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Perspectives For Progress

200th Anniversary of Lactate Research in Muscle

Gladden, L. Bruce

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Exercise and Sport Sciences Reviews: July 2008 - Volume 36 - Issue 3 - p 109-115
doi: 10.1097/JES.0b013e31817c0038
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Discovery of Lactate

Lactate/lactic acid was discovered in sour milk by a Swedish apothecary assistant, Carl Wilhelm Scheele (1742-1786) in 1780 (2[pp6-8]). Benninga (2[pp7-8]) provided a modern translation of Scheele's isolation technique; it is quoted partially here: "Sour whey is evaporated to one eighth of its volume, the curd [precipitated milk proteins] is then removed by filtration. The filtrate is saturated with milk of lime [calcium hydroxide], filtered again and diluted with three times its volume of water" (2). After a series of additional steps, Scheele concluded that (modern translation): "The lactic acid produced is as pure as can be obtained by chemistry" (2). The new acid was named "Mjölksyra," meaning "acid of milk" (2[p8]). Lactate (La) occurs as the acid ingredient of sour dairy products, fermented fruits and vegetables, and sausages (2[p1]) and as a flavor modifier or enhancer in carbonated soft drinks. It has also been used in tanning leather, acid dyeing of wool, and as a pharmaceutical in the form of calcium lactate; its esters have been used as lacquer solvents, and small amounts have been used in plastics. Benninga's book (2) details the history of La and its large scale production for industrial purposes from a biotechnology perspective, offering a viewpoint that is completely outside the mind-set of most biological scientists. Note that lactic acid is more than 99% dissociated into La anions and protons (H+) at the physiological pH levels found in muscle and blood; therefore, it will generally be referred to as "La" in this review.

Scheele also discovered chlorine, manganese, arsenic acid, and silicon fluoride along with numerous other compounds (28[p461]). However, he is best recognized for his work on O2 in which he first demonstrated that air is composed of two components, only one of which will support combustion (28[p461]). Scheele discovered O2 as early as 1772, more than a year before Joseph Priestley (1733-1804). Unfortunately, his experiments (A Chemical Treatise on Air and Fire) were not published until 1777, probably because of procrastination by his friend and advocate, Torbern Bergman (1735-1784), who wrote an introduction to the book (28[pp49,461]). As a result, he shares credit for the discovery of O2 with Priestley.


Although Scheele is remembered as the discoverer of La, it was Jöns Jacob Berzelius (1779-1848), another Swede, who indelibly joined La to the study of exercise when he reported the presence of La in the muscles of hunted stags in either 1807 (19[p41]) or 1808 (20[pxxvii]). Berzelius apparently convinced himself that the amount of La in a muscle was proportional to the amount of exercise that the muscle had performed (19[p41]). Mentioned less often is the fact that Berzelius also discovered pyruvic acid (28[p56]). Accordingly, it is fitting that we pause at the bicentennial of research into lactate metabolism in muscle for a brief historic overview and discussion of current controversies. Presently, there are at least three contentious areas in the physiological/biochemical study of La: 1) the role of La as either a causative or a preventive agent of muscle fatigue, 2) the role of La in the acidosis of intense exercise, and 3) the intracellular pathway of La metabolism in muscle. This review focuses on the third controversy. La metabolism in muscle during and after exercise is of special importance because skeletal muscle is not only the most important source of La but is also the primary consumer of La. For example, during recovery from intense exercise, oxidation is the major pathway for La removal, particularly in skeletal muscles.


The discord surrounding intracellular La metabolism is not only a story about La but also about the enzyme that catalyzes its formation, lactate dehydrogenase (LDH). Berzelius has a distant relationship to this side of the tale as well because he was the first (in 1836) to propose the term catalysis that he used to explain the action of compounds that facilitated chemical reactions without undergoing any change themselves (19[pp30-31]). A long period followed during which scientists studied the ability of "ferments," tissues, or tissue extracts of various organisms to promote reactions. Along the way, the ferments were divided into two groups: 1) those that were disorganized or soluble and 2) those that were organized or insoluble (i.e., they were made up of intact microorganisms). In 1877, Willy Kühne (1837-1900) offered the name "enzymes" (Greek, "in yeast") for the unorganized ferments (28[pp300-301]). Twenty years later, Eduard Buchner (1860-1917) ground yeast cells with sand at a controlled temperature to derive an extract that was free of yeast cells but still able to ferment sucrose to ethanol, demonstrating conclusively that cells were not essential for fermentation (28[pp87-88]). Subsequently in 1926, American James Batcheller Sumner (1877-1955) first isolated the crystalline form of an enzyme, urease, from jack beans (28[p498-499]).

Perhaps not surprisingly, it was Otto Meyerhof (1884-1951) (28[p368]) in 1919, studying skeletal muscle, who first demonstrated the action of LDH. After perhaps hundreds of investigations on the topic of LDH, pure LDH in crystalline form was isolated from the hearts of bullocks. Beginning in the 1950s, several investigators provided evidence that preparations of LDH were heterogeneous. This work culminated in 1959 when Markert and Møller (17), using the superior separation method of starch gel electrophoresis combined with histochemical staining, clearly demonstrated five different forms of the LDH enzyme. They (17) also first proposed the term isozymes to designate the multiple molecular forms of an enzyme. In 1962, Kaplan's group (6) hypothesized the model of tetrameric organization of the LDH isozymes that still applies today: there are two monomer subunits, H (heart) and M (muscle), which can be combined in groups of four to yield five different molecular species; HHHH, HHHM, HHMM, HMMM, and MMMM. Modern nomenclature designates the monomers as A (muscle) and B (heart) yielding LDH1(B4), LDH2(B3A1), LDH3(B2A2), LDH4(B1A3), and LDH5(A4). Kaplan's laboratory (6) went on to propose that the different properties of the isozymes were physiologically important in the regulation of cellular metabolism. Specifically, it was proposed that the sensitivity of the heart forms (H4, H3M1) to pyruvate inhibition directed pyruvate toward oxidation in an aerobic environment such as the heart, whereas the relative insensitivity of the muscle forms (H1M3, M4) to pyruvate inhibition facilitated the anaerobic breakdown of carbohydrates to lactate in exercising muscles (6).

This scheme has been supported by circumstantial evidence. For example, muscle capacity for La utilization is correlated with both the oxidative capacity and the content of the heart-type LDH. As reviewed by Van Hall (27), there is also evidence that oxidative muscle fibers have approximately half of the total LDH activity of glycolytic fibers, and of that activity, a greater relative amount is in the heart forms (H4 and H3M1). Also, endurance training results in a lower total LDH content and a decrease in the muscle forms (H1M3, M4) of LDH (27). However, Newsholme (21) has questioned the potential role of LDH isozyme profile in La production versus utilization on several counts: 1) the LDH reaction is near-equilibrium, suggesting that pyruvate inhibition would have a negligible effect on flux through the reaction, 2) the differences between function of the isozymes may be less in vivo than in vitro because of higher temperature and other factors in the intracellular milieu, 3) the pyruvate inhibition may not apply at the high concentrations of the LDH enzyme found in vivo, and 4) the reported inhibition may be due to traces of the enol form of pyruvate that are likely more prevalent in vitro than in vivo. Further, Van Hall (27) notes the following: 1) that the absolute amount of the heart forms of LDH remains fairly constant among fiber types and with endurance training and 2) that the concentrations of pyruvate and La required for LDH inhibition in vitro are several times greater than the highest concentrations observed in vivo. It is also possible that the binding of LDH to cellular proteins may change its kinetic parameters. My conclusion is that the exact regulatory role of the LDH isozymes remains unknown.


Lactate dehydrogenase has long been considered a "soluble" glycolytic enzyme found in the cytoplasm of cells, predominantly in the I band of striated muscle (18,27). There is also significant evidence that LDH binds reversibly to cytoskeletal proteins including actin, tubulin, and troponin among others (see (18) for references). Furthermore, it seems clear that an LDH fraction is localized to the sarcoplasmic reticulum (SR), particularly in glycolytic skeletal muscle (e.g., (1)). In agreement with the studies previously cited, it is commonly reported that glycolytic activity is found exclusively in the supernatant fraction of tissue homogenates, a fraction that contains essentially no mitochondria.

The story of the location of LDH, and thereby of intracellular La metabolism, became more provocative with a 1971 publication of Baba and Sharma (1). They (1) cited several studies that reported LDH activity in the mitochondrial fractions of tissues as well as numerous histochemical studies that demonstrated LDH activity in mitochondria of various tissues. Their own results (1), obtained with a combination of histochemical and electron microscopy techniques in skeletal muscle, indicated the presence of mainly heart-type isozymes in mitochondria and cytoplasm and primarily muscle-type isozymes in association with the SR. They conjectured that heart forms of LDH might serve a role similar to that of glycerol phosphate dehydrogenase and malate dehydrogenase. However, they concluded that "Permeability of the mitochondria to lactate has not been well-demonstrated, and the lactate shuttle remains a pure speculation" ((1); emphasis is mine).

Subsequently, via a variety of techniques, LDH was found in association with mitochondria by Skilleter and Kun (25), Deimann et al. (8), Kline et al. (16), Brandt et al. (3), and Chretien et al. (7) among others. In 1972, Skilleter and Kun (25) also reported the oxidation of La by isolated liver mitochondria, although, perplexingly, the process seemed to require energy. Szczesna-Kaczmarek (26) became the first investigator to report direct mitochondrial oxidation of La in skeletal muscle in 1990.


Finally, in 1999, Brooks et al. (5) fully elucidated an intracellular lactate shuttle that had only been inferred by Baba and Sharma (1). A central tenet of this intracellular shuttle was that La is an inevitable product of glycolysis, particularly during rapid glycolysis, because LDH has the highest Vmax of any enzyme in the glycolytic pathway, and the Keq for pyruvate to La is far in the direction of La and nicotinamide adenine dinucleotide (NAD+) (4,5). Given this information, Brooks et al. (4) questioned how it would be possible for La to be converted back to pyruvate in the cytosol, thus permitting oxidation of La by well-perfused tissues, a universally accepted phenomenon that provides the foundation for the cell-to-cell lactate shuttle theory (9,10,27). One simple explanation would have been that LDH catalyzes a near-equilibrium reaction, allowing small changes in substrate and product concentrations to immediately direct the reaction in the opposite direction. However, a different explanation was proffered, and in recent years, the Brooks laboratory (4,5,11,13) has reported evidence of the following key components of an intracellular lactate shuttle in skeletal muscle: 1) direct uptake and oxidation of La by isolated mitochondria without prior extramitochondrial conversion of La to pyruvate (Fig. 1), 2) presence of an intramitochondrial pool of LDH, and 3) presence of the La transporter, monocarboxylate transporter 1 (MCT1), in mitochondria, presumably in the inner mitochondrial membrane.

Figure 1
Figure 1:
State 3 lactate and pyruvate oxidation by isolated rat skeletal muscle mitochondria. Concentration of both substrates was set at 10mM, and 2.5 mM malate was included in the medium. Compare with values reported by Yoshidaet al. (30) in Figure 2 who contend that the results in this figure are likely due to contamination. Based on data from Table 1 of Brooks et al. (5).
Figure 2
Figure 2:
Lactate and pyruvate oxidation in intermyofibrillar (Panel A) and subsarcolemmal (Panel C) mitochondria from rat red and white muscle at different concentrations (0.18, 1.8, and 10 mM). Lactate oxidation is also shown on a 30-fold more sensitive scale in both red and white muscle intermyofibrillar (Panel B) and subsarcolemmal (Panel D) mitochondria. Note negligible direct lactate oxidation in subsarcolemmal and intermyofibrillar mitochondria obtained from both red and white rat skeletal muscle. Compare with values reported by Brookset al. (5) in Figure 1. Hashimoto and Brooks (11) contend that these results are likely due to loss of mitochondrial LDH in the isolation procedures. (Reprinted from Yoshida, Y., G.P. Holloway, V. Ljubicic, H. Hatta, L.L. Spriet, D.A. Hood, and A. Bonen. Negligible direct lactate oxidation in subsarcolemmal and intermyofibrillar mitochondria obtained from red and white rat skeletal muscle. J. Physiol. 582:1317-1335, 2007. Copyright © 2007 Blackwell Publishing. Used with permission.)

Operation of an intracellular lactate shuttle such as described by the Brooks group (5) entails constant production of La in the cytosol, with the rate of production increasing with elevated glycolytic activity. Because of its higher concentration relative to pyruvate, La would be the primary monocarboxylate diffusing to mitochondria. In the original version of this shuttle, this La would then be transported across the inner mitochondrial membrane by MCT1. Once inside the mitochondrial matrix, mitochondrial LDH would catalyze the conversion of La back to pyruvate that would be oxidized through the PDH reaction to acetyl coenzyme A (CoA). The acetyl CoA would then enter the tricarboxylic acid cycle. An important point is that this intracellular lactate shuttle would not only deliver substrate in the form of La for conversion to pyruvate, it would also deliver reducing equivalents (reduced form of NAD+ (NADH)), thus supplanting or supplementing the role of the malate-aspartate and glycerol-phosphate shuttles to varying degrees, depending on the rate of La formation and its rate of transport into mitochondria (9).

Is Brooks correct? Can mitochondria oxidize La directly? After Brooks' proposal of the intracellular lactate shuttle, Rasmussen et al. (23) and Sahlin et al. (24) found no evidence that mitochondria can use La as a substrate without prior conversion to pyruvate in the cytoplasm. A preliminary report by Willis et al. (29) also found insignificant activity of the proposed intracellular lactate shuttle in mitochondria isolated from rat skeletal muscle (Types I and IIb) and liver. Ponsot et al. (22) reported no sign of direct mitochondrial La oxidation in skinned fibers from heart muscle, glycolytic skeletal muscle, or oxidative skeletal muscle. Finally, Yoshida et al. (30) from the Bonen laboratory have also recently found minimal direct oxidation of La by either subsarcolemmal or intermyofibrillar mitochondria from either red (oxidative) or white (glycolytic) skeletal muscle (Fig. 2).

A central point in this debate is the exact location of LDH. Although several investigators have reported that LDH is associated with mitochondria (as previously cited), these reports warrant further scrutiny. First, some researchers (23,24,30) note that the amount of LDH associated with mitochondria is quite small and conclude that the mitochondria isolated by Brooks et al. (5) as well as others are contaminated with cytoplasmic LDH. In fact, Chretien and colleagues (7), who found LDH in mitochondria-enriched preparations of human skeletal muscle, considered the LDH to be a contaminant from the cytoplasm. On the contrary, Hashimoto and Brooks (11) point to the difference in mitochondrial isolation techniques and argue that others most likely lost LDH that was associated with mitochondria. Clearly, it would be helpful if someone were to carefully compare LDH activity and La oxidation in mitochondria isolated by the methods of Brooks and coworkers as compared with mitochondria isolated by the techniques of other investigators who do not find mitochondrial La oxidation.

Another critical obstacle to the notion of La oxidation within the mitochondrial matrix is the possible violation of the first law of thermodynamics as described by Sahlin et al. (24). Separate pathways for cytosolic pyruvate and NADH entry into the mitochondrial matrix provide for a large oxidation/reduction potential gradient spanning the inner mitochondrial membrane. Crucial for maintenance of this gradient is the existence of a nonequilibrium step within both the glycerol phosphate and malate-aspartate shuttles. Neither empirical evidence nor theoretical conjecture has been presented in support of a nonequilibrium step in the intracellular lactate shuttle hypothesis.


In my opinion, the weight of the evidence is against the presence of LDH in the mitochondrial matrix and, therefore, the oxidation of La within the mitochondrial matrix. However, LDH may be present in the intermembrane space of mitochondria, perhaps attached (loosely?) to the inner mitochondrial membrane. Baba and Sharma (1), as previously noted, found LDH associated with mitochondria but, at the same time, questioned the permeability of mitochondria to lactate, leaving the intermembrane space as a likely location in the heart and skeletal muscle. Skilleter and Kun (25) undertook submitochondrial fractionation and arrived at the conclusion that LDH in intact mitochondria "is probably on the outer side of the inner membrane" in liver. Deimann et al. (8) used scanning transmission electron microscopy and found the reaction product for LDH "clearly identified in the intermembranous space of mitochondria" in rabbit glycolytic skeletal muscle. Using proteolytic disruption of isolated liver mitochondria, Kline et al. (16) concluded that LDH is "mainly in the outer membrane and periplasmic space." Brandt et al. (3) used digitonin fractionation of mitochondria isolated from rat heart, kidney, liver, and lymphocytes; they reported that "the mitochondrial LDH is located primarily in the periplasmic space." Periplasmic space and intermembrane space are equivalent terms.

Recent observations of Hashimoto et al. (12) from the Brooks laboratory provided additional detail for the possibility of LDH in association with the inner mitochondrial membrane. Using the techniques of confocal laser scanning microscopy and immunoblotting after immunoprecipitation in L6 skeletal muscle cells, Hashimoto et al. (12) found evidence suggesting that LDH, MCT1, the single-span transmembrane glycoprotein CD147, and cytochrome oxidase are colocalized in the inner mitochondrial membrane, with the LDH enzyme apparently residing on the outer surface of the inner membrane. They (12) have called this a lactate oxidation complex and have enumerated their experimental evidence supporting the existence of this complex elsewhere (11). Potential location of LDH loosely attached to the outside of the inner mitochondrial membrane rekindles the possibility that such LDH might be susceptible to loss during the isolation of mitochondria from muscle tissue. However, it seems unlikely that LDH (molecular weight of 134,000) can pass through an intact outer mitochondrial membrane because it is impermeable to molecules larger than 5000 daltons, whereas NAD+/NADH at a molecular weight of approximately 664 moves through readily. It also seems unlikely that LDH within the mitochondrial intermembrane space would be susceptible to destruction by proteases used in mitochondrial isolation (trypsin, molecular weight ≈23,000; nagarse, molecular weight ≈27,000).


Despite the serious reservations previously outlined, it remains quite possible that an intracellular lactate shuttle operates, albeit without intramatrix lactate metabolism (Fig. 3). It is reasonable to speculate that pyruvate and NADH concentrations are lowest adjacent to the inner mitochondrial membrane where the pyruvate carrier and the NADH shuttles (malate-aspartate and glycerol phosphate) are moving pyruvate and NADH equivalents, respectively, into the mitochondria. In other words, actively oxidizing mitochondria would create "sinks" for the utilization of pyruvate and NADH and, therefore, their uptake from adjacent cytosolic locations. At the same time, sites of cellular glycolysis would create driving concentrations of Labecause the primary end product of glycolysis would be La due to the high activity of LDH as described earlier.This situation would lead to the highest La production and concentration at cytosolic locations remote from mitochondria. Then, because of the relatively higher [La] as compared with [pyruvate], La would be the primary species diffusing to areas near mitochondria. The [La] is typically approximately 10-200 times greater than [pyruvate] in skeletal muscle. Adjacent to mitochondria, or if Hashimoto et al. (12) are correct, in the intermembrane space, La and NAD+ would be converted back to pyruvate and NADH via LDH for uptake into the mitochondria. Such a scheme, arguably analogous to the phosphocreatine shuttle, would be in accord with near equilibrium of the LDH reaction throughout the cytosol and would accommodate ready La production with subsequent oxidation and less transport of La out of the cell. I should note clearly that specific location of LDH, either in the intermembrane space or attached to the inner membrane, might not be a requirement for operation of an intracellular lactate shuttle. Finally, despite the evidence for the presence of MCT1 in a lactate oxidation complex (12), it is quite possible, perhaps probable, that pyruvate is transported across the inner mitochondrial membrane via the mitochondrial pyruvate carrier (MPC (14)) that has a very high affinity for pyruvate.

Figure 3
Figure 3:
Illustration of the essential elements of possible intracellular (intramuscular) lactate shuttles, one with lactate dehydrogenase (LDH) in a lactate oxidation complex (12) on the inner mitochondrial membrane and one without LDH attached to the inner membrane or even in the intermembrane space. A high activity of cytosolic LDH is considered to guarantee lactate (La−) formation in the cytoplasm under virtually all conditions but especially during exercise. Although La− could be formed throughout the cytosol, two particular locations are illustrated - one in association with the Na+/K+-ATPase pump in the sarcolemma; and the other, the Ca2+-ATPase in the SR membrane. The sarcolemma is illustrated by the thick double lines at the top of the cartoon, whereas the inner and outer mitochondrial membranes are dramatically enlarged to demonstrate possible La− pathways. The dashed red and black lines connecting Pyr− and La− in the upper left quadrant indicate the near-equilibrium nature of the LDH reaction and the movement of La− and Pyr− mass from a site of net formation to a site of net removal. The gaps in the outer mitochondrial membrane illustrate that it is freely permeable to most small molecules (but probably not permeable to LDH, trypsin, or nagarse; see text). La− is shown in bold and red and larger than pyruvate (Pyr−) to indicate that La− is typically present in much higher concentration than Pyr−. Whether La− were converted back to Pyr− outside the intermembrane space, inside the space, or via a mitochondrial LDH, the resulting NADH + H+ would be shuttled across the inner mitochondrial membrane via the malate-aspartate and glycerol phosphate shuttles. Please note that illustration of these traditional shuttles on the inner mitochondrial membrane is not intended to imply that their components are limited to this location; the reactions that are outside the inner membrane can occur throughout the cytosol. Pyr− could be transported across the inner mitochondrial membrane by either a pyruvate carrier, (MPC, arguably more likely) or a monocarboxylate transporter (MCT1), both of which have been identified in the inner membrane. The MCT1/MPC in the lactate oxidation complex is not meant to imply that Hashimoto et al. (12) reported the presence of MPC there; their evidence supports MCT1. To avoid confusion, arrows indicating possible diffusion routes of NAD+ and NADH + H+ are not shown. COX indicates cytochrome oxidase; cLDH, cytosolic lactate dehydrogenase; CD147, single-span transmembrane glycoprotein; ETC II and III, electron transport chain complexes II and III; Gly, glycogen; Glu, glucose; Inner, inner mitochondrial membrane; La−, lactate; MCT1, monocarboxylate transporter 1; mLDH, mitochondrial LDH; MPC, mitochondrial pyruvate carrier; NADH-dh, NADH dehydrogenase complex I; Outer, outer mitochondrial membrane; Pyr−, pyruvate. [Adapted from Hashimoto, T., R. Hussien, and G.A. Brooks. Colocalization of MCT1, CD147, and LDH in mitochondrial inner membrane of L6 muscle cells: evidence of a mitochondrial lactate oxidation complex. Am. J. Physiol. Endocrinol. Metab. 290:E1237-E1244, 2006. Copyright © 2006 The American Physiological Society. Used with permission.]


The model previously described is consistent with the compartmentation of metabolism as described in several studies. James and colleagues (15) proposed that the Na+/K+-ATPase pump derives its energy heavily from glycolysis that is closely associated with the pump, an idea that has recently been supported in studies of mechanically skinned skeletal muscle fibers. There is also considerable evidence for a functional compartmentation of glycolysis with the SR. Figure 4 provides visual circumstantial evidence for glycolytic compartmentation with the SR. Is it possible that La derived from glycolysis associated with SR Ca2+ pumping is shunted toward intermyofibrillar mitochondria, whereas La derived from glycolysis affiliated with Na+/K+-ATPase activity is shunted toward subsarcolemmal mitochondria? Perhaps future studies will provide evidence in this regard.

Figure 4
Figure 4:
Transmission electron microscopy (TEM) image of a human skeletal muscle fiber (original magnification ×20,000; scale bar = 2 μm). The 60-nm-thick section has been cut precisely on the surface of the myofibril, enabling visualization of the triads situated in the I band on each side of the z line, with paired long mitochondria located transversely at the I band level wrapped around the contractile apparatus and in contact with the SR but clearly separated from the t tubules. Traces of longitudinal tubules of SR can be seen as strings from the terminal cisternae toward the fenestrated collar at the level of the M band. The abundant glycogen granules are visualized asblack dots. Although some glycogen granules are obviously near mitochondria in the micrograph, the density of granules surrounding the SR is suggestive of glycolytic compartmentation with the SR. Human muscle fibers were fixed with 2.5% glutaraldehyde in 0.1 M sodium cacodylate buffer (pH 7.3) for 24 h then rinsed four times in 0.1 M sodium cacodylate buffer, postfixed with 1% osmium tetroxide (OsO4) and 1.5% potassium ferrocyanide (K4Fe(CN)6) in 0.1 M sodium cacodylate buffer for 90 min, rinsed two times in 0.1 M sodium cacodylate buffer, dehydrated through a graded series of alcohol, infiltrated with graded mixtures of propylene oxide and Epon, and embedded in 100% Epon. Ultra-thin sections (∼60 nm) were cut using a Leica Supernova ultramicrotome and contrasted with uranyl acetate and lead citrate. The sections were examined and photographed in a Philips EM 208 electron microscope and a Megaview III FW camera. Images were taken at ×20,000 magnification with a precalibrated transmission electron microscope. Figure courtesy of Niels Ørtenblad and Joachim Nielsen, University of Southern Denmark, Odense, Denmark. Not previously published.


In conclusion, research into muscle La metabolism remains a hotbed of activity 200 yr after the report of elevated La in exercised muscle. A major source of contention surrounds the exact pathway(s) of intracellular La oxidation. The model of interest is the intracellular lactate shuttle. The key questions are as follows: 1) How can La be tracked from one intracellular location to another? 2) Where is LDH precisely located inside muscle cells? 3) Does the intracellular lactate shuttle model require fixed locations of LDH to operate? Future studies may provide conclusive answers to these queries.


The author wishes to thank Matthew L. Goodwin, Andrés Hernández, and James E. Harris for their criticism and discussion of the manuscript drafts.


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intracellular lactate shuttle; lactate dehydrogenase; lactic dehydrogenase; isozymes; history

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