994.
41. Gertz, E. W., J. A. Wisneski, R. Neese, J. A. Bristow, G. L. Searle, and J. T. Hanlon. Myocardial lactate metabolism: evidence of lactate release during net chemical extraction in man. Circulation 63:1273–1279, 1981.
42. Gertz, E. W., J. A. Wisneski, W. C. Stanley, and R. A. Neese. Myocardial substrate utilization during exercise in humans: dual carbon-labeled carbohydrate isotope experiments. J. Clin. Invest. 82:2017–2025, 1988.
43. Gladden, L. B. Lactate uptake by skeletal muscle. Exerc. Sport Sci. Rev. 17:115–155, 1989.
44. 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: Oxford University Press, 1996, pp. 614–648.
45. Gladden, L. B., R. E. Crawford, and M. J. Webster. Effect of lactate concentration and metabolic rate on net lactate uptake by canine skeletal muscle. Am. J. Physiol. 266:R1095–R1101, 1994.
46. Gladden, L. B., and J. W. Yates. Lactic acid infusion in dogs: effects of varying infusate pH. J. Appl. Physiol. 54:1254–1260, 1983.
47. Grimditch, G. K., R. J. Barnard, S. A. Kaplan, and E. Sternlicht. Insulin binding and glucose transport in rat skeletal muscle sarcolemmal vesicles. Am. J. Physiol. 249:E39–E408, 1985.
48. Halestrap, A. P. The mitochondrial pyruvate carrier: kinetics and specificity for substrates and inhibitors. Biochem. J. 148:85–96, 1975.
49. Halestrap, A. P., and R. M. Denton. Specific inhibition of pyruvate transport in rat liver mitochondria and human erythrocytes by alpha-cyano-4-hydroxycinnamate. Biochem. J. 138:313–316, 1974.
50. Hellerstein, M. K., and R. A. Neese. Mass isotopomer distribution analysis: a technique for measuring biosynthesis and turnover of polymers. Am. J. Physiol. 263:E988–E1001, 1992.
51. Hetenyi, G., G. Perez, and M. Vranic. Turnover and precursor-product relationships of nonlipid metabolites. Physiol. Rev. 63:606–667, 1983.
52. Hubbard, J. L. The effect of exercise on lactate metabolism. J. Physiol. 231:1–18, 1973.
53. Hill, A. V., and H. Lupton. Muscular exercise, lactic acid and the supply and utilization of oxygen. Q. J. Med. 16:135–171, 1923.
54. Huie, M. J., G. A. Casazza, M. A. Horning, and G. A. Brooks. Smoking increases conversion of lactate to glucose. J. Appl. Physiol. 80:1554–1559, 1996.
55. Issekutz, B. Effect of beta-adrenergic blockade on lactate turnover in exercising dogs. J. Appl. Physiol. 57:1754–1759, 1984.
56. Issekutz, B., W. A. S. Shaw, and A. C. Issekutz. Lactate metabolism in resting and exercising dogs. J. Appl. Physiol. 40:312–319, 1976.
57. Jackson, V. N., N. T. Price, L. Carpenter, and A. P. Halestrap. Cloning of the monocarboxylate transporter isoform MCT2 from rat testis provides evidence that expression in tissues is species-specific and may involve post-transcriptional regulation. Biochem. J. 324 (Pt 2):447–453, 1997.
58. 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.
59. Jöbsis F. F., and W. N. Stainsby. Oxidation of NADH during contractions of circulated skeletal muscle. Respir. Physiol. 4:292–300, 1968.
60. Johannsson, E., E. A. Nagelhus, K. J. 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.
61. Johnson, J. A., and R. M. Fusaro. The role of skin in carbohydrate metabolism. Adv. Metab. Disord. 6:1–55, 1972.
62. Jorfeldt, L. Metabolism of L-(+)-lactate in human skeletal muscle during exercise. Acta Physiol. Scand. Suppl. 338:1–67, 1970.
63. Juel, C. Intracellular pH recovery and lactate efflux in mouse soleus muscles stimulated in vitro: the involvement of sodium/proton exchange and a lactate carrier. Acta Physiol. Scand. 132:363–371, 1988.
64. Juel, C. Human muscle lactate transport can be studied in sarcolemmal giant vesicles made from needle-biopsies. Acta Physiol. Scand. 142:133–134, 1991.
65. Keul, J., M. Lehman, and K. Wybitul. Zur wirkung von bunitrolol auf herzfrequenz, metabolische grossen bei korperarbeit und leistungsverhalten. Arzeim. Forsch/Drug Res. 31:1948–1953, 1981.
66. Kim, C. M., J. L. Goldstein, and M. S. Brown. cDNA cloning of MEV, a mutant protein that facilitates cellular uptake of mevalonate, and identification of the point mutation responsible for its gain of function. J. Biol. Chem. 267:23113–121, 1992.
67. Kline, E. S. R. B. Brandt, J. E. Laux, S. E. Spainhour, E. S. Higgins, K. S. Rogers, S. B. Tinsley, and M. G. Waters. Localization of L-lactate dehydrogenase in mitochondria. Arch. Biochem. Biophys.
68. Laughlin, M. R., J. Taylor, A. S. Chesnick, M. Degroot, and R. S. Balaban. Pyruvate and lactate metabolism in the in vivo dog heart. Am. J. Physiol. 264:H2068–H2079, 1993.
69. Lehman, S. L. Measurement of lactate production by tracer techniques. Med. Sci. Sports Exerc. 23:935–938, 1991.
70. Magnusson, I., and G. I. Shulman. Pathways of hepatic glycogen synthesis in humans. Med. Sci. Sports Exerc. 23:939–943, 1991.
71. Mainwood, G. W., and P. Worsley-Brown. The effects of extracellular pH and buffer concentration on the efflux of lactate from frog sartorius muscle. J. Physiol. (Lond.) 250:1–22, 1975.
72. McCullagh K. J., R. C. Poole, A. P. Halestrap, K. F. Tipton, M. O’Brien, and A. Bonen. Chronic electrical stimulation increases MCT1 and lactate uptake in red and white skeletal muscle. Am. J. Physiol. 273 (2 Pt 1):E239–E246, 1997.
73. 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.
74. Molé, P. A., P. A. VanHandel, and W. R. Sandel. Extra O2
consumption attributable to NADH2 during maximum lactate oxidation in the heart. Biochem. Biophys. Res. Commun. 85:1143–1149, 1978.
75. Monson, J. P., J. A. Smith, R. D. Cohen, and R. A. Iles. Evidence for a lactate transporter in the plasma membrane of the rat hepatocyte. Clin. Sci. 62:411–420, 1982.
76. Neese R. A., J. M. Schwarz, D. Faix, et al. Gluconeogenesis and intrahepatic triose phosphate flux in response to fasting or substrate loads: application of the mass isotopomer distribution analysis technique with testing of assumptions and potential problems. J. Biol. Chem. 270:14452–14466, 1995.
77. Paradies G., and S. Papa. The transport of monocarboxylic oxoacids in rat liver mitochondria. FEBS Lett. 52:149–152, 1975.
78. Poole R. C., and A. P. Halestrap. Transport of lactate and other monocarboxylates across mammalian plasma membranes. Am. J. Physiol. 264 (Pt. 1):C761–C782, 1993.
79. 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 (Pt 3):755–759, 1994.
80. Reeves, J. T., E. E. Wolfel, H. J. Green, et al. Oxygen transport during exercise at high altitude and the lactate paradox: lessons from Operation Everest II and Pikes Peak. Exerc. Sport Sci. Rev. 20:275–296, 1992.
81. Richter, E. A., B. Kiens, B. Saltin, N. J. Christensen, and G. Savard. Skeletal muscle glucose uptake during dynamic exercise in humans: role of muscle mass. Am. J. Physiol. 254:E555–E561, 1988.
82. Roberts, A. C., G. E. Butterfield, J. T. Reeves, A. Cymerman, E. E. Wolfel, and G. A. Brooks. Altitude and β-blockade augment glucose utilization during submaximal exercise. J. Appl. Physiol. 80:606–615, 1996.
83. Roberts, A. C., G. E. Butterfield, A. Cymerman, J. T. Reeves, E. E. Wolfel, and G. A. Brooks. Acclimatization to 4,300 m altitude decreases reliance on fat as a substrate. J. Appl. Physiol. 81:1762–1771, 1996.
84. Rognstad, R. The role of mitochondrial pyruvate transport in the control of lactate gluconeogenesis. Int. J. Biochem. 15:1417–1421, 1983.
85. Roth, D. A. The sarcolemmal lactate transporter: transmembrane determinants of lactate flux. Med. Sci. Sports Exerc. 23:925–934, 1991.
86. Roth, D. A., and G. A. Brooks. Lactate transport is mediated by a membrane-borne carrier in rat skeletal muscle sarcolemmal vesicles. Arch. Biochem. Biophys. 279:377–385, 1990.
87. 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.
88. Searle G. L., and R. R. Cavalieri. Determination of lactate kinetics in the human analysis of data from single injection vs. continuous infusion methods. Proc. Soc. Exp. Biol. Med. 139:1002–1006, 1972.
89. Stainsby, W. N., W. F. Brechue, and D. M. O’Drobinak. Regulation of muscle lactate production. Med. Sci. Sports Exerc. 23:907–911, 1991.
90. Stainsby, W. N., and G. A. Brooks. Control of lactic acid metabolism in contracting muscles and during exercise. Exerc. Sport Sci. Rev. 18:29–63, 1990.
91. Stainsby, W. N., C. Sumners, and P. D. Eitzman. Effects of catecholamines and their effect on blood lactate and muscle lactate output. J. Appl. Physiol. 57:321–325, 1984.
92. Stanley, W. C. Myocardial lactate metabolism during exercise. Med. Sci. Sports Exerc. 23:920–924, 1991.
93. Stanley, W. C., E. W. Gertz, J. A. Wisneski, D. L. Morris, R. Neese, and G. A. Brooks. Systemic lactate turnover during graded exercise in man. Am. J. Physiol. (Endocrinol. Metab. 12) 249:E59–E602, 1985.
94. Stanley, W. C., E. W. Gertz, J. A. Wisneski, D. L. Morris, R. Neese, and G. A. Brooks. Lactate metabolism in exercising human skeletal muscle: Evidence for lactate extraction during net lactate release. J. Appl. Physiol. 60:1116–1120, 1986.
95. Stanley, W. C., J. A. Wisneski, E. W. Gertz, R. A. Neese, and G. A. Brooks. Glucose and lactate interrelations during moderate intensity exercise in man. Metabolism 37:850–858, 1988.
96. Trosper, T. L., and K. D. Philipson. Lactate transport by cardiac sarcolemmal vesicles. Am. J. Physiol. 252 (Pt 1):C483–C489, 1987.
97. Turcotte, L. P., and G. A. Brooks. Effects of training on glucose metabolism of gluconeogenesis-inhibited, short-term fasted rats. J. Appl. Physiol. 68:944–954, 1990.
98. Turcotte, L. P., A. S. Rovner, R. R. Roark, and G. A. Brooks. Glucose kinetics in gluconeogenesis-inhibited rats during rest and exercise. Am. J. Physiol. (Endocrinol. Metab.) 258:E203–E211, 1990.
99. Wahren, J., P. Felig, G. Ahlborg, and L. Jorfeldt. Glucose metabolism during leg exercise in man. J. Clin. Invest. 50:2715–2725, 1971.
100. Wasserman D. H., C. C. Connolly, and M. J. Pagliassotti. Regulation of hepatic lactate balance during exercise. Med. Sci. Sports Exerc. 23:912–919, 1991.
101. Wasserman, D. H., D. B. Lacey, D. R. Green, P. E. Williams, and A. D. Cherrington. Dynamics of hepatic lactate and glucose balances during prolonged exercise and recovery in the dog. J. Appl. Physiol. 63:2411–2417, 1987.
102. Watt, P. W., P. A. Maclennan, H. S. Hundal, C. M. Kuret, and M. J. Rennie. L(+)-lactate transport in perfused rat skeletal muscle: kinetic characteristics and sensitivity to pH and transport inhibitors. Biochim. Biophys. Acta 944:213–222, 1988.
103. Welch, H. G., and W. N. Stainsby. Oxygen debt in contracting dog skeletal muscle in situ. Respir. Physiol. 3:229–242, 1967.
104. Wolfel, E. E., B. M. Groves, G. A. Brooks, et al. Oxygen transport during steady-state submaximal exercise in chronic hypoxia. J. Appl. Physiol. 70:1129–1136, 1991.
105. 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.
106. Zinker, B. A., R. D. Wilson, and D. H. Wasserman. Interaction of decreased arterial PO2
and exercise on carbohydrate metabolism in the dog. Am. J. Physiol. 269:E409–E417, 1995.
Chair: L. Bruce Gladden