ArticlePDF AvailableLiterature Review

Abstract and Figures

Since its first documented observation in exhausted animal muscle in the early 19th century, the role of lactate (lactic acid) has fascinated muscle physiologists and biochemists. Initial interpretation was that lactate appeared as a waste product and was responsible in some way for exhaustion during exercise. Recent evidence, and new lines of investigation, now place lactate as an active metabolite, capable of moving between cells, tissues and organs, where it may be oxidised as a fuel or reconverted to form pyruvate or glucose. The questions now to be asked concern the effects of lactate at the systemic and cellular level on metabolic processes. Does lactate act as a metabolic signal to specific tissues, becoming a metabolite pseudo-hormone?Does lactate have a role in whole-body coordination of sympathetic/parasympathetic nerve system control? And, finally, does lactate play a role in maintaining muscle excitability during intense muscle contraction? The concept of lactate acting as a signalling compound is a relatively new hypothesis stemming from a combination of comparative, cell and whole-organism investigations. It has been clearly demonstrated that lactate is capable of entering cells via the monocarboxylate transporter (MCT) protein shuttle system and that conversion of lactate to and from pyruvate is governed by specific lactate dehydrogenase isoforms, thereby forming a highly adaptable metabolic intermediate system. This review is structured in three sections,the first covering pertinent topics in lactate's history that led to the model of lactate as a waste product. The second section will discuss the potential of lactate as a signalling compound, and the third section will identify ways in which such a hypothesis might be investigated. In examining the history of lactate research, it appears that periods have occurred when advances in scientific techniques allowed investigation of this metabolite to expand. Similar to developments made first in the 1920s and then in the 1980s, contemporary advances in stable isotope, gene microarray and RNA interference technologies may allow the next stage of understanding of the role of this compound, so that, finally, the fundamental questions of lactate's role in whole-body and localised muscle function may be answered.
Content may be subject to copyright.
If the words exhaustion or fatigue are introduced into a
general conversation regarding exercise, more often than not
someone will relate lactic acid or lactate as a primary cause.
(Note: at physiological pH, lactic acid almost completely
dissociates to lactate and hydrogen ions, which is why lactate,
as opposed to lactic acid, is commonly used.) The perception
of the general public, the athletic community and the majority
of students is that the ‘waste’ product lactate accumulates in
muscle during intensive activity and is therefore the primary
reason why exercise is forced to cease. This logic is rational,
as our perception of lactate for the majority of the past
200·years has been as a metabolic waste end product. Research
dating back beyond the last century has clearly demonstrated
that (1) lactate accumulates in muscle and blood during
exercise of increasing intensity and (2) blood and muscle
lactate is observed to be at its highest at, or just following,
volitional exhaustion. Subsequently, lactate has become
assumed by many to be a muscular waste product serving to
reduce muscle contractile function, thereby acting as a
precursor or instigator of fatigue.
The formulation of the traditional lactate paradigm – intense
exercise, lack of oxygen and fatigue
The exploration of intermediatory metabolism is not a new
field. Interpretation of the role of lactic acid can be traced back
to its identification in 1808 by Berzelius (Berzelius, 1808) and
then later by Araki (1891), who showed that lactic acid
concentrations in exhausted animal muscle were proportional
The Journal of Experimental Biology 208, 4561-4575
Published by The Company of Biologists 2005
Since its first documented observation in exhausted
animal muscle in the early 19th century, the role of lactate
(lactic acid) has fascinated muscle physiologists and
biochemists. Initial interpretation was that lactate
appeared as a waste product and was responsible in some
way for exhaustion during exercise. Recent evidence, and
new lines of investigation, now place lactate as an active
metabolite, capable of moving between cells, tissues and
organs, where it may be oxidised as a fuel or reconverted
to form pyruvate or glucose. The questions now to be
asked concern the effects of lactate at the systemic and
cellular level on metabolic processes. Does lactate act as a
metabolic signal to specific tissues, becoming a metabolite
pseudo-hormone? Does lactate have a role in whole-body
coordination of sympathetic/parasympathetic nerve
system control? And, finally, does lactate play a role in
maintaining muscle excitability during intense muscle
The concept of lactate acting as a signalling compound
is a relatively new hypothesis stemming from a
combination of comparative, cell and whole-organism
investigations. It has been clearly demonstrated that
lactate is capable of entering cells via the monocarboxylate
transporter (MCT) protein shuttle system and that
conversion of lactate to and from pyruvate is governed by
specific lactate dehydrogenase isoforms, thereby forming a
highly adaptable metabolic intermediate system. This
review is structured in three sections, the first covering
pertinent topics in lactate’s history that led to the model of
lactate as a waste product. The second section will discuss
the potential of lactate as a signalling compound, and the
third section will identify ways in which such a hypothesis
might be investigated.
In examining the history of lactate research, it appears
that periods have occurred when advances in scientific
techniques allowed investigation of this metabolite to
expand. Similar to developments made first in the 1920s
and then in the 1980s, contemporary advances in stable
isotope, gene microarray and RNA interference
technologies may allow the next stage of understanding of
the role of this compound, so that, finally, the fundamental
questions of lactate’s role in whole-body and localised
muscle function may be answered.
Key words: lactate metabolism, signalling mechanism, exercise,
mammalian function.
Lactate – a signal coordinating cell and systemic function
Andrew Philp
*, Adam L. Macdonald
and Peter W. Watt
Department of Sport and Exercise Sciences, Chelsea School Research Centre, Welkin Performance Laboratories and
School of
Pharmacy and Biomolecular Sciences, Cockcroft Building, University of Brighton, Eastbourne, BN20 7SP, UK
*Author for correspondence (e-mail:
Accepted 31 October 2005
to the activation of the exercised muscle, the extent of which
was thought to be associated with O
availability. In 1907,
Fletcher and Hopkins conducted a series of experiments
expanding this knowledge to the examination of isolated
amphibian muscle (Fletcher and Hopkins, 1907). Through
progressive investigations, the authors demonstrated that lactic
acid appeared in response to muscle contraction, continuing in
the absence of oxygen. A secondary observation was that,
following the stimulated muscle contraction, the accumulated
lactate disappeared when oxygen was present.
During the 1920s, work by three predominant research
groups, A. V. Hill’s group in London, the Heidelberg group of
Otto Meyerhof, and Dill and Margaria’s group at Harvard
(Margaria et al., 1933), provided much of the basis for our
understanding of lactate metabolism in exercise physiology. In
1923, Hill and Meyerhof combined their research observations
and many of the accepted or hypothesized theories at the time
in a historical review article (Hill and Meyerhof, 1923). The
two main theoretical constructs to emerge from this paper were
the identification and naming of the ‘lactic-acid-cycle’
(describing the processes utilizing the cyclical conversion of
glycogen to lactic acid back to glycogen) and the recognition
that ‘two’ distinct pathways supplied the energy required for
muscle contraction, which were deemed aerobic (in the
presence) and anaerobic (in the absence) of oxygen.
Whilst Meyerhof’s research concerned the lactic acid cycle
on non-circulated amphibian hemicorpus preparations, Hill et
al. (1924a,b) subsequently sought to investigate this
phenomenon in humans during exercise. From a series of
experiments and observations, the authors determined the rise
in lactic acid at the onset of exercise to be as a direct result of
an O
deficit (hypoxia) in exercising skeletal muscle. The
‘oxygen debt model’ that Hill et al. (1924a,b) postulated,
supported by subsequent work from Hill’s laboratory (Hill,
1932), became the primary explanation for the increased
appearance of lactic acid during exercise and ensuing fatigue.
Subsequent recognition of these researcher’s contributions
(Hill and Meyerhof were jointly awarded the Nobel Prize for
science in 1922) saw the O
debt hypothesis accepted as a
leading theory in the physiological understanding of prolonged
human exercise, whilst providing the paradigm for the body of
further human research that ensued (Bassett, 2002).
The interpretation of research conducted during this period
is, in many regards, the reason why lactate has received its
label as an end product. Apart from research such as that
generated by Cori’s laboratory, which demonstrated that
lactate could be converted back to glucose in the liver (Cori
and Cori, 1929, 1933), research during the next 20·years sought
to prove lactate as the cause of fatigue, rather than to question
its function.
A prime example of lactate’s suggested role during exercise
in the years that followed was the introduction and widespread
acceptance of the anaerobic threshold (AT) concept (Davis,
1985). It was observed that during exercise, an increase in
blood lactate accumulation occurred at a standard relative
exercise intensity (~60–75% V
2 max) in individuals with
varying fitness profiles. Combined with the appearance of
lactate in the circulation was an increase in ventilatory drive
and energy expenditure. This transition was seen as the turning
point at which the anaerobic system became the predominant
source of energy provision, with a concomitant increase in
lactate concentrations beyond this transition a consequence of
this metabolic switch. Hill et al.’s O
debt hypothesis (Hill et
al., 1924a,b) seemed to explain the mechanism behind this
increase, as well as progressive recruitment of glycolytic fibres
and changes in substrate utilisation (Davis, 1985).
So is lactate only an anaerobic product?
During the 1980s, other research groups set out to question
whether or not lactate was a waste product (Brooks, 1985;
Connet et al., 1986). Initially, work by Jobsis and Stainsby
(1968), and later by Connet et al. (1986), demonstrated that
stimulated canine muscle was capable of producing and
oxidising lactate at conditions equivalent to moderate intensity
exercise, at which there was, seemingly, an adequate supply of
oxygen. In light of this, Brooks (1986) postulated that for
oxygen deficit (anaerobiosis) to be the primary cause of lactate
accumulation, muscle anoxia must exist, since this was thought
to be the stimulus for lactate production. Numerous research
studies had previously demonstrated that at exercise intensities
of 50–75% V
2 max, where the AT supposedly occurred,
sufficient reserves of cardiac output, localised blood flow and
lactate and glucose arterial–venous differences existed for
muscle to remain suitably perfused for aerobic metabolism to
continue, thus providing conflicting information to that of the
AT theoretical construct (Brooks, 1985, 1986).
Richardson et al. (1998) utilised phosphorous magnetic
resonance spectroscopy (MRS) and myoglobin saturation, as
measured by
H nuclear MRS, to address whether lactate
increase during progressive exercise to exhaustion was due to
muscle hypoxia. They observed that net blood lactate efflux
was unrelated to intracellular oxygen partial pressure (P
across work intensities but was linearly related to O
consumption and intracellular pH. Therefore, the data provided
by Richardson et al. (1998) support the notion that lactate
efflux during exercise is unrelated to muscle cytoplasmic P
effectively dissociating lactate production and hypoxia.
Comparative examination of the glycolytic pathway across
the animal kingdom has provided evidence that anaerobic
conditions are not essential for lactate to be produced,
demonstrating that energy systems work in unison as opposed
to switching on and off, whilst duly confirming the dissociation
between lactate and hypoxic or anoxic conditions. The
tailshaker muscle of the western diamondback rattlesnake
(Crotalus atrox) has provided a model that clearly
demonstrates that aerobic metabolism can meet a high ATP
demand. Species such as the rattlesnake are able to alter the
energy requirement of muscle contraction so that glycolysis
may continue. Tailshaker muscles are capable of sustaining
high-frequency contractions in the region of 20–100·Hz for
several hours with an ATP cost per twitch of 0.015·mmol·l
A. Philp, A. L. Macdonald and P. W. Watt4562
ATP per gram of muscle (Conley and Lindstedt, 1996).
Utilising the same model, this time in ischemia and normoxic
situations, Kemper et al. (2001) demonstrated that such
elevated rates of glycolysis could happen independently of O
levels. Such muscle was capable of exercising without fatigue
due to high blood flow levels allowing the rapid turnover of
and lactate (and presumably other metabolites that might
themselves be involved in a fatigue process) within the cells.
Recent research suggests that mechanical trade-offs between
twitch tension and duration and between joint force and
displacement explain how the tailshaker muscle can alter
rattling frequency rates without increasing the metabolic cost
of activity (Moon et al., 2002).
These data allow for two considerations. Firstly, they allow
for the acceptance that lactate is not only produced as a result
of anoxic or hypoxic conditions but also that it is a metabolite
produced during adequate oxygen provision. Secondly, aerobic
ATP provision is a highly adaptable process, with skeletal
muscle possessing an inherent ability to adapt to the energy
requirements of the organism. It appears that many animal
species are able to minimise the cost of muscle contraction so
that cellular ATP production can meet ATP demand and
sustain high contractile rates (Conley and Lindstedt, 2002)
with lactate formed as an integral part of this working system,
not as an end product per se.
A metabolite on the move…
During conditions of lactate production, at rest and during
submaximal exercise, substrate concentrations support the
conversion of pyruvate to lactate via the lactate dehydrogenase
(LDH) reaction. Until relatively recently, our understanding,
was that lactate moved from the cellular compartment to the
blood via simple diffusion. Increased lactate concentrations
were deemed a consequence of increased glycolytic flux rates,
with cellular function inhibited when lactate was unable to
leave the cytosolic compartment.
This understanding began to change following initial
observations in rodent studies by Donovan and Brooks (1983),
which demonstrated that endurance training reduced post-
exercise lactate concentrations by enhancing lactate clearance,
strongly suggesting that the major fate of lactate during or
following exercise was probably oxidation. Further research
demonstrated that lactate transport was sensitive to pH,
specific transport inhibitors and temperature (Juel, 1988; Watt
et al., 1988; Roth and Brooks, 1990). To directly measure
lactate kinetics in humans, Mazzeo et al. (1986) used the
stable isotope tracer [1-
C]lactate to demonstrate that the rate
of lactate disposal (R
) was directly related to metabolic
clearance rate (MCR). That oxidation, as determined by the
appearance of
C enrichment in CO
, was the major fate of
lactate during exercise, and, subsequent to this, that the
interpretation of lactate kinetics by way of concentrations was
inappropriate, as circulatory endpoint values could not reflect
lactate turnover in muscle (rate of production minus rate of
removal). Donovan’s findings were supported in humans
(MacRae et al., 1992), whilst subsequent animal research in
giant sarcolemmal vesicle and perfused hindlimb preparations
added support to a carrier-mediated process for lactate
transport in and out of skeletal muscle, as well as the
stimulatory effects of contraction, pH and blood flow on both
processes (Juel et al., 1991; Watt et al., 1994; Gladden et al.,
Previous research in erythrocytes suggested three pathways
for lactate transport. First, carrier-mediated transport by a H
coupled transporter; second, exchange with inorganic anions
mediated by the band 3 protein Cl
exchange; and third,
passive diffusion of lactic acid across the lipid bilayer. Under
physiological conditions, it was believed that the transport
pathway mediated up to 90% of observed lactate flux (Deuticke
et al., 1982). In the early 1990s, Kim et al. (1992) sequenced
a membrane protein (Mev) from met-18b-2 hamster ovarian
cells that exhibited an unusually high uptake of the 6-carbon
branched dihydroxymonocarboxylate mevalonate. When a
plasmid expressing a cDNA for Mev (pMev) was introduced
by transfection into wild-type Chinese hamster ovary cells, an
mRNA that hybridizes to the Mev cDNA was identified.
Following cloning and sequencing of the wild-type version of
Mev, coupled with the observation that the cloned protein did
not facilitate mevalonate transport, it was concluded that the
wild-type Mev transported other substances, independently of
mevalonate. Further examination identified that this protein
was related to the previously characterised transport system
found in erythrocytes (Garcia et al., 1994).
Subsequently, an entire family of monocarboxylate
transport (MCT) proteins (now with 14 isoforms) has been
cloned, and their individual roles have been characterised (for
detailed topological characteristics and processes, see
Halestrap and Price, 1999; Halestrap and Meredith, 2004).
The predominant MCTs in human skeletal muscle are MCT1
and MCT4, whilst MCT2 has been identified in the liver
(McClelland et al., 2003). McCullagh et al. (1996) suggested
that MCT1 facilitated uptake of lactate into muscle cells for
oxidative metabolism, as such being coordinately expressed
with the heart isoform of lactate dehydrogenase (LDH), with
both being found in higher concentration in type I fibres. At
a similar time, Wilson et al. (1998) showed that the low-
affinity transporter MCT4 could be responsible for the net
export of lactate from the cell, and as such was predominantly
expressed in glycolytic type IIA fibres, which are known to
be the major physiological producers of lactate when they are
With the increased knowledge of MCT-facilitated lactate
transport, further evidence in support of the lactate shuttle
hypothesis became available. Brooks (1986) postulated the
framework of the lactate shuttle hypothesis prior to the
discoveries of MCT or their distribution (Fig.·1). This
hypothesis proposed that lactate was able to transfer from its
site of production (cytosol) to neighbouring cells and a variety
of organs (e.g. liver, kidney and heart), where its oxidation or
continued metabolism could occur. Of key importance to this
hypothesis was the appreciation that for lactate shuttling to
Lactate signalling at rest and during exercise 4563
occur, as suggested, a cellular protein transport system would
be implicated.
The original lactate shuttle hypothesis has since seen a
number of revisions, with an intracellular component
introduced (Brooks et al., 1999; Fig.·1). The extension to an
intracellular shuttle system has not been without its
controversy. The principle depends upon the presence of
mitochondrial LDH (mLDH) for the re-conversion of lactate,
once it enters the mitochondrion, to pyruvate and for
mitochondrial located MCTs (Brooks et al., 1999). This
component has been strongly challenged by two independent
investigations (Rasmussen et al., 2002; Sahlin et al., 2002).
The principal flaw to the Brooks model, detailed by these
authors, was that lactate entering the mitochondria would
create a futile cycle by which pyruvate is reduced to lactate in
the mitochondria and vice versa in the cytosol. It was suggested
that this would induce a situation compromising energy
production, as both the redox state of the cell and the required
direction of substrate flow would be reversed.
This suggested scenario, however, seems unlikely. Firstly,
in conversion of pyruvate to lactate, lactate accepts an H
from NADH, thereby allowing increased availability of NAD
and maintenance of the redox state of the cell. Secondly, within
the intracellular model there would not be a futile cycle
formed, as lactate entering the mitochondria would be
converted to pyruvate and oxidised. Lactate acts as an
alternative pathway for substrate to enter the mitochondria,
competing with pyruvate for MCT transport. The intracellular
shuttle (Fig.·1) does not suggest that pyruvate is not present in
the intracellular compartment; instead it suggests that the LDH
conversion of lactate to pyruvate is more than a cytosolic
reaction alone. Data provided by Laughlin et al. (1993)
utilising MRS in working canine hearts have proven that
infusion of [
C]pyruvate labelled cytosolic lactate and alanine
pools whereas [
C]lactate did not label cytosolic pyruvate or
alanine. However, the TCA cycle substrate -ketoglutarate
was labelled, suggesting that infused lactate by-passed the
cytosolic LDH reaction and was converted to pyruvate in the
mitochondria. Brooks (2002b) questioned the methods used by
Rasmussen et al. (2002) and Sahlin et al. (2002) in obtaining
mitochondria, suggesting that mLDH could easily have been
lost during this subfractionation process and was the main
reason for the discrepancies in results. The controversy over
mitochondrial-located MCTs might have been resolved by two
recent studies (Butz et al., 2004; Hashimoto et al., 2005), with
the latter using immunohistochemical analysis in combination
with confocal laser scanning microscopy (CLSM) to clearly
demonstrate the co-localisation of MCT1 and cytochrome
oxidase (COX) at both interfibrillar and subsarcolemmal cell
domains. These data would indicate that MCTs and associated
proteins are therefore positioned specifically to facilitate
functions of the lactate shuttle system. For detailed
applications of the lactate shuttle hypothesis, see recent
reviews by Brooks (2002a,b) and Gladden (2004).
Lactate has been suggested to play an important role in
cellular and organelle redox balance, a function demonstrated
in the proposed peroxisomal lactate shuttle (McClelland et al.,
2003). It has long been known that long-chain -oxidation of
fatty acids occurs in mammalian peroxisomes (Lazarow and de
Duve, 1976); however, for -oxidation to continue, both
and NADH must be reoxidized. McGroarty et al.
(1974) first suggested the presence of LDH in rat liver
peroxisomes, however it was not until the study of Baumgart
et al. (1996) that LDH was identified in the peroxisomal
matrix. McClelland et al. (2003) recently confirmed the
findings of Baumgart et al. (1996) identifying the presence of
LDH; further, peroxisomal -oxidation was stimulated by
pyruvate, with lactate generated when pyruvate was added to
A. Philp, A. L. Macdonald and P. W. Watt4564
(6) (7)
Glucose 6-phosphate
Glyceraldehyde 3-phosphate
Lactate re-enters blood
and distributed to othe
tissue (see text)
Fig.·1. The processes involved in the lactate
shuttle hypothesis (Brooks, 1986). The
pathway proposes that (1) glucose enters the
cell, where it is sequentially broken down to
pyruvate (2). Pyruvate enters the
mitochondrion, allowing respiration to
continue in the tricarboxylic acid (TCA) cycle
(3). Lactate is subsequently formed via the
lactate dehydrogenase (LDH) reaction (4) and
is then exported from the cytosolic
compartment via monocarboxylate transporter
(MCT) transport (5), where it is redistributed
to a variety of functional sites. Note the
suggested presence of mitochondrial lactate
dehydrogenase (mLDH) (6), which forms the
construct of the intracellular shuttle system (7)
(see text for description).
peroxisomes. MCT1 and MCT2 were identified as facilitating
the entry of pyruvate into the peroxisomal matrix and lactate
efflux from the organelle, thus forming the basis for a
peroxisomal lactate shuttle and explaining how lactate and its
efflux can regulate specific cellular and organelle redox
balance (Brooks et al., 1999).
MCT expression seems to be rapidly modulated to respond
to changes in muscle activity. Many studies have demonstrated
increases in MCT content following a single exercise bout
(Green et al., 2002) or periods of endurance training (Baker et
al., 1998; Bergman et al., 1999; Pilegaard et al., 1999;
Dubouchaud et al., 2000). Recent research suggests that MCT
increases may occur rapidly following exercise. Zhou et al.
(2000) provided evidence that MCT4 mRNA was transiently
increased during exercise. Further to this, Green et al. (2002)
showed an increase in MCT1 (121%) and MCT4 (120%)
protein expression taken from skeletal muscle biopsies 2 and
4·days after a 5–6·h 60% V
2 peak exercise bout in humans.
Most recently, Coles et al. (2004) have shown that 2·h exercise
, 15% grade) in rats increases MCT1 and MCT4
mRNA 2–3-fold, peaking 10·h post exercise. These responses,
however, were observed to be tissue specific [different
responses found between soleus and extensor digitorum longus
(EDL) muscles] and, in some cases, transiently upregulated so
that protein levels had returned to pre-exercise levels 24·h post
exercise. Subsequently, these authors suggested that the MCT
family of transporters belong to a group of metabolic genes,
rapidly activated following exercise (Hildebrandt et al., 2003).
These gene products (mRNA) are present in small amounts in
cells; however, they have rapid induction times, suggesting that
small quantities of each are required for metabolic function to
be supported (Hildebrandt et al., 2003). It does, however,
remain to be seen whether such rapid induction of MCTs
following exercise is repeated in human skeletal muscle. By
contrast, denervation (Pilegaard and Juel, 1995) and inactivity
(Wilson et al., 1998) lead to a decline in MCT expression.
These discoveries have been important in the recognition of
lactate acting as a mobile metabolite, able to move within
cellular compartments and adjacent muscle fibres and
distributed widely across systemic circulation to inactive tissue
and organs. Thus, lactate has the capacity to act as a metabolic
signal at the cellular, localised and whole-body level, either
directly or through its effects on H
or other metabolic
regulators. Further, the rapid induction of MCT following
repeated muscle contraction means that the mechanisms of
lactate transport can quickly adapt to an exercise stimulus,
resulting in the notion of lactate as a signal to a rapid adaptable
process maintaining cell homeostasis.
Lactate as the cause or consequence of fatigue?
There is a host of research suggesting an association
between increased lactate concentration and fatigue during
exercise. Initial work by Hill (1932) indicated that the
contraction force of isolated fibres declined at the same time
as lactate accumulation increased. Later work by Fabiato and
Fabiato (1978) and Allen et al. (1995) demonstrated that the
likely mechanism for reduction in force production, by
intracellular lactate acidification, was via reduced sensitivity of
the sarcoplasmic reticulum Ca
pump to Ca
. For some time,
the release of lactate and hydrogen ions was thought to occur
at similar rates, inducing lactate acidaemia. However, evidence
for dissociation between lactate and hydrogen ion release was
demonstrated in vivo in humans by Bangsbo et al. (1997). This
study showed that the release of protons can occur, to a large
extent, through mechanisms other than diffusion of
undissociated lactic acid ions during submaximal exercise. The
non-lactate-related release of protons was estimated to account
for approximately 75% of the total efflux of protons during an
exercise bout, leading to the question as to what role lactate
may therefore play during muscle contraction. Posterino and
Fryer (2000) further demonstrated in vitro that elevated
myoplasmic lactate concentrations had negligible effects on
voltage-dependent Ca
handling and muscle contraction at the
level of the contractile proteins. General acceptance now is that
lactate ions themselves have little effect on muscle contraction
(Lindinger et al., 1995; Posterino et al., 2001), whilst the
importance of acidosis in muscle fatigue has also become
questioned and may not be such a major factor (Westerblad et
al., 2002). Recently, Robergs et al. (2004) reviewed evidence
to suggest that there is no biochemical support for lactate
production causing all of the intracellular acidosis, with lactate
production actually retarding it, perhaps delaying the onset of
muscle fatigue, whilst acidification resulted from other
biochemical processes such as ATP breakdown and the earlier
stages of glycolysis.
Some of the methods employed by Robergs et al. (2004) to
illustrate their argument have been questioned by subsequent
papers (Boning et al., 2005; Kemp, 2005); however, the
general consensus from a variety of experimental approaches
appears to be that lactate has minimal involvement in the onset
of fatigue. Instead, recent research suggests an increase of
inorganic phosphate (P
) produced during contraction as the
leading contender responsible for initiating muscle fatigue at
the level of muscle function (see review by Westerblad et al.,
2002). Contemporary explanation of fatigue certainly points to
a combination of effects, as opposed to one mechanism,
causing fatigue, certainly in whole-organism function.
Accordingly, it is probably premature to also accept the P
hypothesis as the sole cause of fatigue until further research is
carried out, particularly in vivo (Gladden, 2004), just as care
should be taken when dismissing H
accumulation from the
aetiology of fatigue until our overall understanding of fatigue
is improved (Fitts, 2003; Boning et al., 2005).
It would now seem that lactate ions may in fact have a
protective effect on contraction force, as first demonstrated by
Nielsen et al. (2001). In their experiments, it was observed that
a reduction in tetanic force of intact isolated muscle fibres
caused by elevated potassium (K
) could be almost completely
reversed when incubated in lactate (20·mmol·l
). The
substrate concentration used within this experiment led the
authors to hypothesise that at high exercise intensities, where
Lactate signalling at rest and during exercise 4565
intra-muscle lactate is known to range between ~15 and
, lactate acts to increase force, counteracting the
force-depressing effects of high extracellular K
whilst having
no effect on the membrane potential or Ca
handling of the
muscle. Further research has shown that at a K
incubation of
and a temperature of 30°C, a 16% decline in force
production of intact rat soleus or EDL can be seen compared
with controls. At the same K
concentration, the previously
observed force decrement was restored to control values when
temperature (30–35°C), lactate (10·mmol·l
) and
catecholamine concentrations were all elevated, suggesting
involvement of each of these factors in force restoration
(Pedersen et al., 2003). Further, Karelis et al. (2004) have
shown that maximum dynamic and isometric in situ force
production of electrically stimulated rat plantaris muscle is
elevated during intravenous lactate infusion (12·mmol·l
compared with controls. The authors attributed this observation
to increased maintenance of M-wave characteristics during
electrical stimulation and lactate infusion trials compared with
Nielsen et al.’s original lactate protection hypothesis
(Nielsen et al., 2001) has recently been supported by further
work from this group. Pedersen et al. (2004) reported that, in
the presence of chloride (Cl
), intracellular acidosis increased
the excitability of the T system in depolarized muscle fibres,
counteracting fatigue at a critical phase in the
excitation–contraction coupling process. Acidification reduced
permeability, thereby reducing the stimulus needed to
generate a propagating action potential. This view is not
recognised by all. By contrast, Kristensen et al. (2005)
questioned whether this phenomenon can be extended to a
whole-system model during exercise. These authors reported
that muscle preparations in vitro were unable to produce a
similar amount of force compared with controls when
incubated in a 20·mmol·l
Na-lactate, 12·mmol·l
+ 8·mmol·l
lactic acid or a 20·mmol·l
lactic acid solution
and stimulated to fatigue. It was concluded that, although
lactate regenerates force in passive muscle, this process is not
apparent when muscle is exercised. The authors suggest that
the depolarizing effect of lactate incubation observed by
Nielsen et al. (2001) was not replicated, as K
was less pronounced in vivo when muscle was stimulated.
These data seem to suggest that the extension of the Nielsen et
al. (2001) hypothesis to a full-system model is difficult due to
the number of confounding systems that operate during
exercise in vivo. It appears that lactate may delay the onset of
fatigue by maintaining the excitability of muscle and that this
situation may occur during extremely intensive exercise. The
basis and understanding of this role, however, still remains
poorly understood, whilst the methods to transfer isolated
muscle research into full-system physiology are currently
lacking. Clearly, further approaches to investigate this topic are
warranted to establish whether Nielsen’s hypothesis can be
extended to whole-muscle function in vivo.
Peripheral or localised fatigue is characterised by metabolic
change in specific skeletal muscle or muscle groups, whether
it be a reduction in pH or an increased accumulation of a
compound such as P
. The classical theory of exercise-induced
fatigue proposes that exercise is limited only after oxygen
delivery to the exercising skeletal muscle becomes inadequate,
inducing anaerobiosis (Mitchell and Blomqvist, 1971; Bassett
and Howley, 2000). Noakes and colleagues have suggested an
alternative hypothesis, implicating a ‘central governor’ (CNS),
which regulates the mass of skeletal muscle recruited during
exercise through motoneurone pool recruitment, a
consequence of which would be to protect the heart from
ischaemia during maximal exercise (Noakes, 1998; Noakes et
al., 2001, 2004; St Clair Gibson et al., 2003). This model
predicts that the ultimate control of exercise performance
resides in the brain’s ability to vary the work rate and metabolic
demand by altering the number of skeletal muscle motor units
recruited during exercise (Noakes et al., 2004). Some attempts
have been made by this group to address physiological
parameters in peripheral tissue that may act as the signal to the
CNS to regulate exercise intensity (Rauch et al., 2005);
however, this mechanism still remains unclear.
So could lactate have a role as a peripheral signal to the CNS
during exercise? We now know that lactate is a mobile
metabolite capable of cell and intracellular shuttling, with the
circulation able to shift this metabolite to a number of
facultative sites for oxidation or recycling. There is also
mounting evidence in support of lactate utilisation in the brain
(Ide and Secher, 2000) via the astrocyte–neurone lactate
shuttle, a system clearly capable of affecting substrate delivery
and neurone function (Pellerin et al., 1998; Pellerin and
Magistretti, 2003). So could lactate be one of the peripheral
exercise signals that might be incorporated into Noakes’ model
(Noakes et al., 2004)? Certainly, lactate’s production
characteristics allow it to perform such a role. It is elevated
during exercise and reaches maximal levels at or just following
the termination of exercise. Further, shuttling mechanisms
would allow for an influence of lactate, centrally and
peripherally, again fulfilling roles as part of the central
governor hypothesis. It will be of interest to see whether the
peripheral signal for the central governor is identified in future
research and whether lactate has a role to play in this scenario.
Lactate as a signal?
It appears that we still do not fully understand all of the roles
for lactate in vivo. Whilst much of the data presented so far
have been gleaned from isolated muscle, or cell culture,
understanding how these observations transfer to the whole
organism is perhaps the next important question to be
Suggestion of a role for lactate as a metabolic signal at the
whole-organism level has been postulated by Brooks (2002a),
who proposed that lactate may operate as a pseudo-hormone.
Within this model, blood glucose and glycogen reserves in
diverse tissues are regulated to provide lactate, which may then
be used within the cells where it is made or transported through
the interstitium and vasculature to adjacent or anatomically
A. Philp, A. L. Macdonald and P. W. Watt4566
distributed cells for utilization. In this role, lactate becomes a
quantitatively important oxidizable substrate and
gluconeogenic precursor, as well as a means by which
metabolism in diverse tissues may be coordinated. Lactate has
the ability to regulate cellular redox state, via exchange and
conversion into its more readily oxidized analogue, pyruvate,
and effects on NAD
/NADH ratios. Lactate is released into the
systemic circulation and taken up by distal tissues and organs,
where it also affects the redox state in those cells.
Further evidence for lactate acting as something more than
a metabolite or metabolic by-product comes from wound repair
research, where lactate appears to induce a biochemical
‘perception’ effect (Trabold et al., 2003). It had been suggested
that the elevated acidosis associated with wound regeneration
was a result of localised hypoxia. However, Trabold et al.
(2003) provided evidence that lactate may act as a stimulus
similar to hypoxia without any compromise to O
levels. Green
and Goldberg (1964) demonstrated that collagen synthesis rose
~2-fold in lactate-incubated (15·mmol·l
) fibroblasts, whilst
Constant et al. (2000) showed that increased lactate was
capable of upregulating vascular endothelial growth factor
(VEGF) in similar proportions. To examine this apparent
relationship, Trabold et al. (2003) elevated extracellular lactate
in the wounds of male Sprague-Dawley rats by implanting
purified solid-state, hydrolysable polyglycolide. This
substance raised localised lactate to a maintained
. Elevating lactate resulted in elevations in VEGF
and a 50% increase in collagen deposition over a 3-week
period. These data suggest that lactate is capable of inducing
responses characteristic of O
lack, operating to instigate a
pseudo-hypoxic (as far as concentration of lactate is
concerned) environment. In combination with this action, the
continued presence of molecular oxygen (as the tissue was not
hypoxic) allows endothelial cells and fibroblasts to promote
increased collagen deposition and neovascularization.
The possibility that lactate acts as a metabolic signal is
important to take research further. Based on the hypotheses of
Trabold et al. (2003) and Brooks (2002a), can a working model
of lactate signalling be extended to systemic and localised
exercise function?
Firstly, lactate could, potentially, influence local and central
blood flow during exercise. Hypoxia is known to stimulate
systemic vasodilation via a host of neural, hormonal and local
factors (Skinner and Marshall, 1996). Fattor et al. (2005) have
recently used the lactate clamp method to demonstrate an
autoregulatory loop in sympathetic drive that is governed by
lactate release. Circulatory norepinephrine was reduced during
exercise at 65% V
2 peak when lactate was maintained at
compared with controls (2.115±166·pg·ml
, respectively), with epinephrine
concentrations displaying a similar trend (EX; 262±37·pg·ml
to LC; 113±23·pg·ml
). This lends evidence to the possibility
of modulatory control of catecholamines by lactate. The
infusion of lactate had no effects on other glucoregulatory
hormones (i.e. insulin and glucagon) or cortisol. The authors
suggest that the lactate anion was sensed by either the
ventromedial hypothalamus (VMH) or elsewhere via neuronal
metabolism signalling abundant fuel supply; however, this
theory remains to be tested. Therefore, the release of lactate
into the circulation at the onset of exercise could promote
vasodilation, allowing oxygenated blood to reach active
muscle, acting in an additive or modulatory manner to the
demands of tissues during exercise.
A role for lactate in fuel selection?
In many vertebrate species so far examined, fuel selection
has been shown to correlate closely with exercise intensity
(Roberts et al., 1996; Bergman and Brooks, 1999; Richards et
al., 2002; Conley and Lindstedt, 2002). At rest and moderate
exercise intensities, fat oxidation is the predominant source of
ATP production. As exercise intensity rises, a proportional
increase in carbohydrate (CHO) oxidation occurs, with lactate
production following this trend (Fig.·2). This coordinated
control was first identified and named the glucose–fatty acid
cycle by Randle et al. (1963). In short, elevated glucose
Lactate signalling at rest and during exercise 4567
Progressive fast-twitch fibre recruitment
Alterations in blood flow to active tissue
, ADP,
Lactate production > removal approx. 70% V
Accelerated cardiac and respiratory demand
% V
Marked increase in circulatory lactate concentrations
Fig.·2. Interacting processes suggested
to be involved with increased lactate
accumulation during exercise.
concentrations stimulate the secretion of insulin, which
suppresses non-esterified fatty acid (NEFA) release from
adipose tissue, altering fuel use and supply and leading to the
preferential use of CHO. In the reverse situation, when plasma
NEFA concentrations are elevated (e.g. during starvation,
exercise or low insulin levels), fatty acids are predominantly
released and oxidised, and glucose levels are observed to be
Brooks and Mercier (1994) recognised that a clear crossing
point where fuel utilisation came from fat and CHO equally
was observable in fuel selection. The ‘crossover concept’
suggests that the proportion of substrate utilization in an
individual at any point in time depends on a trade-off between
exercise-intensity-induced responses (which increase CHO
utilization) and endurance-training-induced responses (which
promote lipid mobilisation and oxidation). The crossover point
may be taken as the power output at which energy from CHO-
derived fuels predominates over that from lipids, with
increases in power eliciting further increments in CHO
utilization and decrements in lipid oxidation.
The exercise intensity at which a transitional shift in
substrate supply might occur was originally examined in dogs
and goats by Roberts et al. (1996) through calculated rates of
fat and CHO oxidation from respiratory exchange ratio (RER)
data. Maximal fat oxidation rates were observed at 40% of
maximal exercise intensity in both species, with fat oxidation
shown to provide around 77% of total energy requirements.
Bergman and Brooks (1999) studied this in humans and found
the highest lipid oxidation rate in the fed state at 40% V
2 peak.
Taken together, the data provided by Roberts et al. (1996) and
Bergman and Brooks (1999) would suggest that humans and
other mammals, regardless of differences in aerobic capacities,
genotype and training adaptation, demonstrate similar
substrate utilization patterns when relative exercise intensity is
considered (Bergman and Brooks, 1999). Van Loon et al.
(2001) utilised a continuous infusion of [U-
C]palmitate and
]glucose to provide direct measures of whole-body fat
oxidation, which were increased from rest at approximately
up to a maximum rate of 32±2·kJ·min
at 55%
maximal workload (W
) or approximately 60–75% maximal
oxygen consumption. As exercise intensity increased to 75%
fat oxidation declined by 34% to 19±2·kJ·min
. Free
fatty acid (FFA) concentrations and blood flow were
maintained at the highest exercise intensity, suggesting ample
FFA arterial availability.
Three possibilities have been suggested to explain the
decline in FFA acid oxidation in the face of sufficient supply.
Firstly, gradual depletion or limited turnover of the cytosolic
free carnitine pool could alter long-chain fatty acid (LCFA)
transport across the mitochondrial membrane (Harris and
Foster, 1990). Secondly, reduced transport of FFAs by
escalating cellular or systemic acidosis may limit FFA uptake
due to downregulation of the fatty acid transporter, carnitine
palmitoyl-transferase 1 (CPT1) (Sidossis et al., 1998; Bonen
et al., 1999). Finally, changes in glucose flux and energy
expenditure may regulate the amount of available malonyl-
CoA, an allosteric inhibitor of CPT1, which has been shown
to regulate fat oxidation (Ruderman and Dean, 1998;
Roepstorff et al., 2005). To date, the exact mechanism
regulating the relative contribution of CHO and fat to energy
provision during exercise still remains unknown. The most
recent examination of fuel balance during exercise was
conducted by Roepstorff et al. (2005) who utilised high or low
CHO diets to influence glycogen stores and substrate
utilisation during 60·min bicycle exercise at 65% V
2 peak in
eight healthy male subjects. The authors observed a decline in
muscle malonyl-CoA concentrations from rest to moderate
intensity exercise; however, there was no change observed
when fat oxidation rates were altered by the pre-exercise meal.
Thus, the authors concluded that malonyl-CoA may have a role
in increasing absolute levels of fat oxidation; however, it
would not appear to play a major part in fine-tuning the shifts
in CHO and fat oxidation during the rest-to-exercise transition
or during sustained exercise. By contrast, the availability of
free carnitine to CPT1 appears to participate in regulating fat
oxidation during exercise, as muscle carnintine and fat
oxidation rates were both lower during exercise with high
compared with low glycogen conditions (Roepstorff et al.,
So, is there potential for lactate to play a role in effecting
this transition? Previous research has shown that, in isolated
mitochondria, a reduction in pH decreases the activity of CPT1
by increasing the K
of CPT1 for carnitine (Mills et al., 1984).
Starritt et al. (2000) have shown that a decrease in pH from 7.0
to 6.8 reduces CPT1 activity by 40% in vitro, thereby offering
a potential mechanism for extracellular acidosis to inhibit fat
oxidation by reducing supply to the mitochondria or reducing
the rate of fat oxidation at lower exercise intensities where a
fall in pH of approximately 0.1–0.3·units is common (Starritt
et al., 2000). There is a host of research suggesting a direct
effect of lactate on inhibition of lipolysis and increased re-
esterification of FFA (Issekutz et al., 1975; Ahlborg et al.,
1976; Jeukendrup, 2002). Whilst it seems that this evidence
supports a role for acidification in reducing fatty acid
metabolism, it is not clear whether this can be attributed to an
increase in H
, lactate alone or a combination of each. Most
recently, Corbett et al. (2004) have shown that as plasma
lactate increases at progressive exercise intensities, so NEFA
levels decline. If we put these data into a physiological context,
it is known that the lactate threshold (a sustained increased in
systemic lactate from resting levels) during exercise occurs in
most subjects at 60–75% V
2 max, with the accumulation of
circulatory lactate known to increase non-uniformly beyond
this exercise transition. This relationship could, of course, be
chance, with lactate increase solely due to increased CHO
oxidation or glycolytic flux. However, if we examine the
increase in lactate in the context of a signalling hypothesis,
lactate’s role could be perceived as something very different.
We know that ample tissue oxygenation is available in skeletal
muscle at intensities of approximately 60–75% V
2 max,
allowing oxidative phosphorylation to proceed (Richardson et
al., 1998), so lactate is not released as a result of tissue hypoxia.
A. Philp, A. L. Macdonald and P. W. Watt4568
Similarly, lactate will be maintained at a steady state beyond
the lactate threshold, up to a maximal lactate steady state,
indicating that lactate clearance capacity is not exceeded at
these conditions (Billat et al., 2003). Could it be that lactate is
released to signal a progressive switch in fuel utilisation from
fat to CHO, reducing FFA substrate availability for the CPT
complex whilst also acting, perhaps in combination with H
accumulation, to reduce pH, subsequently downregulating
CPT1-facilitated FFA transport? This model may provide an
efficient way of regulating fuel supply as lactate is produced,
signals to its targets and is then re-used as a fuel, allowing
continuation of glycolysis and oxidative phosphorylation.
As previously discussed, lactate is preferentially utilised,
compared with glucose and pyruvate, in cardiac muscle
(Laughlin et al., 1993). Further, Chatham et al. (2001) have
reported a similar selectivity for [
C]lactate to be
preferentially oxidised ahead of [
C]glucose, again in cardiac
muscle preparations. Miller et al. (2002) extended this
observation when they reported that infused lactate was
preferentially oxidised in preference to glucose at rest and
during whole-body exercise in humans. The authors concluded
that lactate, provided by intravenous infusion, acted in a
glucose sparing role, allowing glucose and glycogen stores to
be maintained, to be utilized later in periods of increased
exercise stress. Artificially elevating lactate concentrations,
such as the lactate clamp method utilised by Miller et al.
(2002), allows for the investigation of lactate’s role in a variety
of processes; however, it does provide a non-physiological
situation, as lactate is added independently of glucose usage.
The elevated lactate concentrations could therefore serve to
stunt glycolysis, as opposed to sparing glucose concentrations.
Infused lactate, if the intracellular lactate shuttle is indeed
correct, will bypass glycolysis, becoming readily accepted into
the mitochondria, where it is converted to pyruvate via mLDH.
Therefore, lactate synthesis in the cytosol would be reduced,
and an increase in H
would follow, since lactate production
from pyruvate normally accepts an H
from NADH. This
increased acidification could suppress glycolysis by inhibiting
phosphofructokinase (PFK) activity whilst affecting the redox
state of the cell. Glucose and glycogen would then be spared
by lactate oxidation; however, this process cannot occur during
regular exercise as, without the infusion, the only source of
lactate production would be as a consequence of glycolysis
Lactate and pain
The notion that lactate causes pain during exercise and may
contribute to exercise cessation has been suggested and
propagated by coaches, trainers and athletes for some time.
There is no direct evidence available in the literature to warrant
these claims; in fact, lactate infusion trials report no adverse
effects of increased lactate on perceived effort
of exercise (Miller et al., 2002, 2005) or in
initiating the sensation of pain in muscle or
Recent research could, however, implicate
lactate as influential in the sensation of pain
during exercise. Following the discovery of a
receptor for protons in the nerve cell membrane
(Krishtal and Pidoplichko, 1980), a family of
receptor channel molecules has been identified
and cloned (Waldmann and Lazdunski, 1998).
These are the acid-sensitive ion channel family,
or ASICs. Four ASIC isoforms have been
identified in the human genome, each
displaying a characteristic biophysical
behaviour with respect to gating properties and
pH dependence (see Krishtal, 2003 for a
review). There has been a suggestion that
lactate, in combination with extracellular H
may influence sensory mechanotransduction
via an ASIC pathway, which in turn may
modulate targeting of nociceptive sensation
(Immke and McClesky, 2001).
ASICs are Na
channels. Immke and
McClesky (2003) proposed that the ASIC
channel is blocked at a site, near the external
entry to the pore, by Ca
. Binding of hydrogen
ions diminishes the affinity for Ca
, which
promotes Ca
release, thus allowing Na
through the channel, where it will act to
Lactate signalling at rest and during exercise 4569
(3) (2)
Glucose 6-phosphate
Glyceraldehyde 3-phosphate
Fig.·3. The effect of artificially elevated lactate concentrations (lactate clamp) on
metabolic processes. Increased circulatory lactate concentrations (1) result in lactate
entering the cytosol, where it then enters the mitochondrion via MCT1 (2). Within
the mitochondrion, lactate is converted to pyruvate via mLDH (3), which then
progresses into the tricarboxylic acid (TCA) cycle (4). However, artificially raised
cytosolic lactate concentrations (5) lead to suppression in glycolysis. Therefore, a
resulting increase in H
and NADH occurs, and acidosis inhibits phosphofructokinase
(PFK) activity (6). This suppression finally results in reduced glycolytic activation
and a reduction, or sparing, of glycogenolysis.
depolarize the excitable tissue. At a pH of 7.4, Ca
remains high (K
) so that few channels can open;
however, at pH 7.0 the affinity is low enough
) that ASIC channels open. Lactic acid (it
was not clarified whether it was lactate or H
) seems to enhance
the sensitivity of ASIC3, allowing the ASIC channel to open
at lower H
levels and making the pore more sensitive to lactic
acidosis (Immke and McClesky, 2001). This process has been
implicated in the aetiology of stroke and seizure (ASICs have
been detected throughout the CNS). The drop in pH and
increased Ca
in both conditions are likely to affect CNS and
peripheral nerve (e.g. nociceptor) function (Akaike and Ueno,
1994). Drew et al. (2004) recently utilised wild-type and
ASIC2/3 double-knockout mice to conclude that the ASIC
mechanism does not contribute to mechanically activated
currents in mammalian sensory neurones. It was suggested
that an alternative ion channel type was the most likely source
of mechanotransduction, with receptor classes of the transient
receptor potential (TRP) channel family suggested as a
potential candidate (Clapham, 2003).
The recent detection of ASIC isoforms in a cell line of
skeletal muscle characteristics points to other roles for ASIC
isoforms apart from pain sensation. Gitterman et al. (2005)
demonstrated that the rhabdomyosarcoma cell line (SJ-RH30)
possesses endogenous acid-gated currents, similar to the
properties of currents arising from ASIC1 subunits
(Gunthorpe et al., 2001). Further blocking of the acid-gated
current was demonstrated firstly by 30·mol·l
of the known
ASIC1 inhibitor amiloride and then secondly by a 1:1000
dilution of the ASIC1 antagonist psalmotoxin 1, found in
Psalmopoeus venom (Escoubas et al., 2000). It was further
demonstrated by these authors that the removal of extracellular
enhanced channel conductance at pH 6.5 by ~250%.
Preliminary investigation using TaqMan
(Applied Systems,
Warrington, UK) mRNA quantification provided evidence for
expression of both ASIC1 and ASIC3 mRNA in adult human
muscle (Gitterman et al., 2005). The question of whether
human muscle is subject to quick fluctuations of pH of a
magnitude capable of activating ASICs has been raised
previously by Krishtal (2003) and is clearly paramount if
lactate is involved in skeletal muscle ASIC activation in vivo.
It has been suggested that blood lactate concentrations
following strenuous exercise can rise to the region of
(Fitts, 1994); however, common levels range
between 10 and 15·mmol·l
in healthy active subjects.
Concentrations of this magnitude alongside a pH change could
be hypothesised to produce some degree of channel activation
and increase in membrane Na
conductance or membrane
depolarization. Such changes in membrane ion conductance
and polarization could be a signal in themselves for changes in
metabolite use and intracellular signalling pathways, either
directly or through their modulation.
Microdialysis might allow further investigation of the
Immke and McClesky (2001) hypothesis, having been used by
a number of research groups (Rosdahl et al., 1993; Maclean et
al., 1999; Green et al., 2000; Street et al., 2001; Rooyackers,
2005). Maclean et al. (1999) confirmed that a substantial
increase in interstitial lactate occurs during the transition from
rest to exercise, exceeding values seen in plasma. Street et al.
(2001) added to these data by observing that interstitial pH
declined in a near linear manner as intensity increased. The
lowest pH observed 1·min after a 5·min bout of one-legged
knee extensor exercise (70·W) was 6.93, with a mean of 7.04.
A pH change of this nature could alter ASIC activation (Immke
and McClesky, 2003) and act to increase muscle contractility,
delay the onset of fatigue or act as a signal to cease exercise.
There clearly are discrepancies in research findings between
whole-body and localised fatigue. Whilst our understanding of
lactate action on ASIC function in vivo and the presence of
ASIC protein in nerve and skeletal muscle is in its infancy, the
revisiting of lactate’s involvement in pain sensation is an
interesting renewal of a long debate. It could be that, instead
of pain, as such, lactate assists in the detection of severe
exercise stress, signalling the termination or scaling down of
exercise before muscle or other organ damage occurs. Lactate
could potentially signal to nerve cells indicating the exercise
stress, to which the sensation of pain would be produced and
exercise would be reduced or cease.
Signalling with regard to in vivo processes – a working
Accordingly, we would like to suggest the following
signalling hypothesis (Fig.·4). In this scenario, lactate becomes
mobilised at the onset of exercise (rate depending on mode and
intensity of exercise). During this exercise transition, there is
approximately a 2-fold elevation in circulating lactate
(~1–2·min, increasing lactate to 1–2·mmol·l
), and this
concentration is greater still in muscle and interstitium. Lactate
has a modulatory effect on vasodilation and catecholamine
release, stimulating fat and carbohydrate oxidation. Lactate is
then shuttled from its site of production in the cytosol to
adjacent muscle fibres, where it is reconverted to pyruvate and
enters the tricarboxylic acid cycle for oxidative
phosphorylation, or is mobilised into the circulation, where it
is reconverted to glucose by the liver, therefore providing an
efficient signal-to-fuel process as lactate is recycled during
gluconeogenesis or oxidised. In turn, lactate also promotes
vasodilation of active musculature and stimulates ventilatory
drive (Hardason et al., 1998; Gargaglioni et al., 2003).
As exercise progresses into the moderate to high exercise
zone (65–85% V
2 max; lactate 2–10·mmol·l
), lactate
production exceeds the removal capacity of the MCT transport
system. Lactate and H
ions influence CPT1 function, thereby
reducing fat oxidation and prompting a shift towards
carbohydrate oxidation becoming the predominant fuel
utilised. Availability of O
is still adequate for oxidative
phosphorylation; however, the presence of lactate simulates
conditions that may be recognised as hypoxic in nature,
influencing angiogenesis, oxidative defence mechanisms and
collagen synthesis, all serving to improve muscle function.
Lactate has also previously been suggested to act as a
A. Philp, A. L. Macdonald and P. W. Watt4570
scavenger for free radicals released into the circulation
(Groussard et al., 2000) and could potentially operate in this
manner as exercise intensity increases.
As exercise progresses towards exhaustion, whole-body
lactate levels continue to rise (detectable as 8–20·mmol·l
blood and higher in muscle). ATP provision in active muscle
is approaching its maximal capacity and there is a gradual
decline in cellular and systemic pH. Elevated lactate helps
reduce glucose usage and glycogenolysis, minimising
depletion of these stores as escalating acidosis reduces PFK
function. Further, H
ions combined with lactate cause an
opening in ASIC pores, signalling exercise termination. In this
role, lactate is filling a dual purpose. Firstly, its release is
indicating stress placed upon active muscle, whilst, secondly,
high concentrations of intracellular lactate could potentially be
acting in a protective manner. Acting as a peripheral signal,
lactate could therefore provide a mechanism by which the CNS
detects localised, at the level of muscle or muscle group,
exercise stress and causes exercise to terminate (Noakes et al.,
Future research
Lactate infusion studies have been used to artificially raise
circulating lactate levels at rest and exercise, allowing
examination of the effect of lactate on a variety of processes
(see below). Whilst such methods have been routinely used in
animal and human studies for a number of years, it is the
combination of such infusion with improved stable isotope
methods that has provided more mechanistic information.
The lactate clamp (LC) method (Gao et al., 1998) has been
used to demonstrate that artificially elevated lactate levels
during moderate exercise may increase lactate oxidation, spare
blood glucose, reduce glucose production (Miller et al., 2002)
whilst also increasing gluconeogenesis (Roef et al., 2003).
Miller et al. (2005) have reported that the LC method allows
an increase in lactate without causing acidosis; in fact, LC
caused a mild alkalosis. LC did not increase ventilation or
rating of perceived exertion, suggesting that the LC can be used
to solely study the effect of lactate, rather than acidosis, on
metabolic functions.
A number of exercise scenarios, as well as pathological
conditions, exist that may also allow many of the ideas
suggested in this paper to be scrutinised. Does lactate function
in a signalling role during hypoxic stress? We know that
following prolonged exposure to hypoxia, lactate levels have
been shown to decline, in what is termed ‘the lactate paradox’
(Hochachka et al., 2002). This condition could test further the
role of lactate during exercise. Also, what happens during
exercise in myophosphorylase-deficient patients (McArdle’s
disease), who are unable to increase their production of lactate
during exercise, or during chronic hyperlactatemia such as that
experienced by type II diabetes and HIV patients? Why might
lactate be elevated in these scenarios?
Lactate signalling at rest and during exercise 4571
Low Moderate/high Severe
Exercise intensity transition zones
% W
[BLa] (mmol l
Fig. 4. Potential roles for lactate signalling during exercise of increasing intensity. At the onset of exercise, elevated lactate concentrations signal
increased ventilatory drive and vasodilation, whilst sparing glucose and glycogen stores. As exercise intensity moves to the moderate zone, the
increase in lactate mimics hypoxic conditions and triggers a number of adaptive responses. In this zone, lactate may also be involved with the
transition to carbohydrate metabolism by inhibiting lipolysis. At severe exercise intensities, lactate acts as a peripheral signal to indicate exercise
stress, whilst also maintaining the integrity of the muscle. High levels of lactate signal severe exercise stress and exercise is terminated, possibly
through a central governor mechanism. Abbreviations: La, lactate; BLa, blood lactate; PRO, lactate protection; Glu, glucose; FA, fatty acid;
EP, epinephrine; NEP, nor-epinephrine; VENT, increased ventilatory drive; VASD, vasodilation; W
, maximal power output.
As is evident from much of the research discussed in this
review, improvements in gene analysis and manipulation
technologies have occurred over the past decade. The
sequencing of the human genome, in combination with RT-
PCR and oligonucleotide array technology, now allows the
rapid screening of a host of signalling pathways and novel
ion channels from a relatively small tissue sample. There are
also strategies for examining signalling pathways that may be
involved if phosphorylation is a key event (Knebel et al.,
2001; Haydon et al., 2002). Researchers also have the added
benefit of gene knock-out technology and the use of
transgenic approaches to allow proof of concept previously
unattainable. Further to this, the introduction of siRNA
approaches in whole body systems will allow researchers
to examine and manipulate certain pathways and analyse a
large variety of targets in vivo. The ability to artificially
elevate lactate concentrations safely in vivo, and then
limiting or removing pathways using siRNA manipulation,
will allow direct assessment of lactate’s role in a variety of
local and whole-system processes whilst limiting the
confounding influence of parallel energy systems and
pathways that, to date, greatly restrict the scope of in vivo
The perception of lactate, acidosis and fatigue as being
equivalent should no longer have a place in human physiology
text or tutelage, and a conscious effort should be made to
educate student and public perception of the multi-faceted role
lactate may play at rest and during exercise.
Lactate should be appreciated not as a sink for glycolytic
waste to accumulate or as an acidifier but as an effective
mechanism for coordinated fuel sensing and tissue function.
This fuel is shuttled to a variety of sites where it is directly
oxidised, re-converted back to pyruvate or glucose and
oxidised, allowing the process of glycolysis to restart and ATP
provision maintained. The shuttling facilitators MCT1 and
MCT4, and possibly others in the MCT family, are proteins
with rapid induction capabilities and the ability to respond to
a host of contraction and environmental stimuli. Lactate
production and MCT transport characteristics could allow
them to operate as a signal mechanism activating a variety of
functions during exercise and recovery.
Research should now be directed towards understanding the
function of lactate during exercise in humans. The idea of
lactate signalling to a variety of targets has stemmed from data
across a variety of research areas, from cell and organelle to
whole-body and system based experiments. Lactate’s potential
role in a variety of processes has been clearly demonstrated;
however, the mechanisms underlying these observations in
many cases remain undetermined. Lactate’s role in fuel
selection should be clarified, with the LC method appearing to
be a suitable method of investigating this process. Studies
utilising siRNA application in combination with microarray
analysis could be used to address signalling targets that lactate
may influence during exercise, whilst examination of ASICs in
skeletal muscle may provide a channel by which lactate acts to
increase muscle contractility during in vivo function or to
signal to nerve cells protecting against exercise damage. With
these areas warranting investigation, it certainly seems feasible
that lactate has a few tricks left to show us of its role in exercise
The authors would like to thank Dr Jamie Pringle and Dr
Helen Carter for their helpful criticism, knowledge and advice
in the preparation of this manuscript. We would also like to
acknowledge financial support from the University of
Ahlborg, G., Hagenfeldt, L. and Wahren, J. (1976). Influence of lactate
infusion on glucose and FFA metabolism in man. Scand. J. Clin. Lab. Invest.
36, 193-201.
Akaike, N. and Ueno, S. (1994). Proton-induced current in neuronal cells.
Prog. Neurobiol. 43, 73-83.
Allen, D. G., Lannergren, J. and Westerblad, H. (1995). Muscle cell
function during prolonged activity: cellular mechanisms of fatigue. Exp.
Physiol. 80, 497-527.
Araki, T. (1891). Ueber die bildung von milchsaure und glucose im
organismus bei sauerstoffmangel. Zeitschr. Phys. Chem. 15, 335-370.
Baker, S. K., McCullagh, K. J. A. and Bonen, A. (1998). Training intensity
dependent and tissue specific increases in lactate uptake and MCT1 in heart
and muscle. J. Appl. Physiol. 84, 987-994.
Bangsbo, J., Juel, C., Hellsten, Y. and Saltin, B. (1997). Dissociation
between lactate and proton exchange in muscle during intense exercise in
man. J. Physiol. 504, 489-499.
Bassett, D. R., Jr (2002). Scientific contributions of A. V. Hill: exercise
physiology pioneer. J. Appl. Physiol. 93, 1567-1582.
Bassett, D. R., Jr and Howley, E. T. (2000). Limiting factors for maximum
oxygen uptake and determinants of endurance performance. Med. Sci.
Sports. Exerc. 32, 70-84.
Baumgart, E., Fahimi, H. D., Stich, A. and Volkl, A. (1996). L-Lactate
dehydrogenase A
– and A
B isoforms are bona fide peroxisomal enzymes
in rat liver. J. Biol. Chem. 271, 3846-3855.
Bergman, B. C. and Brooks, G. A. (1999). Respiratory gas-exchange ratios
during graded exercise in fed and fasted trained and untrained men. J. Appl.
Physiol. 86, 479-487.
Bergman, B. C., Wolfel, E. E., Butterfield, G. E., Lopaschuk, G. D.,
Casazza, G. A., Horning, M. A. and Brooks, G. A. (1999). Active muscle
and whole body lactate kinetics after endurance training in men. J. Appl.
Physiol. 87, 1684-1696.
Berzelius, J. J. (1808). Djurkemien. Stockholm: Marquard.
Billat, V. L. S. P., Py, G., Koralsztein, J.-P. and Mercier, J. (2003). The
concept of the maximal lactate steady state: a bridge between biochemistry,
physiology and sport science. Sports Med. 33, 407-426.
Bonen, A., Dyck, D. J., Ibrahimi, A. and Abumrad, N. A. (1999). Muscle
contractile activity increases fatty acid metabolism and transport and
FAT/CD36. Am. J. Physiol. 276, E642-E649.
Boning, D., Strobel, G., Beneke, R. and Maassen, N. (2005). Lactic acid still
remains the real cause of exercise-induced metabolic acidosis. Am. J.
Physiol. Regul. Integr. Comp. Physiol. 289, 902-903.
Brooks, G. A. (1985). Anaerobic threshold: review of the concept and
directions for future research. Med. Sci. Sports. Exerc. 17, 22-34.
Brooks, G. A. (1986). The lactate shuttle during exercise and recovery. Med.
Sci. Sports. Exerc. 18, 360-368.
Brooks, G. A. (2002a). Lactate shuttles in nature. Biochem. Soc. Trans. 30,
Brooks, G. A. (2002b). Lactate shuttle – between but not within cells? J.
Physiol. 541, 333.
Brooks, G. A. and Mercier, J. (1994). Balance of carbohydrate and lipid
utilization during exercise: the ‘crossover’ concept. J. Appl. Physiol. 76,
Brooks, G. A., Dubouchaud, H., Brown, M., Sicurello, J. P. and Butz, C.
A. Philp, A. L. Macdonald and P. W. Watt4572
E. (1999). Role of mitochondrial lactate dehydrogenase and lactate oxidation
in the intracellular lactate shuttle. Proc. Natl. Acad. Sci. USA 96, 1129-1134.
Butz, C. E., McClelland, G. B. and Brooks, G. A. (2004). MCT1 confirmed
in rat striated muscle mitochondria. J. Appl. Physiol. 97, 1059-1066.
Chatham, J. C., Des Rosiers, C. and Forder, J. R. (2001). Evidence of
separate pathways for lactate uptake and release by the perfused rat heart.
Am. J. Physiol. 281, E794-E802.
Clapham, D. E. (2003). TRP channels as cellular sensors. Nature 426, 517-
Coles, L., Litt, J., Hatta, H. and Bonen, A. (2004). Exercise rapidly increases
expression of the monocarboxylate transporters MCT1 and MCT4 in rat
muscle. J. Physiol. 561, 253-261.
Conley, K. E. and Lindstedt, S. L. (1996). Minimal cost per twitch in
rattlesnake tail muscle. Nature 383, 71-72.
Conley, K. E. and Lindstedt, S. L. (2002). Energy-saving mechanisms in
muscle: the minimization strategy. J. Exp. Biol. 205, 2175-2181.
Connett, R. J., Gayeski, T. E. J. and Honig, C. R. (1986). Lactate efflux is
unrelated to intracellular P
2 in a working red muscle in situ. J. Appl.
Physiol. 61, 402-408.
Constant, J. S., Feng, J. J., Zabel, D. D., Yuan, H., Suh, D. Y.,
Scheuenstuhl, H., Hunt, T. K. and Hussain, M. Z. (2000). Lactate elicits
vascular endothelial growth factor from macrophages: a possible alternative
to hypoxia. Wound Repair Regen. 8, 353-360.
Corbett, J., Fallowfield, J. L., Sale, C. and Harris, R. C. (2004).
Relationship between plasma lactate concentration and fat oxidation. Proc.
9th Annu. Congr. Eur. Coll. Sports Sci. 107, P172.
Cori, G. T. and Cori, C. F. (1929). Glycogen formation in the liver from
L-lactic acid. J. Biol. Chem. 81, 389-403.
Cori, G. T. and Cori, C. F. (1933). Changes in hexosephosphate, glycogen,
and lactic acid during contraction and recovery of mammalian muscle. J.
Biol. Chem. 99, 493-505.
Davis, J. A. (1985). Anaerobic threshold: review of the concept and directions
for future research. Med. Sci. Sports. Exerc. 17, 6-18.
Deuticke, B. (1982). Monocarboxylate transport in erythrocytes. J. Membr.
Biol. 70, 89-103.
Donovan, C. and Brooks, G. A. (1983). Endurance training affects lactate
clearance, not lactate production. Am. J. Physiol. 244, E83-E92.
Drew, L. J., Rohrer, D. K., Price, M. P., Blaver, K. E., Cockayne, D. A.,
Cesare, P. and Wood, J. N. (2004). Acid-sensing ion channels ASIC2 and
ASIC3 do not contribute to mechanically activated currents in mammalian
sensory neurones. J. Physiol. 556, 691-710.
Dubouchaud, H., Butterfield, G. E., Wolfel, E. E., Bergman, B. C. and
Brooks, G. A. (2000). Endurance training, expression, and physiology of
LDH, MCT1, and MCT4 in human skeletal muscle. Am. J. Physiol. 278,
Escoubas, P., De Weille, J. R., Lecoq, A., Diochot, S., Waldmann, R.,
Champibny, G., Mionier, D., Menez, A. and Lazdunski, M. (2000).
Isolation of a tarantula toxin specific for a class of proton gated Na
channels. J. Biol. Chem. 275, 25116-25121.
Fabiato, A. and Fabatio, A. (1978). Effects of pH on the myofilaments and
the sarcoplasmic reticulum of skinned cells from cardiac and skeletal
muscles. J. Physiol. 276, 233-255.
Fattor, J. A., Miller, B. F., Jacobs, K. A. and Brooks, G. A. (2005).
Catecholamine response is attenuated during moderate-intensity exercise in
response to the ‘lactate clamp’. Am. J. Physiol. 288, E143-E147.
Fitts, R. H. (1994). Cellular mechanisms of muscle fatigue. Physiol. Rev. 74,
Fitts, R. H. (2003). Mechanisms of muscular fatigue. In Principles of Exercise
Biochemistry. 3rd edition (ed. J. R. Poortmans), pp. 279-300. Basel: Karger.
Fletcher, W. M. and Hopkins, F. G. (1907). Lactic acid in amphibian muscle.
J. Physiol. 35, 247-309.
Gao, J., Islam, M. A., Brennan, C. M., Dunning, B. E. and Foley, J. E.
(1998). Lactate clamp: a method to measure lactate utilisation in vivo. Am.
J. Physiol. 275, E729-E733.
Garcia, C. K., Goldstein, J. L., Pathak, R. K., Anderson, R. G. and Brown,
M. S. (1994). Molecular characterization of a membrane transporter for
lactate, pyruvate, and other monocarboxylates: implications for the Cori
cycle. Cell 76, 865-873.
Gargaglioni, L. H., Bicego, K. C., Steiner, A. A. and Branco, L. G. (2003).
Lactate as a modulator of hypoxia-induced hyperventilation. Respir.
Physiol. Neurobiol. 138, 37-44.
Gitterman, D. P., Wilson, J. and Randall, A. D. (2005). Functional
properties and pharmacological inhibition of ASIC channels in the human
SJ-RH30 skeletal muscle cell line. J. Physiol. 562, 759-769.
Gladden, L. B. (2004). Lactate metabolism: a new paradigm for the third
millennium. J. Physiol. 558, 5-30.
Gladden, L. B., Crawford, R. E., Webster, M. J. and Watt, P. W. (1995).
Rapid tracer lactate influx into canine skeletal muscle. Am. J. Physiol. 78,
Green, H. and Goldberg, B. (1964). Collagen and cell protein synthesis by
established mammalian fibroblast line. Nature 204, 347-349.
Green, H., Halestrap, A., Mockett, C., O’Toole, D., Grant, S. and Ouyang,
J. (2002). Increase in muscle MCT are associated with reductions in muscle
lactate after a single exercise session in humans. Am. J. Physiol. 282, E154-
Green, S., Langderg, H., Skovgaard, D., Bulow, J. and Kjaer, M. (2000).
Interstitial and arterial-venous [K
] in human calf muscle during dynamic
exercise: effect of ischemia and relation to muscle pain. J. Physiol. 529,
Groussard, C., Morel, I., Chevanne, M., Monnier, M., Cillard, J. and
Delamarche, A. (2000). Free radical scavenging and antioxidant effects of
lactate ion: an in vitro study. J. Appl. Physiol. 89, 169-175.
Gunthorpe, M. J., Smith, G. D., Davis, J. B. and Randall, A. D. (2001).
Characterisation of a human acid-sensing ion channel (hASIC1a)
endogenously expressed in HEK293 cells. Pflügers Arch. 442, 668-674.
Halestrap, A. and Meredith, D. (2004). The SLC16 gene family – from
monocarboxylate transporters (MCTs) to aromatic amino acid transporters
and beyond. Pflügers Arch. 447, 619-628.
Halestrap, A. and Price, N. T. (1999). The proton-linked moncarboxylate
transporter (MCT) family: structure, function and regulation. Biochem. J.
343, 281-299.
Hardarson, T., Skarphedinsson, J. O. and Sveinsson, T. (1998).
Importance of the lactate anion in control of breathing. J. Appl. Physiol.
84, 411-416.
Harris, R. C. and Foster, C. V. L. (1990). Changes in muscle free carnitine
and acetylcarnitine with increasing work intensity in the thoroughbred
horse. Eur. J. Appl. Physiol. 60, 81-85.
Hashimoto, T., Masuda, S., Taguchi, S. and Brooks, G. A. (2005).
Immunohistochemical analysis of MCT1, MCT2 and MCT4 expression in
rat plantaris muscle. J. Physiol. 597, 121-129.
Haydon, C. E., Watt, P. W., Morrice, N., Knebel, A., Gaestel, M. and
Cohen, P. (2002). Identification of a phosphorylation site on skeletal muscle
myosin light chain kinase that becomes phosphorylated during muscle
contraction. Arch. Biochem. Biophys. 397, 224-231.
Hildebrandt, A. L., Pilegaard, H. and Neufer, P. D. (2003). Differential
transcriptional activation of select metabolic genes in response to variations
in exercise intensity and duration. Am. J. Physiol. 285, E1021-E1027.
Hill, A. V. (1932). The revolution in muscle physiology. Physiol. Rev. 12, 56-
Hill, A. V. and Meyerhof, O. (1923). Ueber die vorgange bei der
muskelkontraktion. Ergeb. Physiol. Biol. Chem. Exp. Pharmakol. 22, 299-344.
Hill, A. V., Long, C. N. H. and Lupton, H. (1924a). Muscular exercise, lactic
acid, and the supply and utilisation of oxygen. Parts I-III. Proc. R. Soc. Lond.
B 96, 438-475.
Hill, A. V., Long, C. N. H. and Lupton, H. (1924b). Muscular exercise, lactic
acid, and the suppply and utilisation of oxygen. Parts IV-VI. Proc. R. Soc.
Lond. B 97, 84-138.
Hochachka, P. W., Beatty, C. L., Burelle, Y., Trump, M. E., McKenzie,
D. C. and Matheson, G. O. (2002). The lactate paradox in human high-
altitude physiological performance. News Physiol. Sci. 17, 122-126.
Ide, K. and Secher, N. H. (2000). Cerebral blood flow and metabolism during
Prog. Neurobiol. 61, 397-414.
Immke, D. C. and McCleskey, E. W. (2001). Lactate enhances the acid-
sensing Na
channel on ischemia-sensing neurons. Nat. Neurosci. 4, 869-
Immke, D. C. and McCleskey, E. W. (2003). Protons open acid-sensing ion
channels by catalyzing relief of Ca
blockade. Neuron 37, 75-84.
Issekutz, B., Jr, Shaw, W. A. and Issekutz, T. B. (1975). Effect of lactate
on FFA and glycerol turnover in resting and exercising dogs. J. Appl.
Physiol. 39, 349-353.
Jeukendrup, A. E. (2002). Regulation of fat metabolism in skeletal muscle.
Ann. NY Acad. Sci. 967, 217-235.
Jobsis, F. F. and Stainsby, W. N. (1968). Oxidation of NADH during
contractions of circulated mammalian skeletal muscle. Respir. Physiol. 4,
Juel, C. (1988). Intracellular pH recovery and lactate efflux in mouse soleus
muscles stimulated in vitro: the involvement of sodium/proton exchange and
a lactate carrier. Acta Physiol. Scand. 132, 363-371.
Lactate signalling at rest and during exercise 4573
Juel, C., Honig, A. and Pilegaard, H. (1991). Muscle lactate transport studied
in sarcolemmal giant vesicles: dependence on fibre type and age. Acta
Physiol. Scand. 143, 361-365.
Karelis, A. D., Marcil, M., Peronnet, F. and Gardiner, P. F. (2004). Effect
of lactate infusion on M-wave characteristics and force in the rat plantaris
muscle during repeated stimulation in situ. J. Appl. Physiol. 96, 2133-2138.
Kemp, G. (2005). Lactate accumulation, proton buffering, and pH change in
ischemically exercising muscle. Am. J. Physiol. 289, E895-E901.
Kemper, W. F., Lindstedt, S. L., Hartzler, L. K., Hicks, J. W. and Conley,
K. E. (2001). Shaking up glycolysis: Sustained, high lactate flux during
aerobic rattling. Proc. Natl. Acad. Sci. USA 98, 395-397.
Kim, C. M., Goldstein, J. L. and Brown, M. S. (1992). cDNA cloning of
Mev, a mutant protein that facilitates cellular uptake of mevalonate, and
identification of the point mutation responsible for its gain in function. J.
Biol. Chem. 267, 23113-23121.
Knebel, A., Morrice, N. and Cohen, P. (2001). A novel method to identify
protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by
SAPK4/p38. EMBO. J. 20, 4360-4369.
Krishtal, O. (2003). The ASICs: signalling molecules? Modulators? Trends
Neurosci. 26, 477-482.
Krishtal, O. and Pidoplichko, V. L. (1980). A receptor for protons in the
nerve cell membrane. Neuroscience 5, 2325-2327.
Kristensen, M., Albertsen, J., Rentsch, M. and Juel, C. (2005). Lactate and
force production in skeletal muscle. J. Physiol. 562, 521-526.
Laughlin, M. R., Taylor, J., Chesnick, A. S., DeGroot, M. and Balaban,
R. S. (1993). Pyruvate and lactate metabolism in the in vivo dog heart. Am.
J. Physiol. Heart Circ. Physiol. 264, 2068-2079.
Lazarow, P. B. and de Duve, C. (1976). A fatty acyl-CoA oxidizing system
in rat liver peroxisomes: enhancement by clofibrate, a hypolipidemic drug.
Proc. Natl. Acad. Sci. USA 73, 2043-2046.
Lindinger, M. I., McKelvie, R. S. and Heigenhauser, G. J. (1995). K
distribution in humans during and after high-intensity exercise: role in
muscle fatigue attenuation? J. Appl. Physiol. 78, 765-777.
MacLean, D. A., Bangsbo, J. and Saltin, B. (1999). Muscle interstitial
glucose and lactate levels during dynamic exercise in humans determined
by microdialysis. J. Appl. Physiol. 87, 1483-1490.
MacRae, H. S.-H., Dennis, S. C., Bosch, A. N. and Noakes, T. D. (1992).
Effects of training on lactate production and removal during progressive
exercise in humans. J. Appl. Physiol. 72, 1649-1656.
Margaria, R., Edwards, R. H. T. and Dill, D. B. (1933). The possible
mechanisms of contracting and paying the oxygen debt and the role of lactic
acid in muscular contraction. Am. J. Physiol. 106, E689-E715.
Mazzeo, R. S., Brooks, G. A., Schoeller, D. A. and Budinger, T. F. (1986).
Disposal of blood [1-
C]lactate in humans during rest and exercise. J. Appl.
Physiol. 60, 232-241.
McClelland, G. B., Khanna, S., Gonzalez, G. F., Butz, C. E. and Brooks,
G. A. (2003). Peroxisomal membrane monocarboxylate transporters:
evidence for a redox shuttle system? Biochem. Biophys. Res. Commun. 304,
McCullagh, K. J. A., Juel, C., O’Brien, M. and Bonen, A. (1996). Chronic
muscle stimulation increases lactate transport in rat skeletal muscle. Molec.
Cell. Biochem. 156, 51-57.
McGroarty, E., Hsieh, B., Wied, D. M., Gee, R. and Tolbert, N. E. (1974).
Alpha hydroxyl acid oxidation by peroxisomes. Arch. Biochem. Biophys.
161, 194-210.
Miller, B. F., Fattor, J. A., Jacobs, K. A., Horning, M. A., Navazio, F.,
Lindinger, M. I. and Brooks, G. A. (2002). Lactate and glucose
interactions during rest and exercise in men: effect of exogenous lactate
infusion. J. Physiol. 544, 963-975.
Miller, B. F., Lindinger, M. I., Fattor, J. A., Jacobs, K. A., Leblanc, P. J.,
Duong, M., Heigenhauser, G. J. and Brooks, G. A. (2005). Hematological
and acid-base changes in men during prolonged exercise with and without
sodium-lactate infusion. J. Appl. Physiol. 98, 856-865.
Mills, S. E., Foster, D. W. and McGarry, J. D. (1984). Effects of pH on the
interaction of substrates and malonyl-CoA with the mitochondrial carnitine
palmitoyltransferase 1. Biochem. J. 219, 601-608.
Mitchell, J. H. and Blomqvist, G. (1971). Maximal oxygen uptake. New
Engl. J. Med. 284, 1018-1022.
Moon, B. R., Hopp, J. J. and Conley, K. E. (2002). Mechanical trade-offs
explain how performance increases without increasing cost in rattlesnake
tailshaker muscle. J. Exp. Biol. 205, 667-675.
Nielsen, O. B., de Paoli, F. and Overgaard, K. (2001). Protective effects of
lactic acid on force production in rat skeletal muscle. J. Physiol. 536, 161-
Noakes, T. D. (1998). Maximal oxygen uptake: ‘classical’ versus
‘contemporary’ viewpoints: a rebuttal. Med. Sci. Sports Exerc. 30, 1381-
Noakes, T. D., Peltonen, J. E. and Rusko, H. K. (2001). Evidence that a
central governor regulates exercise performance during acute hypoxia and
hyperoxia. J. Exp. Biol. 204, 3225-3234.
Noakes, T. D., St Clair Gibson, A. and Lambert, E. V. (2004). From
catastrophe to complexity: a novel model of integrative central neural
regulation of effort and fatigue during exercise in humans. Br. J. Sports.
Med. 38. 511-514.
Pedersen, T. H., Clausen, T. and Nielsen, O. B. (2003). Loss of force
induced by high extracellular [K
] in rat muscle: effect of temperature, lactic
acid and beta2-agonist. J. Physiol. 551, 277-286.
Pedersen, T. H., Nielsen, O. B., Lamb, G. D. and Stephenson, D. G. (2004).
Intracellular acidosis enhances the excitability of working muscle. Science
305, 1144-1147.
Pellerin, L. and Magistretti, P. J. (2003). How to balance the brain energy
budget while spending glucose differently. J. Physiol. 546, 325.
Pellerin, L., Pellegri, G., Bittar, P. G., Charnay, Y., Bouras, C., Martin,
J.-L., Stella, N. and Magistretti, P. J. (1998). Evidence supporting the
existence of an astrocyte-neuron lactate shuttle. Dev. Neurosci. 20, 291-299.
Pilegaard, H. and Juel, C. (1995). Lactate transport studied in sarcolemmal
giant vesicles from rat skeletal muscles: effect of denervation. Am. J.
Physiol. 269, E679-E682.
Pilegaard, H., Domino, K., Noland, T., Juel, C., Hellsten, Y., Halestrap,
A. P. and Bangsbo, J. (1999). Effect of high-intensity exercise training on
transport capacity in human skeletal muscle. Am. J. Physiol. 276,
Posterino, G. S. and Fryer, M. W. (2000). Effects of high myoplasmic L-
lactate concentration on E-C coupling in mammalian skeletal muscle. J.
Appl. Physiol. 89, 517-528.
Posterino, G. S., Dutka, T. L. and Lamb, G. D. (2001). L(+)-lactate does
not affect twitch and tetanic responses in mechanically skinned mammalian
muscle fibres. Pflügers. Arch. 442, 197-203.
Randle, P. J., Garland, P. B., Hales, C. N. and Newsholme, E. A. (1963).
The glucose fatty acid cycle: its role in insulin sensitivity and the metabolic
disturbances of diabetes mellitus. Lancet 1, 785-789.
Rasmussen, H. N., Van Hall, G. and Rasmussen, U. F. (2002). Lactate
dehydrogenase is not a mitochondrial enzyme in human and mouse vastus
lateralis muscle. J. Physiol. 541, 575-580.
Rauch, H. G., St Clair Gibson, A., Lambert, E. V. and Noakes, T. D.
(2005). A signalling role for muscle glycogen in the regulation of pace
during prolonged exercise. Br. J. Sports. Med. 39, 34-38.
Richards, J. G., Mercado, A. J., Clayton, C. A., Heigenhauser, G. J. F.
and Wood, C. M. (2002). Substrate utilization during graded aerobic
exercise in rainbow trout. J. Exp. Biol. 205, 2067-2077.
Richardson, R. S., Noyszewski, E. A., Leigh, J. S. and Wagner, P. D.
(1998). Lactate efflux from exercising human skeletal muscle: role of
intracellular P
2. J. Appl. Physiol. 85, 627-634.
Robergs, R. A., Ghiasvand, F. and Parker, D. (2004). Biochemistry of
exercise-induced metabolic acidosis. Am. J. Physiol. Regul. Integr. Comp.
Physiol. 287, 502-516.
Roberts, T. J., Weber, J.-M., Hoppeler, H., Weibel, E. R. and Taylor, R.
C. (1996). II. Defining the upper limits of carbohydrate and fat oxidation.
J. Exp. Biol. 199, 1651-1658.
Roef, M. J., de Meer, K., Kalhan, S. C., Straver, H., Berger, R. and
Reijngoud, D.-J. (2003). Gluconeogenesis in humans with hyperlactatemia
during low-intensity exercise. Am. J. Physiol. 284, E1162-E1171.
Roepstorff, C., Halberg, N., Hillig, T., Saha, A. K., Ruderman, N. B.,
Wojtaszewski, J. F. P., Richter, E. A. and Kiens, B. (2005). Malonyl-
CoA and carnitine in regulation of fat oxidation in human skeletal muscle
during exercise. Am. J. Physiol. 288, E133-E142.
Rooyackers, O. (2005). Microdialysis to investigate tissue amino acid
kinetics. Curr. Opin. Clin. Nutr. Metab. Care 8, 77-82.
Rosdahl, H., Ungerstedt, U., Jorfeldt, L. and Henriksson, J. (1993).
Interstitial glucose and lactate balance in human skeletal muscle and adipose
tissue studies by microdialysis. J. Physiol. 471, 637-657.
Roth, D. A. and Brooks, G. A. (1990). Lactate transport is mediated by a
membrane-bound carrier in rat skeletal muscle sarcolemmal vesicles. Arch.
Biochem. Biophys. 279, 377-385.
Ruderman, N. B. and Dean, D. (1998). Malonyl CoA, long chain fatty acyl
CoA and insulin resistance in skeletal muscle. J. Basic. Clin. Physiol.
Pharmacol. 9, 295-308.
Sahlin, K., Fernstrom, M., Svensson, M. and Tonkonogi, M. (2002). No
A. Philp, A. L. Macdonald and P. W. Watt4574
evidence of an intracellular lactate shuttle in rat skeletal muscle. J. Physiol.
541, 569-574.
Sidossis, L. S., Wolfe, R. R. and Coggan, A. R. (1998). Regulation of fatty
acid oxidation in untrained vs. trained men during exercise. Am. J. Physiol.
274, E510-E515.
Skinner, M. R. and Marshall, J. M. (1996). Studies on the roles of ATP,
adenosine and nitric oxide in mediating muscle vasodilation induced in the
rat by acute systemic hypoxia. J. Physiol. 495, 553-560.
St Clair Gibson, A., Baden, D. A., Lambert, M. I., Lambert, E. V., Harley,
Y. X. R., Hampson, D., Russell, V. A. and Noakes, T. D. (2003). The
conscious perception of the sensation of fatigue. Sports Med. 33, 167-176.
Starritt, E. C., Howlett, R. A., Heigenhauser, G. J. and Spriet, L. L. (2000).
Sensitivity of CPT1 to malonyl-CoA in trained and untrained human skeletal
muscle. Am. J. Physiol. 278, E462-E468.
Street, D., Bangsbo, J. and Juel, C. (2001). Interstitial pH in human skeletal
muscle during and after dynamic graded exercise. J. Physiol. 537, 993-998.
Trabold, O., Wagner, S., Wicke, C., Scheuenstuhl, H., Hussain, Z., Rosen,
N., Seremetiev, A., Becker, H. D. and Hunt, T. K. (2003). Lactate and
oxygen constitute a fundamental regulatory mechanism in wound healing.
Wound Rep. Reg. 11, 504-509.
Van Loon, L. J. C., Greenhaff, P. L., Constantin-Teodosiu, D., Saris, W.
H. M. and Wagenmakers, A. J. M. (2001). The effects of increasing
exercise intensity on muscle fuel utilisation in humans. J. Physiol. 536, 295-
Waldmann, R. and Lazdunski, M. (1998). H(+)-gated cation channels:
neuronal acid sensors in the NaC/DEG family of ion channels. Curr. Opin.
Neurobiol. 8, 418-424.
Watt, P. W., MacLennen, P. A., Hundal, H. S., Kuret, C. M. and Rennie,
M. J. (1988). L(+)-lactate transport in perfused rat skeletal muscle: kinetic
characteristics and sensitivity to pH and transport inhibitors. Biochim.
Biophys. Acta 944, 213-222.
Watt, P. W., Gladden, L. B., Hundal, H. S. and Crawford, R. E. (1994).
Effects of flow and contraction on lactate transport in the perfused rat
hindlimb. Am. J. Physiol. 267, E7-E13.
Westerblad, H., Allen, D. G. and Lannergren, J. (2002). Muscle fatigue: lactic
acid or inorganic phosphate the major cause? News Physiol. Sci. 17, 17-21.
Wilson, M. C., Jackson, V. N., Heddle, C., Price, N. T., Pilegaard, H., Juel,
C., Bonen, A., Montgomery, I., Hutter, O. F. and Halestrap, A. P.
(1998). Lactic acid efflux from white skeletal muscle is catalysed by the
monocarboxylate transporter isoform MCT3. J. Biol. Chem. 273, 15920-
Zhou, M., Lin, B.-Z., Coughlin, S., Vallega, G. and Pilch, P. F. (2000).
UCP-3 expression in skeletal muscle: effects of exercise, hypoxia and AMP-
activated protein kinase. Am. J. Physiol. 279, E622-E629.
Lactate signalling at rest and during exercise 4575
... Swedish chemist Carl W. Scheele made his observation in 1780 that lactic acid is found in sour milk products. 1 Presently it is widely used in pharmaceutical and food industry as a preservative. In medicine it is one of the main components of crystalloid solutions (Ringer lactate and Hartmann's solution). ...
... The main limiting factor for their smooth working is the supply of oxygen. 1,4,5 Under anaerobic conditions pyruvate formed at the end of glycolysis is converted to lactic acid (fi gure 1). Excessive lactic acid is cleared from the body either by converting back to pyruvate by lactic dehydrogenase or into glucose (gluconeogenesis) in the liver and kidney through Cori's cycle (fi gure 2). ...
... Lactate also acts like a hormone that indirectly increases the effi ciency of energy utilisation and metabolism. 1,4,5,6 Figure 3 shows the interconversion and relationship between lactic acid and lactate Metabolic acidosis which develops with hyperlactatemia is due to two reasons. Firstly is the formation of lactic acid which quickly dissociates to release H+ ions. ...
... The Cori cycle can use lactate, which is converted to glucose inside the cell, as an energy source. However, as an alternative, lactate can be converted by lactate dehydrogenase enzyme into pyruvate, which is then converted into acetyl-CoA [70]. After being produced, pyruvate is either delivered into the TCA cycle for oxidative phosphorylation or converted to lactate in anaerobic environments [71]. ...
... Given the MCT's mode of action, the hydrogen ion gradient across the epithelial membrane should influence the rate of lactate absorption [96]. Another unique mechanism that potentially allows the movement of lactate across the mucosal membrane, involves the integrity of the [15,69,70]. membrane itself. ...
Full-text available
Even though the pathophysiology of colorectal cancer (CRC) is complicated and poorly understood, interactions between risk factors appear to be key in the development and progression of the malignancy. The popularity of using lactic acid bacteria (LAB) prebiotics and probiotics to modulate the tumor microenvironment (TME) has grown widely over the past decade. The objective of this study was therefore to determine the detrimental effects of LAB-derived lactic acid in the colonic mucosa in colorectal cancer management. Six library databases and a web search engine were used to execute a structured systematic search of the existing literature, considering all publications published up until August 2022. A total of 7817 papers were screened, all of which were published between 1995 and August 2022. However, only 118 articles met the inclusion criterion. Lactic acid has been directly linked to the massive proliferation of cancerous cells since the glycolytic pathway provides cancerous cells with not only ATP, but also biosynthetic intermediates for rapid growth and proliferation. Our research suggests that targeting LAB metabolic pathways is capable of suppressing tumor growth and that the LDH gene is critical for tumorigenesis. Silencing of Lactate dehydrogenase, A (LDHA), B (LDHB), (LDHL), and hicD genes should be explored to inhibit fermentative glycolysis yielding lactic acid as the by-product. More studies are necessary for a solid understanding of this topic so that LAB and their corresponding lactic acid by-products do not have more adverse effects than their widely touted positive outcomes in CRC management.
... Lactate can be transported by the monocarboxylate transporter (MCT) in tissues, cells, and organs and regulates body synthesis and catabolism in the body, where it plays a key role in the pro cess. Lactate can also be used as a carbon source by the human body [31,32]. In addition lactic acid has a specific sensor receptor, the HCAR1 receptor, through which lactic acid can directly inhibit the action of the NLRP3 inflammasome, which is activated by the ac tion of TLR-4 and caspase1. ...
... Lactate can be transported by the monocarboxylate transporter (MCT) in tissues, cells, and organs and regulates body synthesis and catabolism in the body, where it plays a key role in the process. Lactate can also be used as a carbon source by the human body [31,32]. In addition, lactic acid has a specific sensor receptor, the HCAR1 receptor, through which lactic acid can directly inhibit the action of the NLRP3 inflammasome, which is activated by the action of TLR-4 and caspase1. ...
Full-text available
In this study, an electrochemical sensor was developed by immobilizing colon cancer and the adjacent tissues (peripheral healthy tissues on both sides of the tumor) and was used to investigate the receptor sensing kinetics of glucose, sodium glutamate, disodium inosinate, and sodium lactate. The results showed that the electrical signal triggered by the ligand–receptor interaction presented hyperbolic kinetic characteristics similar to the interaction of an enzyme with its substrate. The results indicated that the activation constant values of the colon cancer tissue and adjacent tissues differed by two orders of magnitude for glucose and sodium glutamate and around one order of magnitude for disodium inosinate. The cancer tissues did not sense sodium lactate, whereas the adjacent tissues could sense sodium lactate. Compared with normal cells, cancer cells have significantly improved nutritional sensing ability, and the improvement of cancer cells’ sensing ability mainly depends on the cascade amplification of intracellular signals. However, unlike tumor-adjacent tissues, colon cancer cells lose the ability to sense lactate. This provides key evidence for the Warburg effect of cancer cells. The methods and results in this study are expected to provide a new way for cancer research, treatment, the screening of anticancer drugs, and clinical diagnoses.
... In addition, insulin resistance impairs the pyruvate dehydrogenase complex in muscle [45]. Increased postprandial pyruvate levels may also account from the conversion of lactate to pyruvate by the enzyme lactate dehydrogenase in the liver [46]. In addition, pyruvate would be converted to glucose by gluconeogenesis, given that in insulin resistant states hepatic gluconeogenesis is not inhibited by insulin [40,41]. ...
Full-text available
Background The polycystic ovary syndrome (PCOS) is associated with insulin resistance, obesity and cardiometabolic comorbidities. We here challenged the hypothesis, using state-of-the-art proton nuclear magnetic resonance spectrometry ( ¹ H-NMRS) metabolomics profiling, that androgen excess in women induces a certain masculinization of postprandial metabolism that is modulated by obesity. Materials and methods Participants were 53 Caucasian young adults, including 17 women with classic PCOS consisting of hyperandrogenism and ovulatory dysfunction, 17 non-hyperandrogenic women presenting with regular menses, and 19 healthy men, selected to be similar in terms of age and body mass index (BMI). Half of the subjects had obesity. Patients were submitted to isocaloric separate glucose, lipid and protein oral challenges in alternate days and fasting and postprandial serum samples were submitted to ¹ H-NMRS metabolomics profiling for quantification of 36 low-molecular-weight polar metabolites. Results The largest postprandial changes were observed after glucose and protein intake, with lipid ingestion inducing smaller differences. Changes after glucose intake consisted of a marked increase in carbohydrates and byproducts of glycolysis, and an overall decrease in byproducts of proteolysis, lipolysis and ketogenesis. After the protein load, most amino acids and derivatives increased markedly, in parallel to an increase in pyruvate and a decrease in 3-hydroxybutyric acid and glycerol. Obesity increased β- and d -glucose and pyruvate levels, with this effect being observed mostly after glucose ingestion in women with PCOS. Regardless of the type of macronutrient, men presented increased lysine and decreased 3-hydroxybutyric acid. In addition, non-obese men showed increased postprandial β-glucose and decreased pyroglutamic acid, compared with non-obese control women. We observed a common pattern of postprandial changes in branched-chain and aromatic amino acids, where men showed greater amino acids increases after protein intake than control women and patients with PCOS but only within the non-obese participants. Conversely, this increase was blunted in obese men but not in obese women, who even presented a larger increase in some amino acids compared with their non-obese counterparts. Interestingly, regardless of the type of macronutrient, only obese women with PCOS showed increased leucine, lysine, phenylalanine and tryptophan levels compared with non-obese patients. Conclusions Serum ¹ H-NMRS metabolomics profiling indicated sexual dimorphism in the responses to oral macronutrient challenges, which were apparently driven by the central role of postprandial insulin effects with obesity, and to a lesser extent PCOS, exerting modifying roles derived from insulin resistance. Hence, obesity impaired metabolic flexibility in young adults, yet sex and sex hormones also influenced the regulation of postprandial metabolism. Graphical abstract
... It is a central redox molecule in several biological processes [60]. Depending on its concentration, the cellular context, and kinetics, catalase can either activate highly toxic hydroxyl radicals with redox-active metal ions and physiological levels of H2O2 or function as a signaling molecule [61][62][63][64]. Catalase deficiency results in insulin resistance, and oxidative damage to β-islets mediates it [64]. ...
Full-text available
Although a slight imbalance between oxidative and antioxidative mediators is part of normal physiology that enables cell aging and the removal of dead cells, burns disturb this equilibrium locally and systemically. Topical burn dressings may attenuate local and systemic oxidative stress and positively influence the post-burn clinical course. This review integrated knowledge regarding the impact of burn dressings on oxidative stress. Using keywords and in-text searches, literature was identified from PubMed, Google Scholar, and Google articles, and studies on local or topical applications of wound dressings and associated oxidative stress were selected. As im-balances between oxidative mediators and antioxidative agents significantly contribute to organ dysfunction and healing disturbance, we investigated oxidative stress on organs, metabolic changes, clinical results, and oxidative parameters influenced by applied dressings. We found positive local and systemic effects of external burn dressings in laboratory and animal tests; however, such studies were rare in humans. Nevertheless, we identified successful cases of semi-occlusive, occlusive, and biologically active dressings that reduce oxidative stress in hu-man burns. In particular, we highlight promising clinical and laboratory results from lac-tate-releasing dressings. Our review provides an invaluable resource for future development and clinical applications of burn dressings.
... Pyruvate can then be converted to lactic acid through the action of lactate dehydrogenases [14]. There are two isomer-specific forms of lactate dehydrogenase (LDH), L-LDH and D-LDH, which produce L-lactate and D-lactate, respectively [15][16][17]. The conversion of pyruvate to lactate (specifically L-lactate form) is an essential process for the body to generate energy during times of oxygen deprivation, such as during intense exercise. ...
Full-text available
D-lactate is produced in very low amounts in human tissues. However, certain bacteria in the human intestine produce D-lactate. In some gastrointestinal diseases, increased bacterial D-lactate production and uptake from the gut into the bloodstream take place. In its extreme, excessive accumulation of D-lactate in humans can lead to potentially life-threatening D-lactic acidosis. This metabolic phenomenon is well described in pediatric patients with short bowel syndrome. Less is known about a subclinical rise in D-lactate. We discuss in this review the pathophysiology of D-lactate in the human body. We cover D-lactic acidosis in patients with short bowel syndrome as well as subclinical elevations of D-lactate in other diseases affecting the gastrointestinal tract. Furthermore, we argue for the potential of D-lactate as a marker of intestinal barrier integrity in the context of dysbiosis. Subsequently, we conclude that there is a research need to establish D-lactate as a minimally invasive biomarker in gastrointestinal diseases.
... Blood lactate lev-els reflect the balance between its production and clearance. However, lactate is produced about 1500 mmol daily under normal physiological conditions in skeletal muscle (25%), skin (25%), brain (20%), intestine (10%), and red blood cells (20%) (5) and also in patients from other tissues such as lung, leukocyte, and visceral organs (6). Furthermore, its clearance is carried out in the blood mainly by the liver (60%) and the kidneys (30%), and the heart (10%) (7). ...
Full-text available
Context: During a literature search, we found data indicating how lactate affects cancer patients. Evidence Acquisition: This review discusses metabolism in tumors, the lactate production pathway, and its effects on the host body. Result: Research has described high lactate concentration as an undesirable clinical condition, and lactic acidosis contributes to the death of patients or some metastatic cancers. Conclusions: Lactate can lead to angiogenesis, metastasis in the tumor, and resistance to radiation therapy and chemotherapy, especially immunosuppression. It may be possible to reduce the mortality of this disease by affecting treatment worldwide.
... On the other hand, previous researchers suggested no lactate production during t PCr which was incorrectly (fictitiously) assumed (Heck et al., 2003;Hauser et al., 2014;Adam et al., 2015;Nitzsche et al., 2018;Quittmann et al., 2020;Quittmann et al., 2021). In this regard, it is well known that all three energy systems start to work simultaneously and lactate production occurs independently of O 2 availability such as under anoxic, hypoxic, and normoxic conditions (Gastin, 2001;Philp et al., 2005;Brooks, 2018;Yang et al., 2020;Brooks et al., 2022;Yang et al., 2022b). La − might be accumulated at a relatively low level during the initial seconds of the 15-s ASCT because ATP-PCr is a dominant energy contribution until the achievement of W peak (Serresse et al., 1988;Beneke et al., 2002;Park et al., 2021). ...
Full-text available
Purpose: This study aimed at comparing previous calculating formulas of maximal lactate accumulation rate ( ν La.max) and a modified formula of pure ν La.max (P ν La.max) during a 15-s all-out sprint cycling test (ASCT) to analyze their relationships. Methods: Thirty male national-level track cyclists participated in this study (n = 30) and performed a 15-s ASCT. The anaerobic power output (Wpeak and Wmean), oxygen uptake, and blood lactate concentrations (La⁻) were measured. These parameters were used for different calculations of ν La.max and three energy contributions (phosphagen, W PCr; glycolytic, W Gly; and oxidative, W Oxi). The P ν La.max calculation considered delta La⁻, time until Wpeak (tPCr−peak), and the time contributed by the oxidative system (tOxi). Other ν La.max levels without tOxi were calculated using decreasing time by 3.5% from Wpeak (tPCr −3.5%) and tPCr−peak. Results: The absolute and relative W PCr were higher than W Gly and W Oxi (p < 0.0001, respectively), and the absolute and relative W Gly were significantly higher than W Oxi (p < 0.0001, respectively); ν La.max (tPCr −3.5%) was significantly higher than P ν La.max and ν La.max (tPCr−peak), while ν La.max (tPCr−peak) was lower than P ν La.max (p < 0.0001, respectively). P ν La.max and ν La.max (tPCr−peak) were highly correlated (r = 0.99; R 2 = 0.98). This correlation was higher than the relationship between P ν La.max and ν La.max (tPCr −3.5%) (r = 0.87; R 2 = 0.77). ν La.max (tPCr−peak), P ν La.max, and ν La.max (tPCr −3.5%) were found to correlate with absolute Wmean and W Gly. Conclusion: P ν La.max as a modified calculation of ν La.max provides more detailed insights into the inter-individual differences in energy and glycolytic metabolism than ν La.max (tPCr−peak) and ν La.max (tPCr −3.5%). Because W Oxi and W PCr can differ remarkably between athletes, implementing their values in P ν La.max can establish more optimized individual profiling for elite track cyclists.
Full-text available
Purpose: Although several physiological roles of lactate have been revealed in the last decades, its effects on energy metabolism and substrate oxidation remain unknown. Therefore, we investigated the effects of lactate on the energy metabolism of resting rats. Methods: Male rats were divided into control (Con; distilled water), caffeine (Caf; 10 mg/kg), L-lactate (Lac; 2 g/kg), and lactate-plus-caffeine (Lac+Caf; 2 g/ kg + 10 mg) groups. Following oral administration of supplements, resting energy expenditure (study 1), biochemical blood parameters, and mRNA expression involved in energy metabolism in the soleus muscle were measured at different time points within 120 minutes of administration (study 2). Moreover, glycogen level and Pyruvate dehydrogenase (PDH) activity were measured. Results: Groups did not differ in total energy expenditure throughout the 6 hour post-treatment evaluation. Within the first 4 hours, the Lac and Lac+Caf groups showed higher fat oxidation rates than the Con group (p<0.05). Lactate treatment decreased blood free fatty acid levels (p<0.05) and increased the mRNA expression of fatty acid translocase (FAT/CD36) (p<0.05) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) (p<0.05) in the skeletal muscle. Hepatic glycogen level in the Lac+Caf group was significantly increased (p<0.05). Moreover, after 30 and 120 minutes, PDH activity was significantly higher in lactate-supplemented groups compared to Con group (p<0.05). Conclusion: Our findings showed that Lac+Caf enhanced fat metabolism in the whole body and skeletal muscle while increasing hepatic glycogen concentration and PDH activity. This indicates Lac+Caf can be used as a potential post-workout supplement.
Full-text available
l -lactate is a catabolite from the anaerobic metabolism of glucose, which plays a paramount role as a signaling molecule in various steps of the cell survival. Its activity, as a master tuner of many mechanisms underlying the aging process, for example in the skin, is still presumptive, however its crucial position in the complex cross-talk between mitochondria and the process of cell survival, should suggest that l -lactate may be not a simple waste product but a fine regulator of the aging/survival machinery, probably via mito-hormesis. Actually, emerging evidence is highlighting that ROS are crucial in the signaling of skin health, including mechanisms underlying wound repair, renewal and aging. The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment. Physiological ROS levels are essential for cutaneous health and the wound repair process. Aberrant redox signaling activity drives chronic skin disease in elderly. On the contrary, impaired redox modulation, due to enhanced ROS generation and/or reduced levels of antioxidant defense, suppresses wound healing via promoting lymphatic/vascular endothelial cell apoptosis and death. This review tries to elucidate this issue.
Full-text available
The maximal lactate steady state (MLSS) is defined as the highest blood lactate concentration (MLSSc) and work load (MLSSw) that can be maintained over time without a continual blood lactate accumulation. A close relationship between endurance sport performance and MLSSw has been reported and the average velocity over a marathon is just below MLSSw. This work rate delineates the low-to high-intensity exercises at which carbohydrates contribute more than 50% of the total energy need and at which the fuel mix switches (crosses over) from predominantly fat to predominantly carbohydrate. The rate of metabolic adenosine triphosphate (ATP) turnover increases as a direct function of metabolic power output and the blood lactate at MLSS represents the highest point in the equilibrium between lactate appearance and disappearance both being equal to the lactate turnover. However, MLSSc has been reported to demonstrate a great variability between individuals (from 2–8 mmol/L) in capillary blood and not to be related to MLSSw. The fate of enhanced lactate clearance in trained individuals has been attributed primarily to oxidation in active muscle and gluconeogenesis in liver. The transport of lactate into and out of the cells is facilitated by monocarboxylate transporters (MCTs) which are transmembrane proteins and which are significantly improved by training. Endurance training increases the expression of MCT1 with intervariable effects on MCT4. The relationship between the concentration of the two MCTs and the performance parameters (i.e. the maximal distance run in 20 minutes) in elite athletes has not yet been reported. However, lactate exchange and removal indirectly estimated with velocity constants of the individual blood lactate recovery has been reported to be related to time to exhaustion at maximal oxygen uptake.
Primed-continuous infusion of [2-3H]- and [U-14C]lactate was used to study the effects of endurance training (running 2 h/day at 29.4 m/min up a 15% gradient) on lactate metabolism in rats. Measurements were made under three metabolic conditions: rest (Re), easy exercise (EE, 13.4 m/min, 1% gradient) and hard exercise (HE, 26.8 m/min, 1% gradient). Blood lactate levels in trained animals increased from 1.0 +/- 0.09 mM in Re to 1.64 +/- 0.21 in EE and 2.66 +/- 0.38 in HE. Control animals also demonstrated an increase in blood lactate with increasing work rate, but values were 1.93 +/- 0.21 and 4.62 +/- 0.57 mM at EE and HE, respectively. Lactate turnover rates (RtLA) measured with [U-14C]lactate increased from 214.0 +/- 17.0 in Re to 390.3 +/- 31.6 in EE and 518.1 +/- 56.4 in HE. No significant differences in RtLA were observed between controls and trained animals under any condition. Identical relationships between RtLA and exercise or training were obtained with [2-3H]lactate; however, the values obtained were consistently 90% higher than those observed with [U-14C]lactate. Metabolic clearance rate (MCR) for 14C was not significantly different in Re between controls and trained animals (180.6 +/- 27.7 Metabolic clearance of lactate in trained animals was 37 and 107% greater than in controls during EE and HE, respectively. Results indicate that the effect of endurance training is not on production of lactate but on its clearance from the blood.
Historically, laccatc utilization has been difficult to assess because blood lactate levels do not adequately relied lactate flux. Here we apply the principle of glucose clamp lo quantify whole body lactate utilization in conscious, unstressed rats using dichloroacetate (DCA), a known lactate utilization enhancer, to validate the method. In chronically cannulated animals fasting blood lactate and glucose concentrations 3 h alter DCA treatment (1 mmol/kg. n=4) were almost identical to that of control group (n=4) (1.65±0.4 vs. 1,65±0.2 mM and 82±11 vs. 81±3 mg/dl). Immediately alter the basal blood sample collection, the animals received a bolus lactate infusion followed by a continuous lactate infusion for 90 min at variable rates to clamp the blood lactate at 2 mM. The average lactate infusion rate at steady state (60-90 min) in DCA-Ireated animals was 144% higher than that in the control animals ( 13.2±1.0 vs. 5.4±1.1 mg/kg/min, P<U.OI ). The steady state blood glucose level in DCA-treated group was slightly lower than that in the control group (88±3 vs. 98±3 mg/dl, P=0.08). While the treatment with DCA did not affect basal blood lactate level before the clamp, the markedly increased lactate infusion rate during the clamp indicates that lactate flux was greatly enhanced by the treatment. Despite a large amount of lactate infused, a lower blood glucose level in DCA-treated group during the clamp suggests that most of the lactate infused was oxidized rather than being used as a precursor for liver gluconeogenesis. In conclusion, the lactatc clamp provides a sensitive and reliable method to assess in vivo lactate utilization, a dynamic measurement which may not be clearly demonstrated by blood laclate concentration set point per se.
Monocarboxylates such as lactate and pyruvate play a central role in cellular metabolism and metabolic communication between tissues. Essential to these roles is their rapid transport across the plasma membrane, which is catalysed by a recently identified family of proton-linked monocarboxylate transporters (MCTs). Nine MCT-related sequences have so far been identified in mammals, each having a different tissue distribution, whereas six related proteins can be recognized in Caenorhabditis elegans and 4 in Saccharomyces cerevisiae. Direct demonstration of proton-linked lactate and pyruvate transport has been demonstrated for mammalian MCT1-MCT4, but only for MCT1 and MCT2 have detailed analyses of substrate and inhibitor kinetics been described following heterologous expression in Xenopus oocytes. MCT1 is ubiquitously expressed, but is especially prominent in heart and red muscle, where it is up-regulated in response to increased work, suggesting a special role in lactic acid oxidation. By contrast, MCT4 is most evident in white muscle and other cells with a high glycolytic rate, such as tumour cells and white blood cells, suggesting it is expressed where lactic acid efflux predominates. MCT2 has a ten-fold higher affinity for substrates than MCT1 and MCT4 and is found in cells where rapid uptake at low substrate concentrations may be required, including the proximal kidney tubules, neurons and sperm tails. MCT3 is uniquely expressed in the retinal pigment epithelium. The mechanisms involved in regulating the expression of different MCT isoforms remain to be established. However, there is evidence for alternative splicing of the 5'- and 3'-untranslated regions and the use of alternative promoters for some isoforms. In addition, MCT1 and MCT4 have been shown to interact specifically with OX-47 (CD147), a member of the immunoglobulin superfamily with a single transmembrane helix. This interaction appears to assist MCT expression at the cell surface. There is still much work to be done to characterize the properties of the different isoforms and their regulation, which may have wide-ranging implications for health and disease. In the future it will be interesting to explore the linkage of genetic diseases to particular MCTs through their chromosomal location.