Symposium: The role of skeletal muscle in lactate exchange during exercise
L. Bruce Gladden
Lactate is certainly one of the most thoroughly studied exercise metabolites, and numerous roles have been assigned to it; many, perhaps most, incorrectly. At one time or another, lactate has been considered a) the immediate energy donor for muscle contraction (25), b) a primary factor in muscle soreness (1), c) the central cause of O2 debt (18), and d) a causative agent in muscle fatigue (16). In addition, lactate has been traditionally viewed as a dead-end waste product that can move rapidly across muscle membranes by simple diffusion. This paradigm has changed dramatically over the past 25 years.
Three rather lengthy quotations provide key insights into the reshaping of theory in this field. First, from Lehninger’s biochemistry textbook published in 1970 (30):
“Lactate is the end product of the glycolytic sequence under anaerobic conditions and diffuses through the plasma membrane of the cell to the surroundings as waste. When muscle cells of higher animals function anaerobically during short bursts of exceptionally vigorous activity, lactate escapes from muscle cells into the blood in large quantities and is rebuilt to glucose in the liver during recovery.”
This brief summary of lactate metabolism does not differ greatly from the state of knowledge established in the 1920s by A. V. Hill and others (26–28).
Second, and again from Lehninger’s 1970 textbook (30):
“After a bout of maximal exercise, such as a sprint, a mammal will continue to breathe in excess of the normal resting rate and consume considerable extra oxygen. The extra oxygen so consumed during the recovery period is called the ‘oxygen debt,’ and it corresponds to the oxidation in the liver and heart of some of the excess lactic acid formed during maximal muscular activity. The remainder of the excess lactic acid accumulating in the blood during the sprint is converted to glycogen in the liver; the extra ATP required is derived from that portion of the lactic acid that is oxidized via the tricarboxylic acid cycle in the liver.”
This is classical oxygen debt theory and, in addition to the work of Hill (26–28), includes the studies of the Cori’s from the late 1920s (14).
Little more than 25 years later, the 1996 biochemistry textbook by Mathews and van Holde (31) presents a very different scheme:
“Until recently it was thought that lactate accumulation in skeletal muscle was largely a consequence of anaerobic metabolism, which occurs when the need for tissues to generate energy exceeds their capacity to oxidize the pyruvate produced in glycolysis. Recent metabolic studies, including 31P NMR analyses of the levels of phosphorylated intermediates in living muscle cells during exercise, suggest that lactate is actually an intermediate and not a metabolic ‘dead end,’ whose only fate is reconversion to pyruvate. These studies show that even in fully oxygenated muscle tissue, as much as 50% of the glucose metabolized is converted to lactate. This may represent a means for coordinating energy-storing and energy-generating pathways in different tissues, but the mechanisms involved are not yet clear.”
This reads much like a short paraphrase of the Lactate Shuttle Hypothesis (8–11). Within this hypothesis, lactate is a useful metabolic intermediate because it can be exchanged among tissue compartments.
The important point to be emphasized is that recent studies of exercise and lactate metabolism have altered our understanding of some key tenets and established other, new concepts as well. At least five important advancements can be listed:
1) Traditionally, it was argued that muscle and blood lactate concentrations increase with increasing exercise intensity because of an inadequate O2 supply to the exercising muscles; that is, muscle hypoxia (45–47). Now, a major competing hypothesis has been put forward. This new hypothesis favors the notion that muscle oxygenation is adequate for optimal mitochondrial function at submaximal work rates at which lactate production increases significantly. Alternative causes of the increased lactate concentrations include biochemical regulation that promotes glycolysis, increasing sympathoadrenal activity, progressive recruitment of glycolytic motor units, and a decreasing balance of lactate removal versus production (20). These issues continue to be vigorously debated. Although the role of oxygen in lactate production is not addressed directly in this symposium, Spriet and colleagues (43) provide a detailed discussion of the enzymatic aspects of lactate production.
2) Skeletal muscle has usually been assigned the role of major lactate producer in lactate metabolism. However, it is now well established that in many types of exercise, skeletal muscle releases lactate only transiently and subsequently displays a net uptake of lactate. Skeletal muscle is especially proficient in lactate utilization during steady state exercise if the blood lactate concentration is elevated above rest. In a following paper, I (21) discuss factors that promote lactate consumption by skeletal muscle.
3) From the 1930s through the late 1960s, it was accepted dogma that mammalian skeletal muscle was not capable of reversing the glycolytic pathway to synthesize glycogen from lactate (37). However, numerous studies since 1969 have firmly established that skeletal muscle can in fact convert lactate to glycogen on a quantitative basis (37). Lactate conversion to glycogen has been reported in incubated muscles (6,7,13,18), perfused muscles (18,32,34–36,39,42,44), intact animals of various species (17–19,22,23,29,33,41), and humans (2–4,24,38). Elegant studies by Donovan’s group (34–36) have quantitated glycogen formation from lactate in muscles of differing fiber type composition and shown the relative propensity of different fibers for lactate oxidation as well. In one of the papers of the present symposium, Donovan (15) summarizes this work and presents new analyses that suggest the most likely biochemical pathway for glycogen resynthesis from lactate.
4) In the past, it was assumed that lactate diffused readily across membranes throughout the body thus rapidly equilibrating among the various water compartments. Now, it is clear that a major portion of lactate translocation across most cell membranes, including the sarcolemma, is via monocarboxylate transporters (MCT). To date, investigators have cloned seven MCT proteins. It appears that there is a family of these proteins with differing tissue distribution and probably a differing distribution in muscles of different fiber type as well (40). In this symposium, Bonen (5) reviews the state of knowledge regarding these transport proteins and their possible role in the regulation of lactate exchange.
5) Before the 1980s, the concept of a lactate shuttle was nonexistent. Brooks (8–11) formulated the Lactate Shuttle Hypothesis on the basis of numerous studies in which the fate of isotopic lactate was traced. It is now quite clear that lactate formation and the subsequent distribution of lactate throughout the body is a major mechanism whereby the coordination of intermediary metabolism in different tissues, and cells within those tissues, can be accomplished. Brooks (12) summarizes recent refinements in the Lactate Shuttle Hypothesis in the last paper of this symposium.
The basic processes of lactate metabolism and transport have now been established. The most current knowledge in this field will be addressed in the following symposium papers. The next challenge for this area of exercise metabolism is to determine the important regulatory factors that control lactate exchange at rest, during exercise, and during pathological processes. In this regard, some of these symposium papers provide differing opinions about the potential role of lactate transport versus lactate metabolism in controlling lactate exchange.
This work was supported in part by National Institutes of Health grant 1R01AR40342. I am grateful to Dr. Mike Hogan for his evaluation of the manuscript.
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Chair: L. Bruce Gladden