Intra- and extra-cellular lactate shuttles

GEORGE A. BROOKS
Department of Integrative Biology, University of California, Berkeley, CA 94720

ABSTRACT
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. Key Words: INTRACELLULAR LACTATE SHUTTLE, MONOCAR-
BOXYLATE TRANSPORTER, MCT GLUCONEOGENESIS, CARBOHYDRATE METABOLISM, LACTATE OXIDATION,
CORI CYCLE, GLUCOSE PARADOX, REDOX, MITOCHONDRIA, MITOCHONDRIAL MCT, MITOCHRONDRIAL LDH, LDH

T
he lactate shuttle hypothesis was introduced at the
First International Congress of Comparative Physi-
ology and Biochemistry held at Liege, Belgium, Au-
gust 1984. The subsequent paper appeared in congress pro-
ceedings 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 com-
pared glucose and lactate fluxes in rats during exercise and
recovery (17,19,30,37). Subsequently, we also studied glu-
cose and lactate fluxes in humans (15,16,20,82,83,9395).
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 ex-
ercise 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.
0195-9131/00/3204-0790/0
MEDICINE & SCIENCE IN SPORTS & EXERCISE
Copyright 2000 by the American College of Sports Medicine
Submitted for publication December 1998.
Accepted for publication December 1998.
790
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 vascu-
lature provides a significant carbon source for oxidation and
gluconeogenesis during rest and exercise (9). Subse-
quently, experiments conducted by us and others have con-
firmed 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 lac-
tate shuttle hypothesis did not find wide acceptance be-
cause 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, todays 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 Ex-
change was held. Proceedings were published in Medicine
and Science in Sports and Exercise the following year
(1991) and contained papers on lactate production in skel-
etal 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 Gladdens 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 Physio-
logical Society Handbook of Physiology-Exercise: Regula-
tion and Integration of Multiple Systems (44).
State of the Art, circa 1990
In the proceedings of the 1990 Annual Meeting of the
ACSM (12), the following findings were described:
1. Electrically stimulated dog muscle preparations studied
in situ release lactate on a net basis when contractions start,
but switch to net consumption as contractions continue
(103).
2. Measurements using NADH fluorescence (59) and
myoglobin cryomicroscopy (24) on electrically simulated
canine muscles studied in situ indicate that lactate produc-
tion occurs under fully aerobic conditions.
3. During continual, progressive exercise working human
muscle is a site of net lactate production and release as well
as the site of blood lactate appearance (93,94).
4. During constant rate, submaximal exercise working
human muscle first releases lactate on a net basis when
exercise starts but then switches to net lactate uptake as
contractions continue (1,16,20,81,99).
5. Perfusion with high blood lactate causes canine muscle
contracting in situ to switch from net lactate release to net
consumption (45,46).
6. Addition of arm to leg cycling exercise causes arterial
lactate concentration ([lactate]) to elevate. Consequently, when
the arterial [lactate] rises, exercising legs switch from net
lactate release to net consumption (81). Thus, in both dog
muscle contracting in situ and working human muscle in vivo,
elevation of arterial lactate delivery to working muscle has a
similar effect on shifting the balance of substrate utilization.
7. In resting humans, glucose rate of disappearance (Rd)
exceeds the rate of lactate appearance (Ra), but during
SHUTTLES WITHIN SHUTTLES
exercise the gain in lactate Ra is much greater than the gain
in glucose Rd (95), such that during hard exercise lactate Ra
and oxidation rate (Rox) exceed that of glucose (15,16,95).
8. During exercise, epinephrine secretion is exponentially
related to relative exercise intensity (65), and lactate Ra and
epinephrine concentration ([epinephrine]) are highly corre-
lated (16). However, slope of the lactate Ra-[epinephrine]
relationship is much greater during exercise than during rest.
These results suggest that contraction, not epinephrine, is
the major stimulator of glycolysis in muscle.
9. Working healthy cardiac muscle is a net consumer of
lactate, but free fatty acids are the major energy substrate for
the heart in resting subjects. However, during exercise when
arterial [lactate] rises, exogenous (arterial) lactate becomes
the major fuel for the heart (41,42).
10. Lactate is the major gluconeogenic precursor during
exercise, with gluconeogenesis contributing 2530% to he-
patic glucose production in both laboratory rats
(17,30,31,97,98) and humans (95).
11. Paradoxically, lactate, not glucose is the preferred
substrate for hepatic glycogen synthesis. Thus, the terms
glucose paradox and indirect pathway of liver glycogen
synthesis after eating were emerging and becoming ac-
cepted by the wider scientific community (6,27,35).
12. Lactate exchange through cell membranes in diverse
tissues was suspected to be carrier mediated. Facilitated ex-
change through cell membranes of erythrocytes (29,49), car-
diocytes (96), intestine (85), and by intact skeletal muscles was
known (86,87). Further, Roth and Brooks (86,87) had recently
demonstrated carrier-mediated lactate uptake by sarcolemmal
vesicles. Lactate uptake by sarcolemmal vesicles demonstrat-
ed: concentration dependence, saturation, competitive inhibi-
tion by other monocarboxylates, inhibition by known mono-
carboxylate inhibitors, stereospecificity, temperature, and
hydrogen ion dependence. Further, trans-stimulation was sus-
pected and soon demonstrated (22).
As a result of the knowledge available at the time, at the
1990 Annual ACSM Meeting the lactate shuttle hypothesis
was depicted as originally portrayed (Fig. 1). Features of the
hypothesis included: lactate production at sites of high gly-
colytic flux (e.g., Type IIB muscle fibers), lactate uptake
and removal at highly aerobic sites (Types I and IIA muscle
fibers), lactate transport through the interstitium and vascu-
lature with oxidation and gluconeogenesis representing ma-
jor routes of lactate disposal in heart and liver, respectively.
The Current State of the Art, 1996
Since the last ACSM symposium in 1990, some signifi-
cant progress has been achieved as evidenced by publication
of Dr. Gladdens reviews (43,44) and these proceedings.
Further, there is evidence that the coming year will yield
new and important discoveries in the areas of whole-body
and tissue lactate kinetics, and the biochemistry and molec-
ular biology of lactate exchange and metabolism. However,
for the interim, it is important to record progress in three
areas: the role of working muscle in net lactate release
and consumption, the role of lactate as a gluconeogenic
Medicine & Science in Sports & Exercise 791

Figure 1Model of the lactate shuttle. Lactate is formed in fast-twitch
white skeletal muscle fibers or transiently in populations of red fibers
at the start of exercise. Lactate released into the interstitium from
cellular sites of production can be taken up and oxidized by adjacent
lactate consuming muscle fibers. Alternatively, during exercise, some
lactate released into the circulation reperfuses the active muscle bed
within a fraction of a minute, where uptake and oxidation in red,
highly oxidative fibers occurs. Some of the lactate released from an
active muscle bed can be taken up by the heart and oxidized or taken
up by the liver and kidneys where lactate serves as a gluconeogenic
precursor. [Redrawn with permission from Brooks, G. A. Lactate:
Glycolytic product and oxidative substrate during sustained exercise in
mammalsthe lactate shuttle. In: Comparative Physiology and Bio-
chemistry: Current Topics and Trends, Volume A, RespirationMe-
tabolismCirculation, R. Gilles (Ed.). Berlin: Springer-Verlag, 1985,
pp. 208 218.]
precursor during exercise, and identification of the family of
cellular monocarboxylate transport proteins.
Working Muscle Net Lactate Release and Uptake
Our collaborative studies on Pikes Peak have been in-
valuable in allowing us to evaluate the interactive effects of
ambient hypoxia and exercise on glucose and lactate me-
tabolism (15,16,20,21,82,83). Using data from the 1988
study, I address two hypotheses regarding lactate metabo-
lism: 1) muscle lactate formation is the result of O2 lack, and
2) working muscle is the source of elevated blood lactate in
subjects during exercise and at altitude.
In 1988, and again in 1991, we studied men during
continuous leg cycling exercise at a power output that elic-
ited 50% of VO2max at sea level. The same subjects were
studied on arrival at 4300 m (PB 463 Torr) and after 3 wk
of residency. At altitude, the same power output elicited
65% of VO2max, and residency did not change VO2max
(21,104). Wolfel et al. (104) measured whole-body and
792 Official Journal of the American College of Sports Medicine
working limb VO2 during sustained exercise at altitude and
found O2 supply to be well-matched to demand. Thus, none
of the changes in blood lactate response could be attributed
to tissue O2 lack.
The arterial [lactate] response in each condition of sea
level and altitude exercise is shown in Figure 2. Results
display the typical pattern (33,80) of elevated arterial [lac-
tate] during exercise compared with rest, an increase in
[lactate] upon altitude exposure, and a decline to interme-
diate levels with acclimatization. Again, neither whole-body
nor leg VO2 changed with altitude acclimatization.
The constancy of arterial [lactate] levels during exercise
(Fig. 2) are to be contrasted with patterns of leg net lactate
release shown in Figure 3 (16,21). When exercise starts at
sea level, net lactate release from the legs (L 2
measured blood flow for one leg [v-a]lactate) increases
dramatically (Fig. 3 top), but after a few minutes, net lactate
release declines even though arterial [lactate] is elevated and
constant. Leg net lactate release is exaggerated at the start of
exercise at altitude, but the same pattern as at sea level holds
(Fig. 3, bottom and middle); initial lactate release upon
exercise onset is followed by a decline such that after 1520
min of exercise the working leg ceases to be a site of lactate
net release even though arterial [lactate] is elevated.
In our 1988 experiments on Pikes Peak, we also infused
[3-13C]lactate tracer (16). Thus, we were able to determine
that lactate was undergoing very active turnover in the blood
even though arterial [lactate] was constant. Further, lactate
turnover rate correlated with the circulating [lactate] (Fig.
4). Therefore, we knew that the elevation in circulating
lactate (Fig. 2) required a continuous input, which could not
Figure 2Arterial blood lactate concentration as a function of time
during exercise at sea level, upon acute exposure to 4300-m altitude,
and after 3 wk acclimatization. Values are mean SEM; N 7 each
point. Values plotted at 0 time are means of two preexercise samples.
The exercise elicited 51% of sea level VO2peak. [Redrawn with permis-
sion from Brooks, G. A., G. E. Butterfield, R. R. Wolfe, B. M. Groves,
R. S. Mazzeo, J. R. Sutton, E. E. Wolfel, and J. T. Reeves. Decreased
reliance on lactate during exercise after acclimatization to 4,300 m.
J. Appl. Physiol. 71:333341, 1991.]
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Figure 3Net blood lactate release from the legs during rest and leg
cycling exercise at sea level (top panel), upon acute exposure to 4300-m
altitude (middle panel), and after 3 wk of residency at 4300-m altitude
(bottom panel). Each point mean SEM; N 7 each point. [Redrawn
from Brooks, G. A., E. E. Wolfel, B. M. Groves, P. R. Bender, G. E.
Butterfield, A. Cymerman, R. S. Mazzeo, J. R. Sutton, R. R. Wolfe, and
J. T. Reeves. Muscle accounts for glucose disposal but not blood lactate
appearance during exercise after acclimatization to 4,300 m. J. Appl.
Physiol. 72:24352445, 1992.]
be ascribed to release from working skeletal muscle (Fig. 3).
In fact, because we had measurements of [arterial-venous]
concentration differences for lactate and tracer lactate, we
knew that working muscle readily took up and oxidized
lactate in a concentration-dependent manner (Fig. 5). Thus,
working human limb muscles behaved like dog muscles
contracting in situ (45,46). Moreover, the tracer lactate
extracted by working muscle was quantitatively excreted as
13
CO2, which was measured in the femoral venous blood
and expired air (16). What remains unclear at present is the
identity of the tissue, or tissues, responsible for the contin-
uous lactate production and blood lactate appearance ob-
served. Alpha-adrenergic stimulation of glycolysis in adi-
pose tissue (34) and skin (61) has been observed, and it has
been suggested that these tissues are possible sites of lactate
production during exercise (20,21). In running dogs, the
liver is a source of net lactate release during exercise (101),
but in humans (54,95,99) and rats (17,30,31,97,98) the liver
appears to participate in lactate clearance by accomplishing
gluconeogenesis from lactate.
SHUTTLES WITHIN SHUTTLES
Gluconeogenesis During Exercise
Since the previous symposium, some progress has been
made in the area of evaluating the importance of lactate as
a gluconeogenic precursor during exercise. At present, the
volume of data is small, but different methods have yielded
similar results. Representative results are summarized in
Table 1. Before discussing gluconeogenesis during exercise
in more detail, a context needs to be provided.
During exercise, most (75 80%) of lactate is removed via
oxidation, and 20 25% of the lactate flux is disposed of by
conversion to glucose. We have obtained corresponding
data on rats (17,30) and humans (15,16,21,95), and similar
data have been obtained on dogs (28,56). However, because
the lactate flux during exercise can be far larger than the
glucose flux, conversion of lactate to glucose is sufficient to
make a significant contribution to hepatic glucose produc-
tion. In resting postabsorptive individuals, gluconeogenesis
contributes approximately 1530% to hepatic glucose pro-
duction, and hepatic glycogenolysis the remainder.
The data in Table 1A were obtained by use of the so
called secondary labeling technique. This approach in-
volves infusion of carbon tracer lactate (e.g., [3-13C]lactate)
and measurement of abundance of the label in circulating
glucose (54). However, as has been well described by Hete-
nyi et al. (51) and others, isotopic dilution of 3-C precursors,
such as pyruvate, in the TCA and other pools during glu-
coneogenesis requires application of correction (H) factors
for estimating gluconeogenesis from 3-C precursors. Unfor-
tunately, although the H factors are known to vary according
to condition, they are difficult to estimate and usually re-
quire separate experiments. Therefore, a factor to correct
Figure 4 Mean steady-state arterial [lactate] ( SEM) as a function
of mean lactate rate of appearance (Ra) during exercise in 7 men
studied at sea level (SL), upon acute exposure to 4300 m and after 3 wk
acclimatization to 4300-m altitude. [Drawn with permission from data
in Brooks, G. A., G. E. Butterfield, R. R. Wolfe, B. M. Groves, R. S.
Mazzeo, J. R. Sutton, E. E. Wolfel, and J. T. Reeves. Decreased
reliance on lactate during exercise after acclimatization to 4,300 m.
J. Appl. Physiol. 71:333341, 1991.]
Medicine & Science in Sports & Exercise 793

Figure 5Leg blood lactate extraction as a function of arterial con-
centration during rest (closed symbols) and leg cycling exercise (open
symbols) at sea level (squares), upon acute exposure to 4300-m altitude
(circles), and after 3-wk acclimatization (triangles). Each point N
6 7, mean SEM. Lactate extraction is highly correlated with arterial
concentration. [Redrawn with permission from Brooks, G. A., E. E.
Wolfel, B. M. Groves, P. R. Bender, G. E. Butterfield, A. Cymerman,
R. S. Mazzeo, J. R. Sutton, R. R. Wolfe, and J. T. Reeves. 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.]
for isotopic dilution due to carbon crossover during glu-
coneogenesis is generally assumed, rather than empirically
determined. The data in Table 1A assume H 1.0, which
means no correction for isotopic dilution. Therefore, the
listed values possibly represent underestimations of glu-
coneogenesis from lactate. The values are relevant, how-
ever, as they provide an appreciation of the major role of
lactate as a gluconeogenic precursor.
Another approach to estimating gluconeogenesis is to
employ a dual tracer technique. This technique involves
infusion of hydrogen-tracer glucose (e.g., [6,6-2H]glucose,
an irreversible tracer in which the labeled atoms are lost
to body water during gluconeogenesis), and carbon-tracer
glucose (e.g., [1-13C]glucose, a reversible tracer as the
resulting carbon-labeled lactate, pyruvate, and alanine will
recycle to glucose as the result of the Cori cycle) (26). Of the
3-C precursors, lactate is by far the most abundant and
quantitatively important. The data presented are from the
recent report of Friedlander et al. (36). In men, recycling
accounted for 17% of glucose Ra at rest and 24% during
exercise at 65% VO2max. Because the glucose flux doubled
in the transition from rest to exercise, the actual recycling
rate tripled.
With regard to estimating gluconeogenesis during exer-
cise, a new approach of Hellerstein and Neese and associ-
ates termed mass isotopomer discrimination analysis
(MIDA) (50,76) is emerging. This approach involves infu-
sion of 13C-labeled 3-carbon gluconeogenic precursors (e.g.,
13
C-lactate or -glycerol) and observing the frequency of
label incorporation into glucose. MIDA will yield less am-
biguous results than secondary labeling or dual tracer ap-
proaches, and preliminary data (Trimmer et al., unpublished
data) are consistent with the data in Table 1.
794 Official Journal of the American College of Sports Medicine
Sarcolemmal Monocarboxylate
(Lactate) Transporters
Implicit in the lactate shuttle hypothesis of 1984 (Fig. 1)
is facilitated exchange of lactate between lactate producing
and consuming cells and tissues. The idea that lactate would
exchange between red and white muscle fibers through the
interstitium and vasculature was prompted by observations,
such as those of Baldwin et al. (4), who observed that lactate
content in red regions of rat muscle was lower than in
adjacent white regions of the same muscle, or even arterial
blood. The idea of facilitated lactate exchange along con-
centration gradients in human skeletal muscle was sup-
ported by observations of Jorfeldt (62), and subsequently
Stanley et al. (94), that muscle lactate uptake displayed
saturation. At that time, there existed no definitive data on
carrier-mediated sarcolemmal lactate exchange, but the lit-
erature contained significant data that indicated presence of
carrier-mediated monocarboxylate exchange in erythro-
cytes. Results of two groups, Halestrap and Denton (49) and
Deuticke and associates (29) were prominent in those dis-
coveries. Moreover, lactate uptake by liver (75,84) and heart
(96) preparations was noted. In addition to other characteristics
of carrier-mediated transport, inhibition by -cyano-4-hy-
droxycinnamate (CIN) was prominent. As well, Halestrap and
Denton (48,49) and Paradies and Papa (77) showed that mito-
chondrial pyruvate uptake was sensitive to CIN.
With regard to lactate exchange in skeletal muscle, in
1975 Mainwood and Worsley-Brown (71) showed that pH
could influence lactate release from frog muscle. Subse-
quently, in 1988, independently Juel (63) and Watt et al.
(102) working with mouse and rat muscle preparations,
respectively, provided convincing evidence of facilitated
and proton-linked lactate transport into muscle tissue. Those
observations were followed by the work of Roth and Brooks
(86,87) on isolated sarcolemmal vesicles.
Understanding tissue metabolite exchange is difficult be-
cause the factors determining metabolite uptake and release
are arranged in series and parallel. Difficulties in under-
standing metabolite exchange by cells and tissues has re-
sulted in reductionist approaches including the isolation of
cell membranes and their reconstitution as vesicles. Thus,
preparation of sarcolemmal vesicles has become a standard
means to study the ability of metabolites to enter and leave
muscle cells, with investigators in the field of glucose trans-
port leading the way (47).
TABLE 1. Gluconeogenesis as a percentage of hepatic glucose production in men
during rest and exercise as estimated from: (A) secondary labeling of glucose from
infused carbon-tracer [13C]- or [14C]-lactate, and (B) dual tracer (e.g., [6,6-2H]- and
[1-13C]glucose) techniques. In (A), data are uncorrected for carbon-crossover in
gluconeogenesis (i.e., H 1.0 is assumed).
Exercise Exercise
Rest (%) (%) Intensity Reference
A. Secondary labeling approach
24 23 43% VO2max (95)
26 24 50% VO2max (54)
H 1.0 H 1.0
B. Dual-tracer approach
17 17 45% VO2max (36)
24 65% VO2max (36)
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Figure 6 L() and D() lactate transport kinetics in rat sarcolemmal
vesicles at various concentrations of isomers. Data are mean SEM. Inset
is a Lineweaver-Burk plot of the L() lactate data. [Redrawn with per-
mission from 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. 279:377385, 1990.]
Utilizing the procedures of Grimditch et al. (47), Roth and
Brooks (86,87) were the first to utilize sarcolemmal vesicles
to characterize membrane-mediated lactate transport. Roth
and Brooks (86,87) found sarcolemmal lactate transport to
display characteristics of: concentration dependence, satu-
ration and stereospecificity (Fig. 6), partial inhibition by
other monocarboxylates, blockade by known inhibitors of
monocarboxylate transport (Fig. 7), temperature sensitivity,
and stimulation by hydrogen ion gradients. Important for
understanding the physiology of tissue lactate exchange in
vivo was the demonstration of high Vmax and Km values for
sarcolemmal lactate transport. Those results mean that cell
lactate uptake and release are responsive to gradients in
lactate concentration and hydrogen ion concentration
through the physiological range.
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, trans-
porters can facilitate lactate flux along concentration and
proton gradients, either into or out of muscle cells. Impor-
tantly, 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 pro-
teins 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 eryth-
rocyte transporter including increased pyruvate uptake, proton
symport, trans-stimulation, partial inhibition by other mono-
SHUTTLES WITHIN SHUTTLES
carboxylates (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.
Independent of Garcia et al., Poole and Halestrap (79) and
Jackson et al. (57,58) cloned and sequenced MCT1 and
MCT2 isoforms from rabbit and rat tissues, respectively.
Subsequently, the same group succeeded in identifying
RNAs encoding for four more putative MCTs found in
diverse mammalian tissues. Those results are summarized in
the accompanying paper by Bonen, who presents a detailed
discussion of MCT isoforms.
Notwithstanding that little is published on regulation of
MCT expression in diverse tissues, it is probable that ex-
pression can be affected by chronic activity level. For ex-
ample, 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 an-
tibody 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 phos-
phorylation 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
Figure 7Inhibition of 1 mM L() lactate uptake into rat sarcolem-
mal vesicles by a variety of known inhibitors. [Redrawn with permis-
sion from 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. 279:377385, 1990.]
Medicine & Science in Sports & Exercise 795

Figure 8 Schematic of a proposed intra-myocyte lactate shuttle. In
this model, the pyruvate 7 lactate interaction is fundamentally dif-
ferent from that previously proposed in that lactate, not pyruvate is the
key metabolite in determining oxidation of glycolytic carbon or net
release as lactate. This model explains numerous phenomena incon-
sistent with traditional views of the integration and regulation of
glycolytic and oxidative pathways in muscle and other tissues. Com-
ponents of the model are: isoforms of glucose (GTi) and lactate (LTi)
transporter proteins, isoforms of lactate dehydrogenase (LDHi) lo-
cated in the cytosol and mitochondrial periplasmic space, and glyco-
lytic and oxidative pathways organized in the cytosol and mitochon-
dria, respectively. See text for details. [Redrawn with permission from
Brooks, G. A. Mammalian fuel utilization during sustained exercise.
Comp. Biochem. Physiol. 120:89 107, 1998.]
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 kid-
neys. Thus, rather than by recruitment or activation of sar-
colemmal lactate transport proteins (i.e., MCTs), lactate clear-
ance is most likely controlled by mitochondrial uptake and
oxidation in vivo.
Proposal for an Intracellular Lactate Shuttle
The findings that working cardiac (41,42) and highly
oxidative mammalian (e.g., canine, 106) skeletal muscles
simultaneously consume lactate on a net basis and convert
glucose to lactate, along with numerous other observations
on men and laboratory animals during steady rate exercise,
are interpreted to mean that most glycolytic flux is con-
verted to lactate and disposed of as lactate within a muscle
fiber. Thus, the lactate shuttle hypothesis has been mod-
ified to include an intra- as well as extra-cellular component
(i.e., an intracardiocyte and myocyte lactate shuttle) (Fig.
8) (13). If true, the hypothesis requires a reevaluation of the
traditional way in which intracellular pyruvate 7 lactate
interactions are conceived to operate in vivo.
Current evidence can be interpreted to imply that in
muscle both sarcolemmal (13,39,78,86) and mitochondrial
membranes (13,48,77) contain monocarboxylate (lactate)
transporters. With regard to the possibility of one or several
796 Official Journal of the American College of Sports Medicine
mitochondrial lactate (monocarboxylate) transporters, the
current literature contains the following bits of evidence.
Heart and skeletal muscle homogenates (74) and isolated
heart mitochondria take up and oxidize both pyruvate and
lactate (8,13,13a,67). Pyruvate uptake and oxidation by mi-
tochondria and isolated heart preparations are sensitive to
inhibition by known MCT inhibitors, such as -cyano-4-
hydroxycinnamate (CIN) (7,23,45). As well, we have found
that lactate uptake and oxidation by isolated mitochondria is
CIN-sensitive (13a). Moreover, isolation and partial purifi-
cation of a mitochondrial MCT (mMCT) has been reported
for bovine heart (7). Using similar methodology, we (2)
have used hydroxylapatite column chromatography to iso-
late and partially purify sarcolemmal lactate transport pro-
teins. As with sarcolemmal MCT isoforms, it is unlikely that
the mitochondrial form responds to allosteric activation.
Rather, the mitochondrial MCT isoform likely responds to
changes in substrate concentration dependent on lactate and
pyruvate gradients established as the result of glycolytic
production and mitochondrial consumption rates.
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. De-
pending 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). More-
over, 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 sur-
prising that isolated mitochondria consume and oxidize lac-
tate 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 intra-
cellular lactate shuttle (Fig. 8) (13) makes seemingly diver-
gent 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-oxygen-
ated red muscle and heart. Thus, mitochondrial respiration, not
cell membrane lactate transport, reemerges as the key step in
control of lactate homeostasis.
The model of an intracellular component of the lactate
shuttle (Fig. 8) also predicts several other observations.
http://www.msse.org
Among these are that glycolysis inevitably results in lactate
production because the Vmax of cytosolic LDH is the great-
est of any enzyme in the glycolytic pathway and the Keq is
far in the direction of product. Also, the model predicts that
in a respiratory steady-state, elevation of arterial lactate
concentration results in a switch from muscle lactate net
release to uptake as well as suppression of glucose uptake
(41,81). Similarly, the model allows that epinephrine stim-
ulation of muscle glycogenolysis results in lactate release
during constant oxygen consumption (90,91), whereas -ad-
renergic blockade lowers, but does not eliminate the surge in
muscle lactate release at exercise onset (20). High capacities
for lactate clearance in trained men (95) and animals (30,31)
result in lower muscle and blood lactate accumulations
despite high production rates during exercise. Thus, the
hallmark of low circulating lactate levels after endurance
training is a characteristic attributable to high mitochondrial
densities and lactate clearance in skeletal muscle (11,12).
Therefore, increasing muscle mitochondrial density by in-
creasing mitochondrial lactate and pyruvate transport and
oxidase capacities facilitates function of the intracellular
(intra-cardio/myocyte) lactate shuttle.
In the model proposed (Fig. 8), the sarcolemmal lactate
transporter is shown as facilitated lactate exchange along
concentration and pH gradients. At the level of the whole
tissue, this arrangement is supported by observations that
muscle can switch from net release to consumption (Figs. 3
and 5). As well, trans-stimulation of lactate transport into
and out of sarcolemmal vesicles (22) and erythrocyte ghosts
(78) supports the conclusion that sarcolemmal lactate trans-
porters are bi-directional in their function. That the various
MCT isoforms are specifically oriented trans and cis trans
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This work was supported by NIH grants DK19577 and AR42906.
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