Acta Physiol 2010, 199, 499–508

REVIEW
Lactate kinetics in human tissues at rest and during exercise

Gerrit van Hall

Metabolic Mass-Spectrometry Facility, Rigshospitalet and Department of Biomedical Sciences, Faculty of Health Sciences, University of
Copenhagen, Copenhagen, Denmark

Received 5 July 2009, Abstract

accepted 7 September 2009
Correspondence: G. van Hall,
Metabolic Mass-Spectrometry
Facility, Rigshospitalet, Section
7652, 9 Blegdamsvej, DK-2100
Copenhagen Ø, Denmark.
E-mail: gvanhall@cmrc.dk
Lactate production in skeletal muscle has now been studied for nearly two
centuries and still its production and functional role at rest and during
exercise is much debated. In the early days skeletal muscle was mainly seen as
the site of lactate production during contraction and lactate production
associated with a lack of muscle oxygenation and fatigue. Later it was rec-
ognized that skeletal muscle not only played an important role in lactate
production but also in lactate clearance and this led to a renewed interest,
not the least from the Copenhagen School in the 1930s, in the metabolic role
of lactate in skeletal muscle. With the introduction of lactate isotopes muscle
lactate kinetics and oxidation could be studied and a simultaneous lactate
uptake and release was observed, not only in muscle but also in other tissues.
Therefore, this review will discuss in vivo human: (1) skeletal muscle lactate
metabolism at rest and during exercise and suggestions are put forward to
explain the simultaneous lactate uptake and release; and (2) lactate metab-
olism in the heart, liver, kidneys, brain, adipose tissue and lungs will be
discussed and its potential importance in these tissues.
Keywords glycogenolysis, glycolysis, intracellular compartmentation,
lactate dehydrogenase, lactate shuttle.

Skeletal muscle lactate metabolism has been studied for
nearly two centuries and its production and functional
role at rest and in muscle contraction is still a subject of
debate (for a historical overview, see Karlsson 1971).
The Copenhagen School in the 1930s with Einar
Lundsgaard and Ole Bang also contributed to the debate
but not as much as Lindhard and Krogh. However, Ole
Bang at the Department of Medical Physiology at the
University of Copenhagen with Christian Bohr’s succes-
sor as mentor, Professor V. Henriques, was closely
connected with Krogh and Lindhard and they were both
mentioned in his thesis (Bang 1936). Moreover, Ole
Bang worked much on the improvement of the lactate
analysis but the samples originated from Erik Hohwü-
Christensen’s experiments. Ole Bang was the first to
notice that blood lactate levels increased with exercise
but decreased again after 10–20 min of continuous
exercise and he concluded ‘The removal of lactate during
the initial anaerobic muscular activity is going on during
steady state as an accessory process (possibly some of the
lactate is burned up in the oxidative processes in the
active muscle) until there is no more excess lactate left’
(Bang 1936). This conclusion has magnificently stood
the test of time as will be discussed in this review;
however, it seems to be forgotten by many in sport
physiology. Einar Lundsgaard was more active on the
international scene. In his Harvey lecture in New York
1937 (Lundsgaard 1938) he attacked Meyerhof’s con-
clusion that a constant lactic acid production occurs
from the start to finish of exercise and that it was
essential for muscle contraction. The constant lactic acid
production was supposed to lead, in relative few
minutes, to the attainment of a constant, increased
lactate level in the active muscle, subsequently main-
tained throughout the ‘steady state’ exercise. Lundsg-
aard argued that lactate was not essential for muscle
biochemistry; based on his observation that iodo-acetic
acid poisoning muscle was able to contract. However, he
also mentioned that the amount of work performed by
isolated poisoned muscle was much smaller than that of

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Tissue lactate kinetics Æ G van Hall
a normal one. This review will follow up on this debate
as to whether or not lactate is an essential metabolite in
skeletal muscle metabolism with the extension to the
relevance of lactate metabolism in other tissues.
Skeletal muscle lactate metabolism at rest
and during continuous moderate intensity
exercise
Upon the start of moderate intensity exercise blood
lactate accumulation increases but after some time,
depending on the intensity, it starts to decrease as
already noticed by Ole Bang in the mid-1930s (Fig. 1a).
However, if one measures directly across the muscle
with arterial–venous differences, it can be seen that a
small muscle net lactate release under resting conditions
increases instantaneously many fold where after imme-
diately a steady decrease in net lactate release occurs
(Fig. 1b) and a similar but quantitatively far lower net
release of pyruvate and alanine, suggesting that during
the initial transition from rest to exercise the muscle
exhibits a very high rate of glycogenolysis/glycolysis and
a release of excessive pyruvate and shunting to lactate
via lactate dehydrogenase and alanine via alanine
aminotransferase. However, the picture is more com-
plex as a simultaneous unidirectional lactate uptake and
release occurs (Jorfeldt 1970, van Hall et al. 2003). The
decrease in net lactate release with exercise duration is
brought about by a decrease in lactate release (produc-
tion) with an unchanged lactate uptake (utilization) as
shown for the active forearm when arterial lactate
concentration is similar over time (Jorfeldt & Wahren
1970), implying that the decrease in net lactate release
with exercise duration is mainly caused by decreased
production, not utilization. However, skeletal muscle
has a far more flexible lactate metabolism than can be
seen during normal continuous arm or leg exercise. The
muscle has the ability to switch quickly from a net
lactate producer to a net lactate consumer when arterial
Figure 1 Arterial concentration and net leg release of lactate, pyruvate and alanine at rest and during one-leg knee-extensor
exercise at 70% of maximal power output of the knee-extensors (G. van Hall, B. Saltin & F. Dela, unpublished data).
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Acta Physiol 2010, 199, 499–508
lactate levels are increased by lactate infusion (van Hall
et al. 2009b) or exercise (Richter et al. 1988). In fact,
the active leg consumes more lactate than the resting leg
when arterial lactate levels are increased markedly when
the two-arm ergometer is added to leg exercise (Richter
et al. 1988). The reason that the increase in arterial
lactate concentration can cause the muscle to switch
from net release to uptake is that muscle unidirectional
lactate uptake is tightly correlated with arterial con-
centration/lactate delivery (van Hall et al. 2003, 2009b)
and the lactate taken up is oxidized (van Hall et al.
2002, 2003), whereas the unidirectional lactate release
is related to metabolic rate of the muscle (van Hall et al.
2003). How to explain these observations of (1) the
high initial high rate of glycogenolysis/glycolysis and
lactate production that immediately decreases with
duration of continuous exercise and (2) the simulta-
neous lactate uptake and release by skeletal muscle and
that these two processes both increase with muscle
contraction and not just the lactate release.
Upon the start of exercise muscle adenosine triphos-
phate (ATP) requirement for contraction is instanta-
neously many-fold increased whereas the increase in
muscle oxygen utilization is somewhat delayed (Bang-
sbo et al. 2000, Krustrup et al. 2004, Grassi 2005).
Muscle ATP levels are virtually unchanged, suggesting
that ATP hydrolysis is matched by re-synthesis via PCr
(creative phosphate) and glycogenolysis/glycolysis, the
latter quantitatively most important. These two fast
processes are crucial to match ATP utilization until
oxidative phosphorylation, energy transport of NADH
(nicotinamide adenine dinucleotide) to and into the
mitochondria via the malate-aspartate shuttle system as
the most important one, and adenosine diphosphate
(ADP) via creatine kinase convection to the mitochon-
dria and ATP back to the myofibrils are optimal again
(Hochachka 2003, Hochachka & Beatty 2003, Kaasik
et al. 2003, Grassi 2005) (Fig. 2). An immediate
adjustment of glycolytic rate is thought to be regulated
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Acta Physiol 2010, 199, 499–508 G van Hall Æ Tissue lactate kinetics

Figure 2 Scheme for skeletal muscle lactate metabolism. The myocyte, indifferent whether fast or slow twitch fibre, is suggested to
consist of a glycolytic and an oxidative compartment. The glycolytic compartment close to the myofibrils and their glycogen stores
associated with glycogenolysis/glycolysis and lactate release into the circulation. The other oxidative compartment is in close
proximity of the mitochondria. The mitochondria form a sink for both pyruvate and NADH causing low local concentration and
thus lactate utilization via mass action of the equilibrium enzyme lactate dehydrogenase and associated with lactate uptake from the
circulation and subsequent oxidation. Possibly, the subsarcolemmal mitochondria play an important role due to their localization in
close proximities of the arterioles (Hoppeler & Fluck 2003).

at the site of 6-phosphofructo-1-kinase, activated by dehydrogenase reaction. Thus, lactate formation via de
free ADP, AMP and Pi. Moreover, it is mandatory for a equilibrium enzyme lactate dehydrogenase is caused by
high myofibrillar glycogenolytic/glycolytic rate to main- a local mass action of high pyruvate and NADH
tain NAD+ levels for the glyceraldehydes 3-phosphate concentrations; possibly also essential to re-synthesize

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Tissue lactate kinetics Æ G van Hall
NAD+ to maintain a high glycogenolytic rate and as
argued to prevent an acute local low pH as the protons
are utilized in the lactate dehydrogenase reaction
towards lactate formation (Robergs et al. 2004). When
exercise duration at the same workload continues net
lactate formation ceases as oxidative phosphorylation
and/or ATP transport from mitochondria to myofibril is
matched with demand. Lactate formation will decrease
due to lowering of glycogenolytic rate and thus pyru-
vate and NADH concentration. When workload will be
increased like in for example an incremental exercise
protocol an increased mismatch will occur between the
glycogenolytic and oxidative phosphorylation rate,
hence a higher lactate formation in a linear fashion
(van Hall et al. 2009b).
How to explain the simultaneous lactate uptake and
release by skeletal muscle and the fact that these two
processes both increase with muscle contraction? Orig-
inally, it has been suggested that the slow twitch fibre
took up lactate from the circulation or lactate produced
by neighbouring fast twitch fibres. This was mainly
based on the higher content of heart type lactate
dehydrogenase isoform in slow twitch fibres that was
assumed to promote lactate utilization vs. the higher
lactate production capacity of fast twitch fibres with a
higher content of the muscle lactate dehydrogenase
isoform suggested to promote lactate formation. How-
ever, myocellular compartmentation of both the slow
and fast twitch fibres (Fig. 2) is a more likely explana-
tion for the simultaneous lactate production and utili-
zation. Thus, lactate uptake and subsequent oxidation
vs. production takes place in the same cell depending on
the local intracellular milieu, i.e. myocellular compart-
mentation (Brooks 1991, van Hall 2000) as suggested
previously for vascular smooth muscle (Lynch & Paul
1983) and heart (Peuhkurinen et al. 1983, Schadewaldt
et al. 1983, Bunger 1985, Chatham et al. 2001). In
addition, the overall picture of skeletal muscle lactate
dehydrogenase activity and isoform patterns is that the
heart type lactate dehydrogenase does not necessarily
favour pyruvate production and the muscle type lactate
dehydrogenase lactate production but that all lactate
dehydrogenase isoforms in vivo have the ability to
produce or consume lactate depending on the very local
lactate and pyruvate concentrations and redox state
(van Hall 2000, Newsholme 2003). Convincing evi-
dence is that patients with only the heart type LDH1
isoform in skeletal muscles do accumulate lactate
during ‘semi ischaemic’ exercise and, in fact, in excess
of their absolute lactate dehydrogenase activity com-
pared with healthy individuals (Kanno & Maekawa
1995, Miyajima et al. 1995a,b). Moreover, the relative
quantities of lactate dehydrogenase isoforms may vary
considerably between fibre types or in endurance vs.
strength or sprint-trained athletes – the absolute quan-
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Acta Physiol 2010, 199, 499–508
tity of heart type lactate dehydrogenase is virtually the
same (for an extensive review, see van Hall 2000).
Furthermore, the instantaneous switch from a resting or
active limb, that maintains the same workload, from a
large net lactate release to an uptake (Richter et al.
1988, van Hall et al. 2003) suggests that lactate
dehydrogenase isoform or fibre type recruitment cannot
be important but the local environmental milieu around
the lactate dehydrogenase of pyruvate/NADH vs.
lactate/NAD+. Therefore, a simple two-pool model for
myocellular lactate compartmentation is suggested.
A glycolytic compartment close to the myofibrils and
their glycogen stores associated with glycogenolysis/
glycolysis, and lactate release into the circulation. The
other oxidative compartment is in close proximity of
the mitochondria. The mitochondria form a sink for
both pyruvate and NADH causing low local concen-
trations and thus lactate utilization via mass action of
the equilibrium enzyme lactate dehydrogenase and is
associated with lactate uptake from the circulation and
subsequent oxidation. Observations made in creatine
kinase-deficient mice underscore the concept of com-
partmentation and intramyocellular diffusion limitation
for energy transfer that makes local high rates of
glycolysis and thus lactate formation mandatory. Major
changes are seen in the glycolytic network and mito-
chondrial design when creatine kinase is absent. A large
number of mitochondria is found dispersed between the
myofibrils near the longitudinal sarcoplasmatic reticu-
lum and the myosin filaments (de Groof et al. 2001,
Kaasik et al. 2003, Novotova et al. 2006) reducing the
distance for energy transfer within the myocyte. It
should be emphasized that the glycolytic and oxidative
compartment should not be seen as separated units for
lactate release into and lactate uptake from the circu-
lation respectively. The lactate produced in the glyco-
lytic compartment can diffuse to the oxidative
compartment for oxidation within the cell without
being released into the circulation, most likely the
intramyofibrillar mitochondria are important in that
process. The subsarcolemmal mitochondria on the other
hand may play an important role in the lactate taken up
from the circulation and its subsequent oxidation due to
their localization in close proximities of arterioles
(Hoppeler & Eliich 2003). Of note is that in the
proposed model for skeletal muscle lactate metabolism
there is no role or necessity for mitochondrial lactate
dehydrogenase and thus mitochondrial lactate oxida-
tion as suggested by Szczesna-Kaczmarek (1990a,b) and
pressed by Brooks and co-workers (Brooks et al. 1999,
Hashimoto et al. 2006, 2008). To date, the over-
whelming theoretical (Sahlin et al. 2002) and practical
evidence is against lactate oxidation by skeletal muscle
mitochondria (Popinigis et al. 1991, Rasmussen et al.
2002, Sahlin et al. 2002, Ponsot et al. 2005, Yoshida
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Acta Physiol 2010, 199, 499–508
et al. 2007) and it should be concluded that it does not
occur as summarized by Gladden (2007) and Bonen and
co-workers (Bonen et al. 2007, Yoshida et al. 2007).
Tissue contribution to systemic lactate
turnover
Heart
The heart exhibits a net lactate uptake under resting
conditions; however, similar to skeletal muscle a mutual
unidirectional lactate uptake and release is observed
(Gertz et al. 1981, Wisneski et al. 1985a,b, Neglia et al.
2007) (Fig. 3). The lactate taken up by the heart is
almost entirely oxidized (Wisneski et al. 1985a,b, Gertz
et al. 1988). The unidirectional lactate uptake is highly
positively correlated with the arterial lactate concentra-
tion (Gertz et al. 1988), similar to that seen for skeletal
muscle. However, in contrast to the skeletal muscle, the
heart does not seem to increase much its lactate release
with enhanced metabolic rate during pacing in patients
with coronary artery disease (Wisneski et al. 1985a,b)
and during exercise in healthy individuals (Gertz et al.
1981, 1988). As already discussed for skeletal muscle,
the explanation of the simultaneous lactate uptake and
release by the heart is intracellular compartmentation of
lactate metabolism. Interestingly, carbohydrate oxida-
tion by the heart via lactate is higher than via exogenous
glucose at rest and during exercise. The contribution of
lactate to oxidative energy production is reported to be
about 10–15% at rest (Gertz et al. 1988, Neglia et al.
2007) and increases to about 30% during moderate
G van Hall Æ Tissue lactate kinetics
intensity exercise (Gertz et al. 1988), which is consid-
erably higher than the contribution of exogenous
glucose with 8–14% at rest and exercise respectively.
The important role of lactate in heart energy metabo-
lism is underpinned by a recent study showing that
systemic lactate deprivation is detrimental to myocar-
dial energetic, cardiovascular performance and outcome
in rats (Levy et al. 2007).
Brain
The brain exhibits a net lactate release of about
50 lmol min)1 in post-absorptive healthy individuals
(van Hall et al. 2009b). Nevertheless, lactate as a fuel
for the brain has been debated for many years between
those who claim that glucose is the sole energy substrate
for brain cells and the others who support the concept
that lactate could be an important fuel for neurones
(Pellerin et al. 2007). The lactate for neuronal oxidation
is suggested to originate mainly from astrocytes, i.e. the
astrocyte-to-neurone lactate shuttle (Pellerin & Magist-
retti 1994). Less emphasis has been on a potential brain
lactate uptake from the circulation and subsequent
metabolism despite observation of a net lactate uptake
during exercise when arterial lactate levels are markedly
increased with insulin-induced hypoglycaemia (Lubow
et al. 2006), cardiopulmonary resuscitation (Rivers
et al. 1991) and high-intensity exercise (Ide et al.
2000). Moreover, during hypoglycaemia cognitive func-
tion is improved when lactate is infused similar to
hyperketonaemia (Maran et al. 1994, Veneman et al.
1994, King et al. 1997, 1998). Recently, it was shown

Figure 3 Scheme of tissue contributions to systemic lactate turnover in healthy humans under post-absorptive conditions (a) and
during moderate intensity exercise (b). This scheme is compiled from data of different studies and should be considered as
estimates also in view of extrapolations of local skeletal muscle (leg or forearm) and adipose tissue (abdominal wall) to
whole-body skeletal muscle and adipose tissue and of somewhat different exercise intensities, durations and tracer use
(Ahlborg 1974, Gertz et al. 1988, Consoli et al. 1990, van der Merwe et al. 1999, Cersosimo et al. 2000a,b, Mulla et al. 2000,
van Hall et al. 2002, 2003, 2009a,b, Meyer et al. 2002, Woerle et al. 2003, Neglia et al. 2007, Qvisth et al. 2007).

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Tissue lactate kinetics Æ G van Hall
that despite a brain net lactate release a substantial
simultaneous unidirectional lactate uptake was observed
similar to that in the skeletal muscle (van Hall et al.
2009b). However, in contrast to the skeletal muscle but
similar to the heart, virtually all lactate that is taken up
is oxidized. When lactate levels are elevated due to
lactate infusion or exercise the unidirectional lactate
uptake increases tightly positively correlated with arte-
rial lactate concentration as seen for the heart and the
skeletal muscle. Moreover, cerebral energy requirement
via lactate could account for about 7% under basal
conditions and up to 25% during exercise and lactate
infusion reaching systemic lactate levels of 7 mmol L)1.
The brain contributes substantially to systemic lactate
production and utilization with 13% and 8% under
basal conditions respectively. During exercise the active
skeletal muscle is the predominant tissue in lactate
turnover; however, due to the substantial increase in
cerebral lactate uptake and subsequent oxidation the
brain relative contribution to lactate clearance increased
to 11%. It can be concluded that lactate is an essential
part of cerebral energy metabolism either for neurones
or astrocytes. Astrocytes have also been suggested to
utilize lactate based on their capacity to oxidize lactate
(Peng et al. 1994, Zielke et al. 2007), brain anatomy
and potential astrocytic compartmentation (van Hall
et al. 2009b). An astrocyte has three major anatomical
areas – the soma (cell body), the larger processes
(including those associated with arterioles and venules
as endfeets), and the very fine surface extensions
lamellae and filopodia, also called peripheral astrocytic
processes (PAPs), that are in close apposition with
neuronal elements (including synapses) (Nedergaard
et al. 2003, Hertz et al. 2007). Therefore, in analogy
with the suggestions for skeletal muscle, subcellular
regions within astrocytes may differ in their spatial and
temporal dependence on the glycolytic and oxidative
pathways. The astrocytic oxidative capabilities reside in
the soma and larger cell processes that contain the
mitochondria (Wolff & Chao 2004). The threadlike
PAPs cannot accommodate mitochondria that are
approximately twice as wide. However, they may
respond rapidly to an increase in energy demand from
glycolytic or glycogenolytic-derived ATP because they
have access to glucose and contain glycogen deposits in
contrast to neurones (Hertz et al. 2007).
Adipose tissue
In the post-absorptive state the net lactate release
estimated from arterial and interstitial lactate concen-
tration differences is reported to range from 4 to
10 lmol kg)1 fat tissue min)1 in the abdominal and
femoral region or 60–150 lmol min)1 if extrapolated
to total body fat mass (van der Merwe et al. 1999,
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Acta Physiol 2010, 199, 499–508
Qvisth et al. 2007). Estimates of net lactate release from
lactate concentration differences between an artery and
a subcutaneous fat vein on the anterior abdominal wall
have reported substantial lower net lactate values with
2 lmol kg)1 fat tissue min)1 or 30–40 lmol min)1 for
total body fat mass and an increase during moderate
intensity exercise (Mulla et al. 2000). Despite the
differences in net lactate release, it can be concluded
that adipose tissue significantly contributes to systemic
lactate turnover. Whether adipose tissue also takes up
lactate is unknown.
Kidney
Under post-absorptive conditions the kidneys exhibit a
net lactate uptake of approx. 160 lmol min)1 (Ekberg
et al. 1999, Meyer et al. 2002, Woerle et al. 2003). The
unidirectional lactate uptake can account for 20–30%
of systemic lactate clearance. Moreover, a small but
consistent unidirectional lactate release is found
accounting for 4–5% of systemic lactate production
(Meyer et al. 2002, Woerle et al. 2003). The lactate
taken up can account for more than 50% of renal
gluconeogenesis and is several fold higher than for the
other gluconeogenic precursors glutamine, glycerol and
alanine (Meyer et al. 2002). The contribution of renal
gluconeogensis to whole-body glucose appearance and
thus the contribution of lactate as a gluconeogenic
precursor shows large variability between studies: 5%
(Ekberg et al. 1999), 16% (Cersosimo et al. 2000a,b,
Woerle et al. 2003) and up to 40% (Meyer et al. 2002).
Moreover, the contribution of the kidneys to systemic
glucose appearance can increase considerably upon
fasting (Ekberg et al. 1999), hypoglycaemia (Cersosimo
et al. 2000a,b) and adrenaline infusion (Meyer et al.
2003) with markedly increased lactate concentrations.
It can be concluded that the kidney plays a very
important role in net lactate clearance under the post-
absorptive resting condition, quantitatively nearly
equally important as the liver. Whether the lactate
uptake and release changes during exercise is unknown
but an increase in lactate uptake may be expected based
upon the observations that interventions causing an
increase in arterial lactate levels concomitantly find an
increase in renal net lactate uptake (Meyer et al. 1999,
2003) and in that respect the values for renal lactate
uptake in Figure 3 may be underestimated considering
the higher levels of lactate that can be reached during
moderate intensity exercise.
Liver
Next to the kidneys the liver is the most important
tissue in net lactate clearance under resting conditions.
The actual liver lactate uptake and potential release in
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Acta Physiol 2010, 199, 499–508
humans is difficult to determine and the estimates
shown in Figure 3 are estimated from measurements
across the splanchnic tissues via arterial and hepatic
venous concentration differences. A net lactate uptake
by the splanchnic bed of 200 lmol min)1 at rest under
the post-absorptive condition has been reported (Ahl-
borg 1974, Capaldo et al. 1999) and net lactate uptake
increased with continuous moderate intensity exercise
to 300–400 lmol min)1 at 30% VO2max (Ahlborg
1974) and 50% VO2max (Ahlborg & Juhlin-Dannfelt
1994) bicycling exercise for 4 and 3 h with very small
increases in arterial lactate concentration compared to
rest respectively. From these studies it is difficult to
establish whether increased lactate concentration causes
an increased splanchnic lactate extraction as the range
of lactate concentration was small over the entire
exercise period.
Other tissues that may contribute to lactate turnover
When adding up the major tissues net lactate release to
– or net uptake from – the circulation it seems that
under post-absorptive resting conditions a substantial
net lactate release is lacking. Or to put it in other words,
if tissues clear more lactate (liver, kidney, heart) than
they add (skeletal muscle, adipose tissue, brain), the
arterial lactate concentration would decrease to zero.
The reason for this discrepancy may in part originate
from the fact that data from different studies have been
compiled. Furthermore, under resting conditions net
arterial-tissue venous differences can have a consider-
able variability. Moreover, the extrapolation of arm or
leg skeletal muscle net lactate release to whole-body
muscle mass and abdominal adipose tissue net lactate
release to total fat mass may also cause substantial
variability. In addition, different fat depots have
reported to have rather different metabolic activity
and possibly lactate metabolism. Nevertheless, a tissue
that has not been discussed but that may quantitatively
be very important in net lactate release are the lungs.
The lactate fluxes across the lungs are difficult to
quantify due to the high blood flow and thereby small
lactate concentration gradient across the lungs. No net
exchange, a release and even uptake of lactate by the
lungs have been reported, which means that it is
generally assumed that the lungs do not contribute
significantly to systemic lactate turnover (Mitchell &
Cournand 1954). However, most studies are performed
on a variety of patients. Generally, it seems that patients
with low systemic lactate concentrations exhibit a very
much lower net lactate release compared with patients
with high systemic lactate levels. Nevertheless, the
reported net lactate release of 80–300 lmol min)1 in
patients with near-normal arterial lactate levels would
imply that the lungs can make a substantial contribution
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G van Hall Æ Tissue lactate kinetics
to systemic lactate release (Kellum et al. 1997, Walsh
et al. 1999), even if one assumes a very much lower
contribution in healthy individuals. Therefore, the lungs
may definitely contribute to the lacking net lactate
release under resting conditions. The gut is most likely
also a substantial net lactate producer, the major
substrate being glutamine but glucose is also used as a
substrate. The major fate of glucose is thought not to be
oxidation but lactate and alanine formation (Mithieux
2001, Murphy et al. 2001). However, the liver will
take up most of this lactate produced by the gut
without entering the main circulation and this is
why the gut is not represented in the systemic lactate
turnover scheme.
It is clear that lactate plays an important, not to say
mandatory, role in human metabolism in spite of its
bad rumour from the past as being responsible for
fatigue during exercise or being produced in response
to tissue hypoxia. The importance of lactate for the
liver and the kidneys seems primarily as a carbon
precursor for gluconeogensis. However, lactate is a
crucial intermediate metabolite in energy turnover in
the skeletal muscle, heart and brain, and potentially in
the lungs and gut. Due to intracellular compartmenta-
tion, and possibly intercellular compartmentation
between neurones and astrocytes in the brain, energy
production from glucose and most importantly glyco-
gen to lactate enables these tissues to respond fast to
local increases in energy demands without limitations
in intracellular transport of oxygen, NADH, and
pyruvate to the mitochondria and mitochondrially
produced ATP back to the site of utilization. The great
advantage of lactate metabolism in these tissues is that
the valuable glucose and glycogen is not wasted in the
process of glycogenolysis/glycolysis with its fast but
limited ATP yield but that these tissues can take up
lactate in large quantities from the circulation and have
the ability to be directly oxidized without first being
transformed to glucose via gluconeogensis in the
kidney and liver. All tissues seem to have a large
capacity for lactate transport, both uptake and release.
In vivo, within the physiological lactate concentration
range, the lactate uptake appears dependent on the
extra- and intracellular concentration gradient. In that
respect it has an advantage over glucose that can have
limitation in transport. Also the capacity of lactate
dehydrogenase activity in the direction of pyruvate
formation does not seem limited in view of the high
capacity for lactate oxidation. Therefore, lactate has
properties that make it worthwhile to be used as an
energy source under certain conditions possibly pref-
erably over glucose. Thus, after more than 150 years of
lactate research the area is very much alive and in the
last decades a renewed interest has been witnessed, less
in the classical field of (exercise) physiology as in the
505
Tissue lactate kinetics Æ G van Hall
years of the Copenhagen School but more in medical
research.
Conflict of interest
There is no conflict of interest.
References
Ahlborg, G. 1974. Substrate turnover during prolonged exer-
cise in man splanchnic and leg metabolism of glucose, free
fatty acids, and amino acids. J Clin Invest 53, 1080–1090.
Ahlborg, G. & Juhlin-Dannfelt, A. 1994. Effect of beta-receptor
blockade on splanchnic and muscle metabolism during
prolonged exercise in men. J Appl Physiol 76, 1037–1042.
Bang, O. 1936. The lactate content of blood during and after
muscular exercise in man. Skand Arch Physiol 74, 5182.
Bangsbo, J., Krustrup, P., Gonzalez-Alonso, J., Boushel, R. &
Saltin, B. 2000. Muscle oxygen kinetics at onset of intense
dynamic exercise in humans. Am J Physiol Regul Integr
Comp Physiol 279, R899–R906.
Bonen, A., Hatta, H., Holloway, G., Spriet, L. & Yoshida, Y.
2007. Reply from Arend Bonen, Hideo Hatta, Graham P.
Holloway, Lawrence L. Spriet and Yuko Yoshida. J Physiol
584, 707–708.
Brooks, G.A. 1991. Current concepts in lactate exchange. Med
Sci Sports Exerc 23, 895–906.
Brooks, G.A., Dubouchaud, H., Brown, M., Sicurello, J.P. &
Butz, C.E. 1999. Role of mitochondrial lactate dehydroge-
nase and lactate oxidation in the intracellular lactate shuttle.
Proc Natl Acad Sci USA 96, 1129–1134.
Bunger, R. 1985. Compartmented pyruvate in perfused work-
ing heart. Am J Physiol Heart Circ Physiol 249, H439–
H449.
Capaldo, B., Gastaldelli, A., Antoniello, S., Auletta, M., Pardo,
F., Ciociaro, D., Guida, R., Ferrannini, E. & Sacca, L. 1999.
Splanchnic and leg substrate exchange after ingestion of a
natural mixed meal in humans. Diabetes 48, 958–966.
Cersosimo, E., Garlick, P. & Ferretti, J. 2000a. Regulation of
splanchnic and renal substrate supply by insulin in humans.
Metabolism 49, 676–683.
Cersosimo, E., Garlick, P. & Ferretti, J. 2000b. Renal substrate
metabolism and gluconeogenesis during hypoglycemia in
humans. Diabetes 49, 1186–1193.
Chatham, J.C., Des Rosiers, C. & Forder, J.R. 2001. Evidence
of separate pathways for lactate uptake and release by the
perfused rat heart. Am J Physiol Endocrinol Metab 281,
E794–E802.
Consoli, A., Nurjhan, N., Reilly, J.J., Jr, Bier, D.M. & Gerich,
J.E. 1990. Contribution of liver and skeletal muscle to ala-
nine and lactate metabolism in humans. Am J Physiol
Endocrinol Metab 259, E677–E684.
Ekberg, K., Landau, B.R., Wajngot, A., Chandramouli, V.,
Efendic, S., Brunengraber, H. & Wahren, J. 1999. Contri-
butions by kidney and liver to glucose production in the
postabsorptive state and after 60 h of fasting. Diabetes 48,
292–298.
Gertz, E., Wisneski, J., Neese, R., Bristow, J., Searle, G. &
Hanlon, J. 1981. Myocardial lactate metabolism: evidence of
506 Journal compilation Ó 2010 Scandinavian Physiological Society, doi: 10.1111/j.1748-1716.2010.02122.x
Acta Physiol 2010, 199, 499–508
lactate release during net chemical extraction in man. Cir-
culation 63, 1273–1279.
Gertz, E., Wisneski, J., Stanley, W. & Neese, R. 1988. Myo-
cardial substrate utilization during exercise in humans. Dual
carbon-labeled carbohydrate isotope experiments. J Clin
Invest 82, 2017–2025.
Gladden, L.B. 2007. Is there an intracellular lactate shuttle in
skeletal muscle? J Physiol 582, 899.
Grassi, B. 2005. Delayed metabolic activation of oxidative
phosphorylation in skeletal muscle at exercise onset. Med Sci
Sports Exerc 37, 1567–1573.
de Groof, A., Oerlemans, F., Jost, C. & Wieringa, B. 2001.
Changes in glycolytic network and mitochondrial design in
creatine kinase-deficient muscles. Muscle Nerve 24, 1188–
1196.
van Hall, G. 2000. Lactate as a fuel for mitochondrial respi-
ration. Acta Physiol Scand 168, 643–656.
van Hall, G., Calbet, J.A.L., Sondergaard, H. & Saltin, B.
2002. Similar carbohydrate but enhanced lactate utilization
during exercise after 9 wk of acclimatization to 5,620 m.
Am J Physiol Endocrinol Metab 283, E1203–E1213.
van Hall, G., Jensen-Urstad, M., Rosdahl, H., Holmberg, H.-C.,
Saltin, B. & Calbet, J. 2003. Leg and arm lactate and
substrate kinetics during exercise. Am J Physiol Endocrinol
Metab 284, E193–E205.
van Hall, G., Lundby, C., Araoz, M., Calbet, J.A.L., Sander,
M. & Saltin, B. 2009a. The lactate paradox revisited in
lowlanders during acclimatization to 4100 m and in high-
altitude natives. J Physiol 587, 1117–1129.
van Hall, G., Stromstad, M., Rasmussen, P., Jans, O., Zaar,
M., Gam, C., Quistorff, B., Secher, N.H. & Nielsen, H.B.
2009b. Blood lactate is an important energy source for
the human brain. J Cereb Blood Flow Metab 29, 1121–1129.
Hashimoto, T., Hussien, R. & Brooks, G.A. 2006. Co-locali-
zation 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.
Hashimoto, T., Hussien, R., Cho, H.-S., Kaufer, D. &
Brooks, G.A. 2008. Evidence for the mitochondrial lactate
oxidation complex in rat neurons: demonstration of an
essential component of brain lactate shuttles. PLoS ONE 3,
e2915.
Hertz, L., Peng, L. & Dienel, G.A. 2007. Energy metabolism in
astrocytes: high rate of oxidative metabolism and spatio-
temporal dependence on glycolysis/glycogenolysis. J Cereb
Blood Flow Metab 27, 219–249.
Hochachka, P.W. 2003. Intracellular convection, homeostasis
and metabolic regulation. J Exp Biol 206, 2001–2009.
Hochachka, P.W. & Beatty, C.L. 2003. Patterns of control of
maximum metabolic rate in humans. Comp Biochem Physiol
A Mol Integr Physiol 136, 215–225.
Hoppeler, H. & Fluck, M. 2003. Plasticity of skeletal muscle
mitochondria: structure and function. Med Sci Sports Exerc
35, 95–104.
Ide, K., Schmalbruch, I.K., Quistorff, B., Horn, A. & Secher,
N.H. 2000. Lactate, glucose and O2 uptake in human brain
during recovery from maximal exercise. J Physiol 522, 159–
164.
Ó 2010 The Author
Acta Physiol 2010, 199, 499–508
Jorfeldt, L. 1970. Metabolism L (+)-Lactate in human skeletal
muscle during exercise. Acta Physiol Scand 338(Suppl.),
1–67.
Jorfeldt, L. & Wahren, J. 1970. Human forearm muscle
metabolism during exercise. V. Quantitative aspects of
glucose uptake and lactate production during prolonged
exercise. Scand J Clin Lab Invest 26, 73–81.
Kaasik, A., Veksler, V., Boehm, E., Novotova, M. & Ventura-
Clapier, R. 2003. From energy store to energy flux: a study
in creatine kinase deficient fast skeletal muscle. FASEB J 17,
708–710.
Kanno, T. & Maekawa, M. 1995. Lactate dehydrogenase
M-subunit deficiencies: clinical features, metabolic back-
ground, and genetic heterogeneities. Muscle Nerve 3(Suppl.),
S54–S60.
Karlsson, J. 1971. Lactate and phosphagen concentrations in
working muscle of man. Acta Physiol Scand 358(Suppl.),
1–72.
Kellum, J.A., Kramer, D.J., Lee, K., Mankad, S., Bellomo, R.
& Pinsky, M.R. 1997. Release of lactate by the lung in acute
lung injury. Chest 111, 1301–1305.
King, P., Parkin, H., Macdonald, I., Barber, C. & Tattersall, R.
1997. The effect of intravenous lactate on cerebral function
during hypoglycaemia. Diabet Med 14, 19–28.
King, P., Kong, M., Parkin, H., MacDonald, I., Barber, C. &
Tattersall, R. 1998. Intravenous lactate prevents cerebral
dysfunction during hypoglycaemia in insulin-dependent
diabetes mellitus. Clin Sci 94, 157–163.
Krustrup, P., Hellsten, Y. & Bangsbo, J. 2004. Intense interval
training enhances human skeletal muscle oxygen uptake in
the initial phase of dynamic exercise at high but not at low
intensities. J Physiol 559, 335–345.
Levy, B., Mansart, A., Montemont, C., Gibot, S., Mallie, J.-P.,
Regnault, V., Lecompte, T. & Lacolley, P. 2007. Myocardial
lactate deprivation is associated with decreased cardiovascu-
lar performance, decreased myocardial energetics, and early
death in endotoxic shock. Intensive Care Med 33, 495–502.
Lubow, J.M., Pinon, I.G., Avogaro, A., Cobelli, C., Treeson,
D.M., Mandeville, K.A., Toffolo, G. & Boyle, P.J. 2006.
Brain oxygen utilization is unchanged by hypoglycemia in
normal humans: lactate, alanine, and leucine uptake are not
sufficient to offset energy deficit. Am J Physiol Endocrinol
Metab 290, E149–E153.
Lundsgaard, E. 1938. The Pasteur–Meyerhof reaction in skel-
etal muscle. Bull N Y Acad Med 14, 163–182.
Lynch, R. & Paul, R. 1983. Compartmentation of glycolytic
and glycogenolytic metabolism in vascular smooth muscle.
Science 222, 1344–1346.
Maran, A., Cranston, I., Lomas, J., Macdonald, I. & Amiel,
S.A. 1994. Protection by lactate of cerebral function during
hyperglycaemia. Lancet 343, 16–20.
van der Merwe, M.-T., Jansson, P.-A., Crowther, N.J., Boyd,
I.H., Gray, I.P., Joffe, B.I. & Lonnroth, P.N. 1999. Lactate
and glycerol release from subcutaneous adipose tissue in
black and white lean men. J Clin Endocrinol Metab 84,
2888–2895.
Meyer, C., Dostou, J.M. & Gerich, J.E. 1999. Role of the
human kidney in glucose counterregulation. Diabetes 48,
943–948.
Ó 2010 The Author
Journal compilation Ó 2010 Scandinavian Physiological Society, doi: 10.1111/j.1748-1716.2010.02122.x
G van Hall Æ Tissue lactate kinetics
Meyer, C., Stumvoll, M., Dostou, J., Welle, S., Haymond, M.
& Gerich, J. 2002. Renal substrate exchange and gluco-
neogenesis in normal postabsorptive humans. Am J Physiol
Endocrinol Metab 282, E428–E434.
Meyer, C., Stumvoll, M., Welle, S., Woerle, H.J., Haymond,
M. & Gerich, J. 2003. Relative importance of liver, kidney,
and substrates in epinephrine-induced increased gluconeo-
genesis in humans. Am J Physiol Endocrinol Metab 285,
E819–E826.
Mitchell, A. & Cournand, A. 1954. The fate of circulating
lactic acid in the human lung. J Clin Invest 34, 471–476.
Mithieux, G. 2001. New data and concepts on glutamine and
glucose metabolism in the gut. Curr Opin Clin Nutr Metab
Care 4, 267–271.
Miyajima, H., Takahashi, Y. & Kaneko, E. 1995a. Charac-
terization of the glycolysis in lactate dehydrogenase-A defi-
ciency. Muscle Nerve 18, 874–878.
Miyajima, H., Takahashi, Y. & Kaneko, E. 1995b. Charac-
terization of the oxidative metabolism in lactate dehydro-
genase A deficiency. Int Med 34, 502–506.
Mulla, N., Simonsen, L. & Bülow, J. 2000. Post-exercise
adipose tissue and skeletal muscle lipid metabolism in
humans: the effects of exercise intensity. J Physiol 524,
919–928.
Murphy, N., Kodakat, S., Wendon, J., Jooste, C., Muiesan, P.,
Rela, M. & Heaton, N. 2001. Liver and intestinal lactate
metabolism in patients with acute hepatic failure undergoing
liver transplantation. Crit Care Med 29, 2111–2118.
Nedergaard, M., Ransom, B. & Goldman, S. 2003. New roles
for astrocytes: redefining the functional architecture of the
brain. Trends Neurosci 26, 523–530.
Neglia, D., De Caterina, A., Marraccini, P., Natali, A.,
Ciardetti, M., Vecoli, C., Gastaldelli, A., Ciociaro, D.,
Pellegrini, P., Testa, R., Menichetti, L., L’Abbate, A.,
Stanley, W.C. & Recchia, F.A. 2007. Impaired myocardial
metabolic reserve and substrate selection flexibility during
stress in patients with idiopathic dilated cardiomyopathy.
Am J Physiol Heart Circ Physiol 293, H3270–H3278.
Newsholme, E. 2003. Enzymes, energy and endurance. In:
J. Poortmans (ed.) Principles of Exercise Biochemistry, pp.
1–35. Karger, Basel.
Novotova, M., Pavlovicova, M., Veksler, V., Ventura-Clapier,
R. & Zahradnik, I. 2006. Ultrastructural remodeling of fast
skeletal muscle fibers induced by invalidation of creatine
kinase. Am J Physiol Cell Physiol 291, C1279–C1285.
Pellerin, L. & Magistretti, P. 1994. Glutamate uptake into
astrocytes stimulates aerobic glycolysis: a mechanism cou-
pling neuronal activity to glucose utilization. Proc Natl Acad
Sci USA 91, 10625–10629.
Pellerin, L., Bouzier- Sore, A.-K., Aubert, A., Serres, S., Merle,
M., Costalat, R. & Magistretti, P. 2007. Activity-dependent
regulation of energy metabolism by astrocytes: an update.
Glia 55, 1251–1262.
Peng, L., Zhang, X. & Hertz, L. 1994. High extracellular
potassium concentrations stimulate oxidative metabolism in
a glutamatergic neuronal culture and glycolysis in cultured
astrocytes but have no stimulatory effect in a GABAergic
neuronal culture. Brain Res 663, 168–172.
507
Tissue lactate kinetics Æ G van Hall
Peuhkurinen, K., Hiltunen, J. & Hassinen, I. 1983. Metabolic
compartmentation of pyruvate in the isolated perfused rat
heart. Biochem J 210, 193–198.
Ponsot, E., Zoll, J., N’Guessan, B., Ribera, F., Lampert, E.,
Richard, R., Veksler, V., Ventura-Clapier, R. & Mettauer, B.
2005. Mitochondrial tissue specificity of substrates
utilization in rat cardiac and skeletal muscles. J Cell Physiol
203, 479–486.
Popinigis, J., Antosiewicz, J., Crimi, M., Lenaz, G. & Waka-
bayashi, T. 1991. Human skeletal muscle: participation of
different metabolic activities in oxidation of L-lactate. Acta
Biochim Pol 38, 169–175.
Qvisth, V., Hagstrom-Toft, E., Moberg, E., Sjoberg, S. &
Bolinder, J. 2007. Lactate release from adipose tissue and
skeletal muscle in vivo: defective insulin regulation in insu-
lin-resistant obese women. Am J Physiol Endocrinol Metab
292, E709–E714.
Rasmussen, H., van Hall, G. & Rasmussen, U. 2002. Lactate
dehydrogenase is not a mitochondrial enzyme in human and
mouse vastus lateralis muscle. J Physiol 541, 575–580.
Richter, E.A., Kiens, B., Saltin, B., Christensen, N.J. & Savard,
G. 1988. Skeletal muscle glucose uptake during dynamic
exercise in humans: role of muscle mass. Am J Physiol
Endocrinol Metab 254, E555–E561.
Rivers, E., Paradis, N., Martin, G., Goetting, M., Rosenberg,
J., Smithline, H., Appleton, T. & Nowak, R. 1991. Cerebral
lactate uptake during cardiopulmonary resuscitation in hu-
mans. J Cereb Blood Flow Metab 11, 479–484.
Robergs, R.A., Ghiasvand, F. & Parker, D. 2004. Biochemistry
of exercise-induced metabolic acidosis. Am J Physiol Regul
Integr Comp Physiol 287, R502–R516.
Sahlin, K., Fernström, M., Svensson, M. & Tonkonogi, M.
2002. No evidence of an intracellular lactate shuttle in rat
skeletal muscle. J Physiol 541, 569–574.
Schadewaldt, P., Münch, U. & Staib, W. 1983. Evidence for
the compartmentation of pyruvate metabolism in perfused
rat skeletal muscle. Biochem J 216, 761–764.
Szczesna-Kaczmarek, A. 1990a. Direct oxidation of L-lactate
by mitochondria isolated from different tissues. In: K. Nazar,
508 Journal compilation Ó 2010 Scandinavian Physiological Society, doi: 10.1111/j.1748-1716.2010.02122.x
Acta Physiol 2010, 199, 499–508
R. Terjung, H. Kaciuba-U’scilko, L. Budohoski (eds) Inter-
national Perspectives in Exercise Physiology, pp. 130–131.
Human Kinetics Books, Champaign, IL.
Szczesna-Kaczmarek, A. 1990b. L-lactate oxidation by skeletal
muscle mitochondria. Int J Biochem 22, 617–620.
Veneman, T., Mitrakou, A., Mokan, M., Cryer, P. & Gerich, J.
1994. Effect of hyperketonemia and hyperlacticacidemia on
symptoms, cognitive dysfunction, and counter regulatory
hormone responses during hypoglycemia in normal humans.
Diabetes 43, 1311–1317.
Walsh, T.S., McLellan, S., Mackenzie, S.J. & Lee, A. 1999.
Hyperlactatemia and pulmonary lactate production in
patients with fulminant hepatic failure. Chest 116, 471–
476.
Wisneski, J., Gertz, E., Neese, R., Gruenke, L. & Craig, J.
1985a. Dual carbon-labeled isotope experiments using
D-[6-14C] glucose and L-[1,2,3-13C3] lactate: a new
approach for investigating human myocardial metabolism
during ischemia. J Am Coll Cardiol 5, 1138–1346.
Wisneski, J., Gertz, E., Neese, R., Gruenke, L., Morris, D. &
Craig, J. 1985b. Metabolic fate of extracted glucose in
normal human myocardium. J Clin Invest 76, 819–1827.
Woerle, H.J., Meyer, C., Popa, E.M., Cryer, P.E. & Gerich,
J.E. 2003. Renal compensation for impaired hepatic glucose
release during hypoglycemia in type 2 diabetes. Diabetes 52,
1386–1392.
Wolff, J. & Chao, T. 2004. Architectonics of non-neural cells
of the nervous system. In: L. Hertz (ed.) Non-Neuronal Cell
of the Nervous System: Function and Dysfunction, pp. 1–52.
Elsevier, Amsterdam.
Yoshida, Y., Holloway, G.P., Ljubicic, V., Hatta, H., Spriet,
L.L., Hood, D.A. & Bonen, A. 2007. Negligible direct lac-
tate oxidation in subsarcolemmal and intermyofibrillar
mitochondria obtained from red and white rat skeletal
muscle. J Physiol 582, 1317–1335.
Zielke, H., Zielke, C., Baab, P. & Tildon, J. 2007. Effect of
fluorocitrate on cerebral oxidation of lactate and glucose in
freely moving rats. J Neurochem 101, 9–16.
Ó 2010 The Author