BROOKS, G. A. Intra- and extra-cellular lactate shuttles. Med. Sci. Sports Exerc., Vol. 32, No. 4, pp. 790–799, 2000. The “lactate shuttle hypothesis” holds that lactate plays a key role in the distribution of carbohydrate potential energy that occurs among various tissue and cellular compartments such as between: cytosol and mitochondria, muscle and blood, blood and muscle, active and inactive muscles, white and red muscles, blood and heart, arterial blood and liver, liver and other tissues such as exercising muscle, intestine and portal blood, portal blood and liver, zones of the liver, and skin and blood. Studies on resting and exercising humans indicate that most lactate (75–80%) is disposed of through oxidation, with much of the remainder converted to glucose and glycogen. Lactate transport across cellular membranes occurs by means of facilitated exchange along pH and concentration gradients involving a family of lactate transport proteins, now called monocarboxylate transporters (MCTs). Current evidence is that muscle and other cell membrane lactate transporters are abundant with characteristics of high Km and Vmax. There appears to be long-term plasticity in the number of cell membrane transporters, but short-term regulation by allosteric modulation or phosphorylation is not known. In addition to cell membranes, mitochondria also contain monocarboxylate transporters (mMCT) and lactic dehydrogenase (mLDH). Therefore, mitochondrial monocarboxylate uptake and oxidation, rather than translocation of transporters to the cell surfaces, probably regulate lactate flux in vivo. Accordingly, the “lactate shuttle” hypothesis has been modified to include a new, intracellular component involving cytosolic to mitochondrial exchange. The intracellular lactate shuttle emphasizes the role of mitochondrial redox in the oxidation and disposal of lactate during exercise and other conditions.
The “lactate shuttle” hypothesis was introduced at the First International Congress of Comparative Physiology and Biochemistry held at Liège, Belgium, August 1984. The subsequent paper appeared in congress proceedings published the following year (9), and a derivative of the idea appeared in a peer-reviewed paper (18). As well, two related papers appeared in 1986 (10,11). The initial hypothesis was developed based on results of isotope tracer studies conducted on laboratory rats (17,19,30), dogs (28,55,56), and humans (52,62,88). In our work, we compared glucose and lactate fluxes in rats during exercise and recovery (17,19,30,37). Subsequently, we also studied glucose and lactate fluxes in humans (15,16,20,82,83,93–95). Results consistently indicated that oxidation was the major route of lactate disposal (75%) during steady rate exercise and recovery from exercise, with conversion to glucose and glycogen accounting for most of the remainder during exercise and recovery, respectively. Further, results indicated that during exercise, lactate flux and oxidation could equal or exceed glucose flux and oxidation. Thus, the working hypothesis was developed that much of the glycolytic flux during exercise passed through lactate. Several discoveries contributed to development of the lactate shuttle hypothesis. Among these were long-standing knowledge that lactate is a gluconeogenic precursor, as well as the then new knowledge of a heterogeneity of skeletal muscle fiber types (5), and observations that white sections of working muscle beds contained more lactate than arterial blood, but that red sections of the same tissue beds contained less lactate than arterial blood (4). The hypothesis was constructed to allow that lactate flux among cells within and between tissues could serve as a vehicle to promote diverse functions.
The lactate shuttle hypothesis was defined as follows: “the shuttling of lactate through the interstitium and vasculature provides a significant carbon source for oxidation and gluconeogenesis during rest and exercise” (9). Subsequently, experiments conducted by us and others have confirmed important aspects of the hypothesis, and new and important facets of the hypothesis have been developed. Admittedly, when the hypothesis was introduced, the initial reaction was mixed. Retrospectively, part of the response was attributable to controversies surrounding interpretation of isotope tracer-derived data (9–11). In part also, the “lactate shuttle” hypothesis did not find wide acceptance because it made no sense to those accepting classic “O2 debt” and “anaerobic threshold” theories. Those theories held that lactate is produced in muscle because of O2 lack and that lactate produced during exercise was a dead-end metabolite that could only be removed during recovery (53). Concepts that lactate was produced all the time in fully oxygenated cells and tissues (24,25) and that lactate production, distribution, and removal could serve the organism well (9–11,35) were simply too radical for the early to mid-1980s. Obviously, today’s views are very different.
Before delving into aspects of the current state of the hypothesis, it will be helpful for students of the subject to note several publications. At the 37th Annual Meeting of the American College of Sports Medicine held in Salt Lake City, the symposium “Current Concepts In Lactate Exchange” was held. Proceedings were published in Medicine and Science in Sports and Exercise the following year (1991) and contained papers on lactate production in skeletal muscle by Stainsby and associates (89), hepatic uptake and release by Wasserman and associates (100), the indirect pathway of hepatic glycogen formation by Magnusson and Shulman (70), the regulation of lactate metabolism in the heart by Stanley (92), the search for muscle membrane lactate transporters by Roth (85), and attempts to model lactate fluxes in vivo by Lehman (69). Additionally, this author contributed a paper on the lactate shuttle hypothesis (12). Moreover, in addition to the other papers associated with these proceedings of the 44th meeting of the ACSM, readers are referred to Gladden’s paper that appeared in Exercise and Sport Sciences Reviews (43) as well as his most recent review: “Lactate transport and exchange during exercise,” which appeared in the 1996 American Physiological Society Handbook of Physiology-Exercise: Regulation and Integration of Multiple Systems (44).
Department of Integrative Biology, University of California, Berkeley, CA 94720
Submitted for publication December 1998.
Accepted for publication December 1998.
Address for correspondence: Professor George A. Brooks, Ph.D., Department of Integrative Biology, 5101 VLSB, University of California, Berkeley, CA 94720-3140; E-mail: GBrooks@Socrates.Berkeley.Edu.