Lactate Metabolism: A New Paradigm For The Third Millennium: L. B. Gladden

J Physiol 558.
1 (2004) pp 5–30 5
TOPICAL REVIEW
Lactate metabolism: a new paradigm

for the third millennium
L. B. Gladden
Department of Health and Human Performance, 2050 Memorial Coliseum, Auburn University, Auburn, AL 36849-5323, USA
For much of the 20th century, lactate was largely considered a dead-end waste product of
glycolysis due to hypoxia, the primary cause of the O2 debt following exercise, a major cause of
muscle fatigue, and a key factor in acidosis-induced tissue damage. Since the 1970s, a ‘lactate
revolution’ has occurred. At present, we are in the midst of a lactate shuttle era; the lactate
paradigm has shifted. It now appears that increased lactate production and concentration as
a result of anoxia or dysoxia are often the exception rather than the rule. Lactic acidosis is
being re-evaluated as a factor in muscle fatigue. Lactate is an important intermediate in the
process of wound repair and regeneration. The origin of elevated [lactate] in injury and sepsis
is being re-investigated. There is essentially unanimous experimental support for a cell-to-cell
lactate shuttle, along with mounting evidence for astrocyte–neuron, lactate–alanine,
peroxisomal and spermatogenic lactate shuttles. The bulk of the evidence suggests that lactate
is an important intermediary in numerous metabolic processes, a particularly mobile fuel for
aerobic metabolism, and perhaps a mediator of redox state among various compartments both
within and between cells. Lactate can no longer be considered the usual suspect for metabolic
‘crimes’, but is instead a central player in cellular, regional and whole body metabolism. Overall,
the cell-to-cell lactate shuttle has expanded far beyond its initial conception as an explanation
for lactate metabolism during muscle contractions and exercise to now subsume all of the other
shuttles as a grand description of the role(s) of lactate in numerous metabolic processes and
pathways.
(Received 25 November 2003; accepted after revision 29 April 2004; first published online 30 April 2004)
Corresponding author L. B. Gladden: Department of Health and Human Performance, 2050 Memorial Coliseum,
Auburn University, Auburn, AL 36849-5323, USA. Email: gladdlb@auburn.edu
to determine which of these phosphagens might be the

Introduction
direct energy donor for muscle contraction (see Brooks &
In 1950, von Muralt distinguished four different eras in Gladden, 2003). These discoveries and new ideas changed
the development of muscle chemistry: pre-lactic acid, the field of muscle energetics so profoundly that A. V.
lactic acid, phosphorylation, and myosin. The pre-lactic Hill (1932) called the experiments over the 1926–32 time
acid era began in 1808 with Berzelius’s discovery of period ‘the revolution in muscle physiology’. Accordingly,
an elevated concentration of lactate in ‘ the muscles of the 1930s marked the beginning of the phosphorylation
hunted stags’ (see Brooks & Gladden, 2003). Although period of muscle chemistry. In 1939, the myosin period
there were several studies of lactic acid (HLa) in the next began with the finding that the enzyme responsible for
99 years (see Brooks & Gladden, 2003), confusion reigned ATP hydrolysis was associated with the muscle protein,
until the landmark studies of Fletcher & Hopkins (1907). myosin (see von Muralt, 1950 for details and references).
Their paper ushered in the lactic acid era during which By the early 1940s, the full Emben-Meyerhof (glycolytic)
A. V. Hill’s studies suggested that HLa was the immediate pathway had also been elaborated.
energy donor for muscle contractions and Meyerhof If we restrict our considerations to HLa and its
demonstrated that glycogen was the precursor of lactate metabolism, we might term the period from the 1930s to
(La− ) (e.g. Meyerhof, 1920). Between 1926 and 1932, ATP approximately the early 1970s the dead-end waste product
and PCr were discovered and investigations were begun era. During this period, La− was largely considered to be

C The Physiological Society 2004 DOI: 10.1113/jphysiol.2003.058701
6 L. B. Gladden J Physiol 558.1
a dead-end metabolite of glycolysis resulting from muscle cause of increased HLa production and accompanying
hypoxia (Wasserman, 1984). Lactic acid was also believed increases in muscle and blood [La− ] during submaximal
to be the primary cause of the slow component of the O2 exercise (e.g. Connett et al. 1986) and in some clinical
debt (Margaria et al. 1933) and a major cause of muscle situations as well (see below). Recently, Richardson et al.
fatigue (Hermansen, 1981). Since the early 1970s, a ‘lactate (1998) used proton magnetic resonance spectroscopy
revolution’ has occurred. At present, we are in the midst (1 H-MRS) to determine myoglobin saturation (and
of a lactate shuttle era which began in 1984 with the thereby estimate intramuscular P O2 ) during progressive
introduction of the lactate shuttle hypothesis by George single-leg quadriceps exercise in humans. Increasing
Brooks (1985a). La− efflux with increasing work rate did not appear
In the following sections, I will attempt to capsulize to be the result of inadequate O2 and thereby
some of the new ideas that are currently at the cutting-edge O2 -limited oxidative phosphorylation. Instead, as the
of continued investigations into La− metabolism in this intramuscular P O2 (iP O2 ) decreases, oxidative metabolism
lactate shuttle era. In order to limit the list of references, becomes O2 dependent (see Gladden, 1996). Within
I will often cite examples and recent reviews rather than some low range of iP O2 (< 20 Torr?), larger increases in
using complete, chronological sets of citations. [NADH]/[NAD+ ] and ([ADP][Pi ]/[ATP]) are required
to maintain adequate stimulation of cellular respiration
to meet the aerobic ATP demand. The connection to
Lactate and O2 during exercise: is lactate
increasing La− production and higher muscle and blood
an anaerobic metabolite?
[La− ] is that the requisite increase in ([ADP][Pi ]/[ATP]),
Numerous studies beginning with those of Pasteur (see to compensate for the lower iP O2 , is a potent stimulus
Keilin, 1966) in the 18th century demonstrated that of glycolysis. (For further details of this paradigm, see
anoxia and hypoxia stimulate cellular HLa production. Connett et al. 1990; Gladden, 1996.) Accordingly, the best
For example, in 1891, Araki (cited in Karlsson, 1971) evidence indicates that O2 is only one of several interacting
reported elevated La− levels in the blood and urine of a factors that cause an increase in muscle and blood [La− ]
variety of animals subjected to hypoxia. Then, Fletcher at submaximal exercise intensities. Additional factors are
& Hopkins (1907) found an accumulation of La− in listed in Table 1 and some are discussed in detail by
anoxia as well as after prolonged stimulation to fatigue Gladden (2003).
in amphibian muscle in vitro. Subsequently, based on the So, is La− an anaerobic metabolite? Yes, in the presence
work of Fletcher & Hopkins (1907) as well as his own of anoxia; but La− is also an hypoxic metabolite in the
studies, Hill et al. (1924) postulated that HLa increased presence of dysoxia, and an aerobic metabolite in the
during muscular exercise because of a lack of O2 for the presence of an adequate O2 supply and utilization of
energy requirements of the contracting muscles. glucose or glycogen as a fuel.
There is no disagreement that P O2 values in the range of
∼0.5 Torr or less result in O2 -limited cytochrome turnover,
Lactic acid, lactate and fatigue
and therefore O2 -limited oxidative phosphorylation, a
condition termed dysoxia (Connett et al. 1990). However, Lactic acidosis and fatigue. Lactic acid is more than 99%
problems have arisen because of the application of dissociated into La− anions and protons (H+ ) at physio-
the converse of this construct, i.e. that elevated HLa logical pH. During exercise and muscle contractions,
production and accumulation necessarily indicate the muscle and blood [La− ] and [H+ ] can rise to very high
presence of dysoxia. This supposition formed the levels (Fitts, 2003; Sahlin et al. 1976). Most researchers
groundwork for the anaerobic threshold concept, which have argued that any detrimental effects of HLa on muscle
was introduced and detailed by Wasserman and colleagues and exercise performance are due to H+ rather than La−
in the 1960s and early 1970s (see Wasserman, 1984). The (Fitts, 2003). There is a vast literature in which a decline
basic anaerobic threshold paradigm is that elevated HLa in maximal muscle force generation is correlated with a
production and concentration during muscular contrac- decrease in muscle pH (Hermansen, 1981; Sahlin, 1992).
tions or exercise are the result of O2 -limited oxidative Evidence from numerous experimental approaches (Fitts,
phosphoryation. Similarly, standard medical practice has 2003) suggests that an elevated muscle [H+ ] could depress
accepted an elevated blood La− concentration ([La− ]) as muscle function by (1) reducing the transition of the cross-
the herald of O2 insufficiency (Mizock & Falk, 1992). bridge from the low- to the high-force state, (2) inhibiting
Over the past 35 years, considerable evidence has maximal shortening velocity, (3) inhibiting myofibrillar
mounted against the idea of dysoxia as the primary ATPase, (4) inhibiting glycolytic rate, (5) reducing

C The Physiological Society 2004
J Physiol 558.1 Lactate metabolism 7
Table 1. Causes of increased lactate accumulation with increasing exercise intensity
I Accelerating glycolysis
1. a. La− production depends on a competition for pyruvate and NADH between LDH and the NADH shuttles (malate–aspartate
and glycerol phosphate) and the pyruvate transporter (e.g. Gladden, 1996).
and/or
b. High activity of LDH and K eq of pyruvate to lactate reaction guarantees HLa production particularly with increasing glycolytic
rate (e.g. Brooks, 1998, 2000; Brooks et al. 1999a,b).
2. a. More broadly, La− production can be viewed as dependent on the balance of biochemical competition between the activities
of Phos/PFK versus the activity of PDH (Parolin et al. 1999).
b. Phos is activated by increased work rate probably due to ↑ [Ca2+ ], ↑ [Pi ] and ↑ [AMP]; this increases glycolytic rate ⇒ ↑ La−
production (e.g. Spriet, 1992; Parolin et al. 1999; Rush & Spriet, 2001).
c. With increased exercise intensity; [ATP] ↓, [ADP] ↑, [AMP] ↑, [Pi ] ↑, and [ammonia] ↑ ⇒ PFK activation and ↑ La− production
(e.g. Spriet, 1991).
d. Sympathoadrenal activity increases with work rate; adrenaline activates Phos and thereby ↑ glycolysis and La− production
(e.g. Drummond et al. 1969; Spriet, 1992; Parolin et al. 1999).
e. ↑ [Ca2+ ] may act in a feed-forward manner to activate Phos and PFK independently of metabolic feedback (e.g. Parolin et al.
1999).
3. Coordinated changes in the activities of other glycolytic enzymes occur via mechanisms that are not fully understood (metabolic
control analysis) (e.g. Thomas & Fell, 1998)?
4. Intracellular perfusion rates increase in proportion to escalating ATP demand, thus increasing enzyme-substrate encounter rates
(Hochachka, 1999)?
5. Na+ –K+ -ATPase is progressively stimulated by increasing exercise intensity (via ↑ [Na+
i ]?) and by increasing hormonal
concentrations, particularly the catecholamines (Nielsen & Clausen, 2000)? Increased Na+ –K+ -ATPase activity leads to increased
lactate production perhaps by way of an association of glycolytic enzymes with Na+ –K+ pumps (James et al. 1999a,b)?
II O2 -dependent metabolism
With increasing exercise intensity, intramuscular P O2 decreases either progressively or sharply at ∼60% of V̇O2 max . Regardless of
pattern, oxidative phosphorylation becomes O2 -dependent (not O2 -limited) and greater increases in ([ADP][Pi ]/[ATP]) are required
to stimulate the needed oxidative phosphorylation rate. This same increase in ([ADP][Pi ]/[ATP]) is a potent stimulus of glycolysis
leading to ↑ La− production (see Gladden, 1996).
III Lactate removal
1. Sympathoadrenal activity causes vasoconstriction and ↓ blood flow to liver, kidney, and inactive muscle ⇒ ↓ La− oxidation and
removal (e.g. Nielsen et al. 2002).
2. Adrenaline decreases lactate removal by exercising muscles and perhaps by resting muscles (Hamann et al. 2001).
3. Increased frequency of stimulation of previously recruited muscle fibres places more fibres in La− production mode instead of
removal mode.
4. La− production exceeds removal ⇒ ↑ muscle and blood [La− ] (e.g. Brooks, 1985b).
IV Fast twitch fibre recruitment
More fast twitch fibres are recruited as exercise intensity increases. These fibres are more suited to La− production (e.g. Armstrong,
1988).
Abbreviations: LDH: lactate dehydrogenase; Phos: phosphorylase; PFK: phosphofructokinase; PDH: pyruvate dehydrogenase; ?: newer
ideas that are more Gypothetical and await more direct evidence.
crossbridge activation by competitively inhibiting Ca2+ a report that muscle acidity does not reduce muscle
binding to troponin C, and (6) reducing Ca2+ re-uptake by glycogenolysis/glycolysis during intense exercise in man
inhibiting the sarcoplasmic ATPase (leading to subsequent (Bangsbo et al. 1996). One study in isolated rat soleus
reduction of Ca2+ release). muscles in vitro observed that, rather than decreasing force
Particularly over the last 10 years, the role of acidosis generation, lactic acidosis actually protected against the
as an important cause of fatigue has been challenged detrimental effects of elevated external [K+ ] on muscle
(see Westerblad et al. 2002). These studies have reported excitability and force (Nielsen et al. 2001).
that the effect of increased [H+ ] to reduce Ca2+ In place of acidosis, studies on skinned muscle fibres
sensitivity, maximal tension, and shortening velocity are pointing to inorganic phosphate (Pi ) as a major cause
in skinned muscle fibres in vitro is absent when the of muscle fatigue (see review by Westerblad et al. 2002
experiments are performed at temperatures that are for details). Pi increases during intense muscle contrac-
closer to those encountered physiologically. There is also tions or exercise due to breakdown of PCr. However, these

studies have not evaluated the effects of high [H+ ] on peak even though muscle pH was not altered from control
power or the combined effects of a reduced Ca2+ release, conditions (Hogan et al. 1995). These results were
a low pH and an elevated Pi (Fitts, 2003). Accordingly, subsequently supported by studies on muscles in
Fitts (2003) notes that it is premature to dismiss H+ as vitro (Spangenburg et al. 1998), skinned muscle fibres
an important factor in muscle fatigue. Further, at least (Andrews et al. 1996), and sarcoplasmic reticulum vesicles
two questions arise concerning the role of Pi as a primary (e.g. Favero et al. 1995; Spangenburg et al. 1998). In
fatigue agent during short-term intense exercise in intact Langendorff perfused rat hearts, La− appeared to
humans. First, since most of the PCr breakdown occurs irreversibly depress developed pressure (Samaja et al.
within the first 10 s of such intense exercise, would the 1999). More recently, studies of skinned mammalian
primary role of Pi be restricted to that time frame? Second, muscle fibres (e.g. Posterino et al. 2001) have reported
can changes in Pi explain the reduction in performance minimal effects (5% or less) of La− on muscle contractility.
observed in humans following prior intense exercise with While these recent studies on skinned fibres suggest a
different muscle groups? Despite well over 150 years of minimal role for La− in the fatigue process, further studies
active research, the exact causes of muscle fatigue remain on more intact systems are needed.
elusive.
Shuttles, shuttles, everywhere
Lactic acid and pH. As noted in the preceding section, HLa
Cell-to-cell lactate shuttle. What is now known as the cell-
is more than 99% dissociated at physiological pH. This has
to-cell lactate shuttle was introduced by Brooks (1985a)
led to the incorrect notion that the donation of a proton
simply as the lactate shuttle. Since its introduction, this
by each HLa causes a decreased pH during conditions
hypothesis has been repeatedly supported by studies using
such as exercise. In 1981, Peter Stewart reintroduced
a wide variety of experimental approaches. It posits that
and clarified the concept of physicochemical analysis of
La− formation and its subsequent distribution throughout
body fluid acid–base status; this represented a return
the body is a major mechanism whereby the coordination
to the thinking of Henderson and van Slyke and other
of intermediary metabolism in different tissues, and cells
lesser-known investigators of acid–base balance in the
within those tissues, can be accomplished. The importance
early 20th century (Lindinger, 2003; Johnson et al. 1996).
of La− as a carbohydrate fuel source is underscored by
Stewart (1981) emphasized that [H+ ] (pH) and [HCO3 − ]
the fact that during moderate intensity exercise, blood
are dependent acid–base variables; that is, they are not
La− flux may exceed glucose flux (Brooks, 2000). Because
causative factors. Instead, acid–base status is determined
of its large mass and metabolic capacity, skeletal muscle
by the independent effects of carbon dioxide (P CO2 ),
is probably the major component of the lactate shuttle,
the concentration of weak acid buffers ([Atot ], in plasma
not only in terms of La− production but also in terms of
mainly the amino acids in plasma proteins), and the
net La− uptake and utilization as well. At rest, muscles
strong ion difference [SID]. [SID] is the sum of the strong
slowly release La− into the blood on a net basis, although
cations minus the sum of the strong anions; e.g. [SID] =
at times they may show a small net uptake. During
([Na+ ] + [K+ ] + [Ca2+ ]) − ([Cl− ] + [La− ]) (Kowalchuk
exercise, particularly short-term, high-intensity exercise,
et al. 1988). In this method, it is obvious that although
muscles produce La− rapidly while La− clearance is slowed.
La− can be a significant component of [SID] acting to
This results in an increased intramuscular [La− ] and an
increase the [H+ ], it is definitely not the only factor
increased net output of La− from muscles into the blood.
involved in pH changes. The utility of this approach for
Later, during recovery from short-term exercise, or even
determining underlying mechanisms in the study of acid–
during continued, prolonged exercise, there is net La−
base balance during exercise has been clearly demonstrated
uptake from the blood by resting muscles or by other
in numerous studies (e.g. Kowalchuk et al. 1988; Lindinger
muscles that are exercising at a low to moderate intensity
et al. 1992).
(Richter et al. 1988; Brooks, 2000; Gladden, 2000). During
prolonged exercise of low to moderate intensity, the
Lactate anion and fatigue. Over the years, La− has been muscles that originally released La− on a net basis at
considered unimportant in the development of fatigue. the onset of the exercise may actually reverse to net La−
However, in the 1990s, several studies raised the possibility uptake (Stainsby & Welch, 1966; Gladden, 1991; Gladden
that La− per se might play some role in the fatigue et al. 1994; Brooks, 2000). Particularly during moderate to
process. In isolated dog gastrocnemii in situ, perfusion with high intensity exercise, glycolytic muscle fibres are likely
l-(+)-lactate reduced twitch contraction force by 15% to be producing and releasing La− . While some of the

La− escapes into the circulation, some of it may diffuse to an important gluconeogenic precursor. These LC studies
neighbouring oxidative muscle fibres which can take up the along with many other investigations of different types
La− and oxidize it (Baldwin et al. 1977; Stanley et al. 1986; emphasize the role of La− as arguably the most important
Brooks, 2000). Clearly, La− exchange is a dynamic process substrate for gluconeogenesis. The obvious conclusion
with simultaneous muscle uptake and release at rest and from numerous studies is that La− is a useful metabolic
during exercise (Jorfeldt, 1970; Brooks, 1985a; Stanley et al. intermediate that can be exchanged rapidly among tissue
1986; Van Hall et al. 2002). Most of the La− taken up by compartments. The cell-to-cell lactate shuttle provides the
muscles is removed via oxidation with the absolute rate basic framework for interpretation of La− metabolism.
depending on the metabolic rate of both exercising and Blood provides the route by which tissues throughout
resting muscles (Stanley et al. 1986; Mazzeo et al. 1986; the body are linked together in the cell-to-cell lactate
Bergman et al. 2000; Kelley et al. 2002). Oxidative skeletal shuttle. During exercise, intense exercise in particular,
muscles that are contracting in a submaximal steady state La− and H+ move out of contracting muscles primarily
condition are ideally suited for La− consumption. Since via monocarboxylate transporters MCT1 and MCT4
cardiac muscle is more highly oxidative than even the (Halestrap & Price, 1999; Juel & Halestrap, 1999; Bonen,
most oxidative skeletal muscle, it is not surprising that 2001; Dubouchaud et al. 2000; Juel, 2001). Diffusion of
the heart is an active La− consumer. Evidence from several undissociated HLa constitutes a smaller component of
different experimental approaches suggests that as blood La− and H+ transport at physiological La− concentrations
[La− ], myocardial blood flow and myocardial V̇O2 increase, (Gladden, 1996). From the interstitial fluid, La− and
La− becomes the preferred fuel for the heart, accounting H+ gain access to the blood through endothelial clefts
for as much as 60% of the substrate utilized (Stanley, and probably across endothelial cells as well. La−
1991; Chatham et al. 1999). Tracer studies indicate that uptake and utilization as a fuel have been reported in
essentially all of the La− taken up by the heart is oxidized endothelial cells (Krützfeldt et al. 1990), and mono-
(Stanley, 1991). Even the brain can take up La− from the carboxylate transporters MCT1 and MCT2 have been
blood. Recently, Ide & Secher (2000) provided compelling detected in brain endothelial cells (Mac & Nalecz, 2003)
evidence for net La− uptake by the brain, particularly and in immortalized rat retinal capillary endothelial cells
during intense exercise; this uptake continued during a (Hosoya et al. 2001). Nevertheless, the extent to which La−
30-min recovery period. Although the contribution of and H+ move from interstitial fluid to blood or vice versa
brain uptake to whole body La− uptake is negligible, it is of by way of facilitated transport through endothelial cells in
great interest in the consideration of brain metabolism per most tissues is unknown.
se as noted below in the discussion of the astrocyte–neuron From interstitial fluid of active muscles, La− enters the
lactate shuttle. plasma. During intense exercise, a system designed to
Several studies by Gladden and colleagues (Gladden, cotransport La− and H+ from the plasma into the red
1991, 2000; Gladden et al. 1994; Hamann et al. 2001; blood cells (RBCs) could aid in establishing a gradient
Kelley et al. 2002) have demonstrated that isolated, between the plasma and interstitial fluid, and enhancing
blood-perfused oxidative skeletal muscle readily consumes the available space for efflux of La− and H+ ions from
exogenously infused La− as a fuel. Recently, these findings the exercising muscles (Gladden, 1996). Indeed, the
have been confirmed and extended in lactate clamp (LC) transport of La− across the RBC membrane proceeds
studies in humans. Miller et al. (2002a,b) investigated by three distinct pathways: (1) non-ionic diffusion of
subjects exercising at a moderate exercise intensity (∼55% undissociated HLa, (2) an inorganic anion exchange
V̇O2 peak ) with La− infusion to maintain [La− ] at ∼4 mm. system, often referred to as the Band 3 system, and (3)
Overall, they (Miller et al. 2002a) found a significant a monocarboxylate-specific carrier mechanism (MCT)
increase in La− oxidation accompanied by a decrease (Deuticke et al. 1982). MCT1 is the monocarboxylate
in glucose oxidation; the interpretation is that La− transporter in RBC membranes (Garcia et al. 1994, 1995;
competes successfully with glucose as a carbohydrate Halestrap & Price, 1999) and it is the primary pathway
fuel source, thus sparing blood glucose for use by other of La− transport (Skelton et al. 1995, 1998). As blood
tissues. Additionally, Miller et al. (2002b) found that circulates through the body to liver, heart, inactive and
although La− served as a gluconeogenic substrate, the active skeletal muscles, and all tissues, the pathway is
absolute rate of gluconeogenesis was unchanged by LC. typically reversed with La− exiting the plasma into the
In contrast, LC increased the absolute gluconeogenic rate interstitial fluid and on into the various tissues down the
during low intensity exercise, ∼34% V̇O2 peak (Roef et al. [La− ] gradient. As plasma [La− ] declines, La− will leave the
2003). At both low and moderate intensities, La− was RBCs. Several investigations have nicely illustrated the role

of plasma and RBCs in picking up La− from active muscles cytosol and its production rate would increase with
and delivering it to inactive muscles (see Lindinger et al. increases in glycolytic rate. Due to its higher concentration,
1995 for review). La− would be the primary monocarboxylate diffusing to
Under most conditions, including exercise, RBCs can mitochondria where it would be transported across the
take up La− at a rate that is proportional to its rate of inner mitochondrial membrane by MCT1. Once inside the
entry into the plasma. As a result, RBC [La− ] reaches an mitochondria, in the matrix, mitochondrial LDH would
equilibrium with plasma [La− ] and the RBC/plasma ratio catalyse the conversion of La− back to pyruvate, which
is relatively constant and similar to its value under normal, would be oxidized through the PDH reaction to acetyl-
rest conditions. This ratio is approximately 0.5 and reflects CoA. The acetyl-CoA would then continue through the
a gradient between plasma [La− ] and RBC [La− ] in which TCA cycle. Note that the intracellular lactate shuttle would
the [La− ] in plasma is approximately twice that inside the not only deliver substrate in the form of La− for conversion
RBCs (Smith et al. 1997, 1998), a condition that appears to to pyruvate; it would also deliver reducing equivalents
be largely established by a Donnan equilibrium (Johnson thus supplanting the role of the malate–aspartate and
et al. 1945). At elevated [La− ], such as occur during glycerol phosphate shuttles to varying degrees depending
exercise or other conditions, the gradient between plasma on the rate of La− formation and its rate of transport into
and RBCs can become substantial as the RBC : plasma mitochondria.
[La− ] ratio remains unchanged (Smith et al. 1997, 1998). Can this fascinating and exciting hypothesis be accepted
The result is that under most conditions, the plasma as the explanation for net La− oxidation by aerobic muscle?
will contain ∼70% and the RBCs ∼30% of the whole Two direct tests of the hypothesis by other laboratories
blood La− content (Gladden, 1996). An exception to (Rasmussen et al. 2002; Sahlin et al. 2002) have failed
[La− ] equilibration between plasma and RBCs occurs to confirm its central tenets. Both Sahlin et al. (2002)
immediately following intense ‘all-out’ exercise, when and Rasmussen et al. (2002) found (1) no evidence that
La− entry into the plasma occurs at a proportionally mitochondria can use La− as a substrate without prior
faster rate than uptake of La− into the RBCs (Juel et al. conversion to pyruvate in the cytosol, and (2) insignificant
1990). activities of LDH in the mitochondrial fraction. Further,
both groups argue that the idea of La− conversion to
pyruvate inside mitochondria is not feasible on the basis
Intracellular lactate shuttle
of thermodynamic principles. They point to a much
Brooks (1998) proposed an intracellular lactate shuttle and higher reduction of the NAD+ /NADH redox couple inside
provided supportive data in a subsequent paper (Brooks mitochondria; so much higher that in fact it would
et al. 1999b). This hypothetical shuttle is illustrated in theoretically eliminate the possibility of La− to pyruvate
Fig. 1. A central tenet of this intracellular shuttle is that HLa conversion. Sahlin et al. (2002) go on to suggest that if LDH
is an inevitable product of glycolysis, particularly during were present in the mitochondrial matrix, it would lead to
rapid glycolysis; this is so because LDH has the highest a futile cycle in which pyruvate would be reduced to La−
V max of any enzyme in the glycolytic pathway and the K eq in mitochondria and vice versa in the cytosol, oxidizing
for pyruvate to La− is far in the direction of La− (Brooks, mitochondrial NADH and finally removing the driving
1998, 2000; Brooks et al. 1999a,b). Given this information, force for the electron transport chain. An earlier report
Brooks et al. (1999a) questioned how the well-known on human skeletal muscle by Popinigis et al. (1991) also
oxidation of La− by well-perfused tissues could occur failed to show either mitochondrial LDH or La− oxidation
through net lactate-to-pyruvate conversion in the cytosol. coupled to mitochondria.
Brooks et al. (1999a,b) and Dubouchaud et al. (2000) have Can these criticisms be countered? Brooks (Brooks
reported the following evidence for key components of an et al. 1999b; Brooks, 2000, 2002a,b) points out that
intracellular lactate shuttle in skeletal muscle: (1) direct the intracellular lactate shuttle concept is compatible
uptake and oxidation of La− by isolated mitochondria with most of the available data on La− oxidation in
without prior extramitochondrial conversion of La− to cardiac and skeletal muscles of humans and other
pyruvate, (2) presence of an intramitochondrial pool of mammals gathered through the use of isotopic tracers,
LDH, and (3) presence of the La− transporter, MCT1, arterial–venous mass balance techniques, and the
in mitochondria, presumably in the inner mitochondrial combination of the two methods. The experimental
membrane. models included perfused muscles and intact humans.
In the intracellular lactate shuttle scenario (Gladden, A key example is the recent study of Chatham et al.
2001), HLa would be produced constantly in the (2001) in which [3-13 C]lactate was used to study

the perfused rat heart. Their data implied that from either exogenous pyruvate or glycolytically derived
glycolytically derived pyruvate was preferentially pyruvate. However, it must be recognized that while most
metabolized to La− rather than to acetyl-CoA of the results of the wide literature on La− transport and
whereas pyruvate derived from exogenous La− was metabolism can be viewed as broadly consistent with
preferentially directed to acetyl-CoA formation, results the intracellular lactate shuttle hypothesis, this does not
that are consistent with the concept of an intracellular provide any direct proof of the hypothesis, nor does it
lactate shuttle. Additional support for compartmentation address the thermodynamics question.
of cardiac carbohydrate metabolism has come from studies Could microcompartmentation explain the
of the metabolic effects of insulin and dichloroacetate intracellular shuttle hypothesis? In other words, could
(DCA) on fuel oxidation by perfused rat hearts (Lloyd there be a ‘sink’ for pyruvate in the mitochondria that
et al. 2003). In these studies, insulin and DCA (a would allow pyruvate concentration to be low enough (and
stimulator of pyruvate dehydrogenase activity) increased correspondingly NADH/NAD+ ) to allow La− conversion
the oxidation of glucose and exogenous pyruvate, but not to pyruvate? For this type of compartmentation to be
of exogenous La− . The implication is that lactate-derived feasible, pyruvate concentration would still have to be
pyruvate is oxidized by way of a different pathway high enough to accomodate the PDH reaction, and
Figure 1. Illustration of the essential elements of the hypothetical intracellular (intramuscular) lactate
shuttle in comparison to the well-established malate–aspartate NAD+ /NADH shuttle
Note that for purposes of clarity the well-established glycerol phosphate shuttle is not shown. Redrawn with
permission from Gladden (2001). The H+ ions for pyruvate and lactate are inserted to emphasize that the MCT1 and
presumably PYR symports a proton; MCT1 can transport both pyruvate and lactate. Note that operation of such an
intracellular lactate shuttle would deliver both reducing equivalents and substrate for oxidation to mitochondria.
Key components of this hypothesis are in bold lettering and/or red fill for comparison to the malate–aspartate
shuttle in normal font and blue fill: a high activity of cytosolic LDH is considered to guarantee La− formation in
the cytosol under virtually all conditions but especially during exercise; MCT1 has been reported to be present
in mitochondrial membrane allowing La− transport from cytosol into mitochondria; LDH inside mitochondria is
required to complete the intracellular shuttle by converting La− to pyruvate. The asterisk beside the mitochondrial
LDH denotes that the presence of LDH inside mitochondria is disputed and that some investigators consider
operation of such a shuttle to be thermodynamically unfeasible. MCT1: monocarboxylate transporter 1; PYR: the
mitochondrial pyruvate transporter; ETC: electron transport chain; Shuttles: the malate–aspartate NAD+ /NADH
shuttle and the glycerol phosphate shuttle, which is not shown.

[NADH] would still have to be sufficient to drive the cytosolic locations. Then, due to the relatively higher La−
electron transport chain. concentration as compared to pyruvate, La− would be
Baba & Sharma (1971) combined histochemical and the primary species diffusing to areas near mitochondria.
electron microscopy techniques and were apparently the Adjacent to mitochondria, La− and NAD+ would be
first to find LDH localized in the mitochondria of rat heart converted back to pyruvate and NADH for uptake into
and skeletal muscle. Subsequently, Kline et al. (1986) and the mitochondria. Such a scheme would accommodate
Brandt et al. (1987) used cell fractionation techniques to ready La− production with subsequent oxidation and less
demonstrate the presence of LDH in rat liver, kidney, and transport of La− out of the cell.
heart mitochondria. Szczesna-Kaczmarek (1990) reported
both mitochondrial LDH and oxidation of La− by isolated
Astrocyte–neuron lactate shuttle
mitochondria. Interpretation of these results varies as
might be expected. Brooks (2002a,b) cites many of these Increased nervous system activity requires increased
earlier findings as support for the intracellular La− shuttle energy metabolism in neurons. The conventional view
and contends (Brooks, 2002a) that Sahlin et al. (2002) is that neuronal energy metabolism is fuelled by glucose
and Rasmussen et al. (2002) most likely lost LDH in their oxidation (Chih et al. 2001). The action potentials of
isolation procedures to obtain mitochondria. To the neuron activity result in Na+ entry and K+ efflux
contrary, Sahlin et al. (2002) and Rasmussen et al. (2002) which activates Na+ –K+ -ATPase in the neuronal plasma
speculate that the mitochondria of Brooks et al. (1999b) membrane; this ATPase pump activity in turn leads to
and others (see above) were contaminated with cytosolic ↓[ATP], ↑[ADP], ↑[Pi ], and ↑[AMP], standard activators
LDH. of glycolysis, the TCA cycle and mitochondrial oxidative
Another complicating factor is the nature of phosphorylation. ATP synthesis will increase via these
pyruvate/lactate transport into the mitochondria. Brooks energetic pathways with a concomitant utilization of
et al. (1999a) present evidence of MCT1 in the intracellular glucose that lowers [glucose], leading to
mitochondria and suggest that MCT1 has a higher affinity an increased uptake of glucose into neurons via the
for La− than for pyruvate (Brooks, 1998). However, a neuronal glucose transporter, GLUT3 (Chih et al. 2001),
recent study of MCT1 (Bröer et al. 1998) reports a K m which is found in both pre- and postsynaptic elements.
for pyruvate that is about one-third that found for La− In this scenario, rapid glycolysis is likely to result
although the pyruvate V max is 45% of the La− V max . in some La− production and inhibition of oxidation
Further, the ‘traditional’ mitochondrial pyruvate carrier of exogenously supplied La− . The primary excitatory
apparently has a very high affinity for pyruvate and is not a neurotransmitter in the brain is glutamate. Glutamate
member of the MCT family; it has a six-transmembrane- is taken up by surrounding astrocytes via a carrier
helix structure as compared to the 12-transmembrane- that cotransports Na+ . In a process similar to that
helix structure of the MCT family (Kuan & Saier, 1993; in the neurons, astrocyte metabolism (glycolysis, TCA
Palmieri et al. 1996; Halestrap & Price, 1999; Sugden cycle, oxidative phosphorylation) is activated to supply
& Holness, 2003). A single candidate protein for this ATP for restoring Na+ –K+ balance; metabolism is also
mitochondrial pyruvate carrier has recently been identified stimulated to supply energy for glutamine synthesis from
in yeast (Hildyard & Halestrap, 2003; Sugden & Holness, the glutamate that has been taken up.
2003); further studies are required in mammalian systems. Pellerin & Magistretti (1994) challenged this
No doubt future experimentation will provide conventional scheme of nervous system energetics
additional evidence either supporting or refuting the with their introduction of the astrocyte–neuron lactate
hypothesis. In the meantime, the original intracellular shuttle hypothesis (ANLSH); see Fig. 3. In this model
lactate hypothesis proposed by Stainsby & Brooks (1990) (Pellerin & Magistretti, 1994, 2003; Magistretti &
should receive attention as well. In this older hypothesis, Pellerin, 1999; Magistretti et al. 1999; Bouzier-Sore et al.
illustrated in Fig. 2, pyruvate and NADH concentrations 2002; Pellerin, 2003), glutamate that is released as a
would be greatest in cytosolic locations that are farthest neurotransmitter from the neurons is primarily taken up
removed from mitochondria. Pyruvate and NADH into astrocytes via a transporter that carries one glutamate,
concentrations would be lowest adjacent to mitochondria three Na+ , and one H+ inward while one K+ is moved
where the pyruvate carrier and the NADH shuttles would out of the cell (Attwell, 2000). This astrocytic transport
be moving pyruvate and NADH equivalents, respectively, activity then leads to Na+ –K+ -ATPase activation (perhaps
into the mitochondria. This situation could lead to the via an increase in [Na+ ]i ) to restore ionic balance, and
highest La− production and concentration in remote to glutamine synthesis from the glutamate that has

been taken up. The energy costs of the ATPase pump to restore ionic balance and resynthesis of glutamate
and glutamine synthesis result in ↓[ATP], ↑[ADP], from glutamine, largely derived from astrocytes. While
↑[Pi ], and ↑[AMP], which largely stimulate glycolysis glucose can be taken up by neurons via their GLUT3
in the astrocytes with resultant La− production. Here, transporters, larger amounts of glucose may be used
glycolytic enzymes may be compartmentalized with by astrocytes, and taken up into astrocytes via their
the ATPase pump and glutamine synthesis pathway, GLUT1 transporters. In fact, Loaiza et al. (2003) have
allowing preferential activation of the glycolytic energy reported that glutamate stimulates glucose transport
system. The increased [La− ] moves La− outward along into cultured hippocampal astrocytes more rapidly than
its concentration gradient via MCT1 transporters in the any stimulation of mammalian glucose transport yet
astrocyte plasma membrane. Next, extracellular space known. In short, in the ANLSH, much of the fuel for
[La− ] rises, driving La− into the neighbouring neurons via increased energy demands of neurons is supplied by La−
MCT2 transporters in the neuronal plasma membrane. from surrounding astrocytes. As a result, metabolism
Inside the neurons, La− , along with glucose, serves as an of the astrocytes is largely glycolytic while that of the
oxidative fuel for elevated neuronal energy metabolism neurons is largely oxidative. The ANLSH has also
that has been triggered by an activated Na+ –K+ -ATPase been proposed for other support cell–neuron/receptor
Figure 2. Illustration of a simpler intracellular (intramuscular) lactate shuttle hypothesis originally

proposed by Stainsby & Brooks (1990)
Note that the space above and to the right of the diagonal dashed line denotes sites that are remote from
mitochondria and/or compartmentalized while the space down and to the left of the line denotes sites near
mitochondria. La− is in large, bold lettering in the sites remote from mitochondria indicating that (a) [La− ] should
be highest here, and (b) [La− ] is much greater than pyruvate concentration, especially during exercise. In this
model, La− would be the predominant species diffusing from sites of glycolytic formation to low [La− ] areas just
outside mitochondrial membranes where La− would be converted back to pyruvate with delivery of NADH to the
malate–aspartate (and glycerol phosphate) NAD+ /NADH shuttles. This model does not require intramitochondrial
LDH. MCT1 is shown because pyruvate might enter mitochondria via this transporter in addition to the traditional
pyruvate carrier (PYR). LDH: lactate dehydrogenase; MCT1: monocarboxylate transporter 1; PYR: the mitochondrial
pyruvate transporter; ETC: electron transport chain; Shuttles: the malate–aspartate NAD+ /NADH shuttle and the
glycerol phosphate shuttle, which is not shown for purposes of clarity. Redrawn with permission from Gladden
(1996) from Handbook of Physiology, section 12, Exercise: Regulation and Integration of Multiple Systems, edited
by Loring B. Rowell & John T. Shepherd, copyright 1996 by The American Physiological Society. Used by permission
of Oxford University Press, Inc.

energetic interactions such as those between Schwann cells mechanisms of nervous system metabolism, the ANLSH
and peripheral neurons (Véga et al. 1998), and between offers intriguing explanations for functional brain imaging
Müller glial cells and photoreceptors (Poitry-Yamate et al. (Magistretti & Pellerin, 1999; Magistretti et al. 1999). Local
1995). brain activity is monitored by visualization of changes in
The implications of the ANLSH are extremely broad. blood flow, glucose usage, and oxygen consumption via
For example, apart from its inferences concerning basic positron emission tomography (PET), changes in blood
Figure 3. Illustration of the putative astrocyte–neuron lactate shuttle

The basic outline of the astrocyte–neuron lactate shuttle hypothesis is as follows. Blood glucose is a major energy
substrate that can be taken up by both neurons and astrocytes via their specific glucose transporters (GLUT3 in
neurons and GLUT1 in astrocytes); note that GLUT1 is also present in the plasma membrane of endothelial cells
making up capillaries. Blood glucose may be more readily available to astrocytes because the surface of intra-
parenchymal capillaries is covered by specialized astrocytic end-feet. Release of the neurotransmitter, glutamate, at
glutamatergic synapses leads to glutamate uptake into surrounding astrocytes via glutamate transporters GLT-1 and
GLAST to terminate the action of glutamate on postsynaptic receptors. Glutamate entry into astrocytes is powered
by the Na+ concentration gradient and current evidence suggests that one glutamate enters with three Na+ and one
H+ while one K+ is simultaneously extruded. The resulting increase in intra-astrocytic [Na+ ] activates a glia-specific
Na+ –K+ -ATPase α 2 subunit. Glutamate is converted to glutamine by glutamine synthetase. Both the ATPase pump
activation and the glutamine synthesis activate astrocytic glycolysis that is possibly compartmentalized with these
processes; presence of LDH5, the muscle form of LDH, is argued to promote La− formation. The end result is La−
accumulation and efflux into the extracellular fluid, facilitated by MCT1. Subsequently, La− is taken up into neurons
via MCT2. Glutamine also diffuses from astrocytes into the extracellular fluid and on into neurons where it is used
to resynthesize glutamate. La− taken up into neurons is preferentially converted to pyruvate, arguably because of
pyruvate utilization as an aerobic fuel and the presence of LDH1, the heart form of LDH. In this hypothesis, the
energy metabolism of neurons is largely aerobic with La− serving as the major fuel. See text and Table 2 for further
details of the hypothesis, and Table 3 for concerns/questions about the hypothesis. GLUT1 and GLUT3: specific
glucose transporters located in the membranes of brain endothelial cells and astrocytes (GLUT1), and neurons
(GLUT3); MCT1 and MCT2: specific monocarboxylate transporters located in the membranes of brain endothelial
cells and astrocytes (MCT1), and neurons (MCT2); Gluc: glucose; Gly: glycogen; Pyr− : pyruvate; La− : lactate; Glu:
glutamate; Gln: glutamine; GS: glutamine synthetase; LDH1 and LDH5: specific forms of lactate dehydrogenase
in neurons (LDH1) and astrocytes (LDH5); ECF: extracellular fluid; GLT-1 and GLAST: glutamate transporters; α 2 :
glia-specific Na+ –K+ -ATPase subunit. Redrawn with permission from Pellerin (2003), Lactate as a pivotal element
in neuron-glia metabolic cooperation, Neurochemistry International 43, 331–338. Used by permission of Elsevier.

Table 2. Some of the key evidence supporting the astrocyte–neuron lactate shuttle hypothesis
1. Rate at which metabolized glucose enters the neuronal TCA cycle equals the rate of glial glutamate cycling (Sibson et al. 1998).
2. In cultured mouse astrocytes (Pellerin & Magistretti, 1994) and glial Müller cells in retina (Poitry-Yamate et al. 1995), uptake of
exogenous glutamate is strongly associated with increased La− production.
3. Neuronal tissue can use La− as a fuel and may prefer it.
a. Studies on brain tissue, isolated nerves, and sympathetic ganglia have reported La− utilization in replacement of glucose (e.g.
McIlwain, 1956; Carpenter, 1959; Brown et al. 2001).
b. La− can substitute for, or is preferred to, glucose, in cultured cortical neurons (Pellerin et al. 1998; Bouzier-Sore et al. 2003), chick
sympathetic ganglia (e.g. Larrabee, 1995), vagus nerve (Véga et al. 1998), and photoreceptors in the retina (Poitry-Yamate et al.
1995) and human brain in vivo (Smith et al. 2003).
c. La− is metabolized through the TCA cycle in GABAergic and glutamatergic neurons with labelling of TCA cycle intermediates
and several amino acids derived from cycle intermediates (Schousboe et al. 1997; Waagepetersen et al. 2000).
d. LDH1 is the predominant isoform of LDH in neurons and it has been argued that this isoform is more likely to convert La− to
pyruvate because of its lower K m for La− . LDH5, the predominant isoform in astrocytes, is arguably more suited for pyruvate to
La− conversion (e.g. Bittar et al. 1996; Pellerin et al. 1998).
e. Nuclear magnetic resonance spectroscopy has provided evidence of La− utilization as an energy substrate in brain tissue,
specifically as a neuronal fuel (e.g. Hassel & Brathe, 2000; Qu et al. 2000).
4. Glutamate is the primary excitatory neurotransmitter of the cerebral cortex. Some observations suggest a specific mechanism for
detection of glutamatergic activity by astrocytic processes surrounding glutamatergic synapses, and a resulting La− production and
release.
a. An α 2 Na+ –K+ -ATPase is expressed together with glutamate transporters (GLT-1 and GLAST) in astrocytic processes surrounding
glutamatergic synapses (e.g. Robinson & Dowd, 1997; Cholet et al. 2002).
b. Astrocytic glutamate transport is largely electrogenic with one glutamate molecule transported inward with three Na+ ions
(Bouvier et al. 1992). Increased intracellular [Na+ ] stimulates astrocytic Na+ –K+ -ATPase (Kimelberg et al. 1993).
c. Mobilization of a ouabain-sensitive isoform, akin to the α 2 Na+ –K+ -ATPase, appears responsible for the
glutamate-uptake-stimulated aerobic glycolysis of cortical astrocytes (Pellerin & Magistretti, 1997).
d. Ouabain completely inhibits glutamate-evoked 2-deoxyglucose uptake by astrocytes (Pellerin & Magistretti, 1994).
e. Glial glutamate transporter knockout mice show reduced glucose utilization in the somatosensory cortex and cortical astrocytes
from the same mice show abolition of glutamate-stimulated glucose utilization and La− production (Voutsinos-Porche et al.
2003).
5. There is a cell-specific expression of monocarboxylate transporters (MCTs) in the central nervous system. In cultured mouse cortex
preparations, MCT1 and MCT1 RNA are found almost exclusively in astrocytes while MCT2 and its RNA are exclusive to neurons.
(Bröer et al. 1997; Debernardi et al. 2003). Adult rat brain cells show a similar pattern with MCT1 also present in endothelial cells of
the blood–brain barrier (Mac & Nalecz, 2003).
6. Neurons, but not glia, respond to La− with elevation of cytosolic ATP (Ainscow et al. 2002).
7. Anatomical considerations suggest that astrocytes are an important intermediary between capillaries, neurons, and the synapses of
the neurons (Magistretti & Pellerin, 1999).
a. In the brain, the entire surface of intraparenchymal capillaries is covered by specialized astrocytic end-feet (Peters et al. 1991).
b. Specialized astrocytic processes are wrapped around synaptic contacts (Rohlmann & Wolff, 1996; Bushong et al. 2002).
c. In most brain regions, the astrocyte:neuron ratio is 10 : 1 (Bignami, 1991).
This table is derived heavily from Magistretti & Pellerin (1999), Chih et al. (2001), Bouzier-Sore et al. (2002) and Pellerin (2003).
oxygenation via functional magnetic resonance imaging propositions. However, criticisms and questions remain
(fMRI), and spatio-temporal patterns of metabolic such that it has not been universally embraced. Table 2
intermediates such as glucose and La− via magnetic summarizes key points of evidence offered in support of
resonance spectroscopy (MRS). Magistretti & Pellerin the ANLSH whereas Table 3 summarizes the most salient
(1999) argue that the ANLSH ‘provides a cellular criticisms. In its strictest rendition, the model suggests
and molecular basis for . . . functional brain imaging that glial cells account for about 6.5% (two ATP from
techniques’. Is it possible that neuroimaging is a more substrate phosphorylation in the glycolytic conversion
direct reflection of astrocyte function rather than neuronal of one glucose to two HLa) of nervous system activity
function (Meeks & Mennerick, 2003)? while neuronal energy expenditure accounts for the other
Since the introduction of the ANLSH (Pellerin & ∼93.5% (29 ATP from oxidation of two HLa; Salway,
Magistretti, 1994), there has been a virtual explosion of 1999). For the glial cells, it has been proposed that one
publications on the topic, with many supporting its basic glycolytic ATP is used to extrude three Na+ ions via the

Table 3. Some key concerns/questions about the astrocyte–neuron lactate shuttle hypothesis
1. There is no solid explanation as to why neural activity either in situ or in vivo should activate glial glycolysis but not neuronal
glycolysis (Chih et al. 2001).
a. Neurons have high levels of the key glycolytic enzyme, hexokinase (Lai et al. 1999).
b. The predominant neuronal glucose transporter, GLUT3, transports glucose much faster than does the primary glial transporter,
GLUT1.
2. Is the LDH isoform (LDH1 in neurons and LDH5 in astrocytes) relevant? LDH catalyses a near-equilibrium reaction; therefore, the
particular LDH isoform may have little effect on flux through the reaction in vivo (Newsholme, 2003).
3. Neuronal activity has been reported to increase cytoplasmic pyruvate and NADH levels, making it unclear that increases in [La− ]
are sufficient to drive the LDH reaction towards pyruvate and NAD+ formation (see Chih et al. 2001).
4. Does sufficient Na+ enter astrocytes during the transient presence of extracellular glutamate to stimulate significant
Na+ –K+ -ATPase activity and thereby significant glycolysis? (Meeks & Mennerick, 2003).
5. Some results from cultured astrocytes indicate that glutamate uptake fuels oxidative metabolism, primarily of glutamate itself
while glycolysis may be slightly inhibited (Meeks & Mennerick, 2003).
6. Dienel & Hertz (2001) argue that the evidence suggests that ‘metabolic trafficking’ of La− is at most 25% of the rate of glucose
oxidation at physiologically occurring La− concentrations. They suggest that brain activation in vivo is often accompanied by
overflow of glycolytically generated La− to different brain areas and sometimes to circulating blood. Further, [La− ] appears to
increase equally in neurons and astrocytes.
7. Not all studies find that La− replaces glucose as a cerebral metabolic substrate or that La− is of significance for total net brain
energy consumption (Leegsma-Vogt et al. 2003).
8. Not all studies find that glutamate stimulates glycolysis in brain tissue (Gramsbergen et al. 2003).
9. The end feet of astrocytes are not a part of the blood–brain barrier and therefore do not direct glucose utilization specifically to
the astrocytes (see Gjedde & Marrett, 2001).
10. Some find that astrocytic metabolism is not particularly less oxidative than the metabolism of neurons, and that neurons use
pyruvate derived directly from neuronal glycolysis rather than from astrocytic glycolysis (Gjedde & Marrett, 2001).
11. Whereas the astrocyte–neuron lactate shuttle predicts an initial La− overproduction, recent experiments using time-resolved
proton magnetic resonance spectroscopy found a significant decrease in [La− ] 5 s after visual stimulation in humans (Mangia et al.
2003a).
12. MCT isoforms do not confer directionality to La− flux (Juel, 2001).
Na+ –K+ -ATPase pump while the second ATP is spent to neurons. Zwingmann et al. (2000) studied GABAergic
convert glutamate to glutamine (Magistretti & Pellerin, neurons whereas Waagepetersen et al. (2000) studied
1999). It seems unlikely that metabolism is so tightly glutamatergic neurons. Such a shuttle would supplement
coupled and compartmentalized as to allow such strict the well-known glutamine–glutamate cycle (Berl &
stoichiometry. A more probable scenario may be a mixture Clarke, 1983). In glutamatergic neurons, glutamate is
of the ANLSH with the conventional view. In this scheme, released as a neurotransmitter. As described above for
astrocytes would utilize at least some of their own the ANLSH, much of this glutamate is then taken
glycolytic products in oxidative metabolism and neurons up into surrounding astrocytes. Astrocytes synthesize
would utilize some La− from astrocytes in addition to glutamine from glutamate and ammonia (NH4 + ) via cyto-
endogenous, neuronal glycolytic products (Mangia et al. solic glutamine synthetase. This glutamine is released
2003b). Nevertheless, as Table 2 illustrates, evidence is from astrocytes and taken up by neurons where it is
mounting that the ANLSH constitutes a major metabolic converted back to glutamate with ammonia formation
pathway in neural tissue. via mitochondrial glutaminase. This series of reactions
(the glutamine–glutamate cycle) describes the pathway of
the carbon skeleton for this interaction between neurons
Lactate–alanine shuttle
and astrocytes but does not account for the nitrogen.
On the basis of stable isotope tracer studies in cultured This is where the proposed lactate–alanine cycle would
astrocytes, neurons, and cocultures, Zwingmann et al. play a role. In this shuttle, the ammonia from glutamine
(2000) and Waagepetersen et al. (2000) independently breakdown in neurons is combined with 2-oxoglutarate
proposed a lactate–alanine shuttle between astrocytes and for conversion to glutamate via mitochondrial glutamate

dehydrogenase. The resulting glutamate is then used of glutamine to glutamate plus ammonia. Accordingly,
to transaminate pyruvate and form 2-oxoglutarate and further experimentation is warranted to fully clarify the
alanine. The alanine is released from neurons, taken lactate–alanine shuttle.
up by astrocytes, combined with 2-oxoglutarate, and
converted to pyruvate and glutamate via transamination.
Peroxisomal lactate shuttle
This glutamate formation returns to the starting point
described above for the glutamine–glutamate cycle. The Lazarow & de Duve (1976) were the first to confirm
astrocytic pyruvate is now converted to La− which can be β-oxidation of fatty acids in mammalian peroxisomes.
released and taken up into the neurons where it goes back Current thinking is that about 90% of short- and medium-
to pyruvate thus completing the lactate–alanine shuttle. chain length fatty acids are oxidized in mitochondria
This shuttle would provide a pathway for the transfer of while the remaining 10% are oxidized in peroxisomes
ammonia from neurons to astrocytes, a requirement of the under basal conditions. However, the main function
glutamine–glutamate cycle. See Fig. 4 for a diagrammatic of peroxisomal β-oxidation is believed to be chain-
outline of the lactate–alanine shuttle as proposed for shortening of very-long-chain fatty acids (i.e. C22 and
glutamatergic neurons and astrocytes. Schousboe et al. longer) in preparation for subsequent oxidation by
(2003) have questioned the synthesis of glutamate in mitochondria (Salway, 1999). Additionally, the acetyl-
GABAergic neurons via the glutamate dehydrogenase CoA from peroxisomal β-oxidation is known to supply
reaction because the ammonia concentration is likely to substrate for the synthesis of bile acids, phospholipids,
be low in these neurons. They (Schousboe et al. 2003) cholesterol and fatty acids (Hayashi & Takahata, 1991).
have also noted that alanine formation in glutamatergic In order for this β-oxidation to continue, both FADH2
neurons may account for only about 25% of the conversion and NADH must be reoxidized. Unlike the case for
Figure 4. Illustration of the proposed lactate–alanine shuttle between astrocytes and glutamatergic
neurons
This diagram focuses on the recycling of glutamate and ammonia. Glutamate released by neurons as a neuro-
transmitter is taken up by astrocytes and incorporated with ammonia (NH4 + ) to form glutamine. The glutamine
is released to be taken up by neurons to re-form glutamate with ammonia release. The ammonia is used to
synthesize glutamate via glutamate dehydrogenase and this glutamate then transaminates pyruvate to alanine.
The alanine can leave the neurons to be taken up by astrocytes and combined with 2-oxoglutarate to be trans-
aminated back to glutamate with accompanying pyruvate formation. Pyruvate in the astrocytes forms La− that
is released and taken up into neurons. In the neurons, La− is converted back to pyruvate thus completing the
lactate–alanine shuttle. LDH: lactate dehydrogenase; AAT: alanine aminotransferase; GDH: glutamate
dehydrogenase; GS: glutamine synthetase; Glnase: glutaminase; mit: mitochondrial; cyt: cytosolic; Pyr− :
pyruvate; Ala: alanine; Glu: glutamate; 2-oxoglu: 2-oxoglutarate; Gln: glutamine. Redrawn with permission from
Waagepetersen et al. (2000), A possible role of alanine for ammonia transfer between astrocytes and glutamatergic
neurons, Journal of Neurochemistry 75, 471–479. Used by permission of Blackwell Publishing Ltd.

mitochondria, FADH2 that is formed in the peroxisomal had no effect (Osmundsen, 1982). Confirmation of the
β-oxidation process is re-oxidized by a direct transfer presence of LDH in the peroxisomal matrix and evidence
of electrons to O2 (Mathews et al. 2000). However, the of its participation in the reoxidation of NADH came
mechanism for NADH reoxidation has been puzzling. in an elegant study by Baumgart et al. (1996). Three
Tolbert’s group (McGroarty et al. 1974) first suggested different approaches clearly demonstrated that LDH
the association of LDH with rat liver peroxisomes but was present in the matrix of rat liver peroxisomes: (1)
their methodology did not permit a firm conclusion, analytical subcellular fractionation with determination
allowing the assumption that LDH activity in peroxisomal of enzyme activity, (2) immunodetection of LDH in
fractions was due to the adsorption of the cytosolic isolated subcellular fractions using a monospecific anti-
enzyme to the outer surface of the peroxisomal membrane. body, and (3) immunoelectron microscopy applied to
Accordingly, it was considered possible that NADH from liver sections and to isolated peroxisomal fractions.
peroxisomal β-oxidation passed through the peroxisomal Additional experiments demonstrated direct involvement
membrane for reoxidation to NAD+ in the cytosol with of peroxisomal LDH in the reoxidation of NADH
subsequent entry of the NAD+ back into the peroxisome produced by the β-oxidation of palmitoyl-CoA: (a)
(Osmundsen et al. 1994). However, two other findings NADH reoxidation increased in response to increasing
brought consideration of a peroxisomal lactate shuttle to pyruvate concentration before LDH inhibition occurred
the forefront: (1) the peroxisomal membrane in the yeast at concentrations above 2 mm, and (b) NADH reoxidation
Saccharomyces cerevisiae was reported to be impermeable was reduced by the LDH inhibitor, oxamate. Sub-
to NAD+ /NADH in vivo (Van Roermund et al. 1995), sequently, Brooks’s group (McClelland et al. 2003)
and (2) the addition of pyruvate to a liver peroxisomal confirmed the presence of LDH in peroxisomes and
assay in vitro was found to stimulate the β-oxidation stimulation of peroxisomal β-oxidation by pyruvate.
of palmitoyl-CoA while the addition of exogenous LDH As further evidence of the shuttle, they found
Figure 5. Illustration of the proposed peroxisomal lactate shuttle

Based on McClelland et al. 2003), Salway (1999) and Baumgart et al. (1996). The outline of reactions displays the
β-oxidation of very-long-chain fatty acids with acetyl-CoA release to the cytosol. Although not shown, shortened
fatty acyl-CoA molecules could be released to the cytosol as well. Key elements of the peroxisomal lactate shuttle
are highlighted in red indicating that NADH is reoxidized to NAD+ inside the peroxisome by the conversion of
pyruvate to La− ; La− then leaves the peroxisome via the monocarboxylate carrier, MCT2. In the cytosol, La− is
converted back to pyruvate with concomitant conversion of NAD+ to NADH, thus delivering reducing equivalents
from the peroxisome to the cytosol. The resulting pyruvate returns to the peroxisome via the MCT2 to continue
the shuttle. This shuttle provides an avenue for NADH reoxidation in the peroxisome, a necessary process for
the continuation of peroxisomal β-oxidation of fatty acids. E1: acyl-CoA oxidase; E2: enoyl-CoA hydratase; E3:
L-3-hydroxyacyl-CoA dehydrogenase; E4: thiolase; E5: catalase; pLDH: LDH located inside the peroxisome; cLDH:
LDH located in the cytosol, outside the peroxisome; Pyr− : pyruvate; La− : lactate.

peroxisomal La− generation upon the addition of transport inhibitor, α-cyano-4-hydroxycinnamate, and
pyruvate. Most importantly, McClelland and Colleagues by oxamate, an inhibitor of LDH (Calvin & Tubbs,
(2003) reported that peroxisomal membranes contain 1978). More recently, these results were supported by
the monocarboxylate transporters, MCT1 and MCT2, experiments on sperm-type mitochondria from rats and
thus providing a mechanism for pyruvate entry into, rabbits; these experiments also showed an inhibition
and La− efflux from, peroxisomes. The significance of the lactate–pyruvate shuttle by the monocarboxylate
of these transporters was demonstrated by the fact transport inhibitor, mersalyl (Gallina et al. 1994).
that the rate of pyruvate-stimulated peroxisomal Function of the shuttle was further confirmed in intact
β-oxidation was inhibited by the MCT blocker, α-cyano- boar sperm and hypotonically treated spermatozoa (Jones,
4-hydroxycinnamate. Figure 5 illustrates the proposed 1997). The boar sperm oxidatively metabolized fructose,
peroxisomal lactate shuttle. To be complete, it should be glucose, glycerol, glycerol 3-phosphate and La− to CO2
noted that other redox shuttles are likely to be operative in while only small amounts of CO2 were produced from
peroxisomes as well (Baumgart et al. 1996). pyruvate. La− was the most preferred of the substrates and
was oxidized preferentially in the presence of pyruvate.
Mersalyl, an inhibitor of La− transport, reduced La−
Spermatogenic lactate shuttles
metabolism in a dose–response manner. To be complete,
For 40 years, it has been known that mammalian it should be noted that the lactate shuttle is not present
spermatozoa can use La− as an aerobic energy source in mouse spermatozoa (Gallina et al. 1994) and that a
(see Storey & Kayne, 1977). In fact, La− stimulates malate–aspartate shuttle is likely to be present in some
respiration in ejaculated bovine sperm (Halangk et al. types of spermatozoa in addition to the lactate shuttle
1985) and maintains bovine sperm motility as well (Calvin & Tubbs, 1978).
as glucose does (Inskeep & Hammerstedt, 1985). La− Function of an ‘intracellular’ lactate shuttle of course
metabolism by sperm apparently involves La− transport requires the presence of LDH inside the mitochondria as
into mitochondria followed by oxidation of the La− to well as in the cytosol and typically involves carrier proteins
pyruvate and subsequent intramitochondrial metabolism for membrane flux. Numerous studies have substantiated
of the pyruvate via aerobic pathways. In a flurry of the presence of a unique form of LDH (LDH C4 , previously
activity in 1977–78, evidence for such a lactate shuttle LDH X), both in the cytosol and inside the mitochondria
was reported for rabbit sperm (Storey & Kayne, 1977), of spermatozoa (for references see Storey & Kayne, 1977;
bovine sperm (Milkowski & Lardy, 1977), and boar sperm Jones, 1997). Although monocarboxylates can traverse
(Calvin & Tubbs, 1978). All three of these studies utilized membranes by simple diffusion in their undissociated
hypotonically treated spermatozoa (Keyhani & Storey, forms, transporters (MCTs) typically account for the
1973) to generate part or all of the results. This treatment majority of transmembrane traffic at physiological La−
breaks plasma membranes but leaves the cell structure concentrations (Juel & Halestrap, 1999). Accordingly,
and mitochondria intact, including the outer and inner the presence of such transporters would offer additional
mitochondrial membranes (Storey & Kayne, 1977); these support for a spermatozoan lactate shuttle. Two different
sperm-type mitochondria behave similarly in many ways isoforms of the monocarboxylate transporter have been
to mitochondria isolated from other cells (Keyhani & found in the testis and epididymis of hamsters (Garcia
Storey, 1973). et al. 1995). Relative to the present issue, MCT1 was
Hypotonically treated rabbit spermatozoa were found present on sperm heads but disappeared with maturation
to oxidize external La− rapidly as evidenced by whereas MCT2 was present on the tails of sperm and
oxygen consumption measurements. Fluorometric studies never disappeared. Presumably, then, it is MCT2 that
demonstrated intramitochondrial reduction of NAD+ would be involved in the spermatozoan lactate shuttle
in response to the addition of extramitochondrial La− although more specific studies have not been done and
(Storey & Kayne, 1977). Other fluorometric studies of other species have not been studied. As noted earlier in
both whole bovine sperm and bovine sperm mitochondria the discussion of a possible intracellular lactate shuttle
(hypotonically treated spermatozoa) demonstrated that in skeletal muscle, tissues typically maintain a more
the redox state was altered in a manner consistent with reduced redox state inside mitochondria as compared
a pyruvate/lactate redox couple (Milkowski & Lardy, to the cytosol; this facilitates cytosolic glycolysis and
1977). In hypotonically treated boar spermatozoa, external intramitochondrial oxidation (Milkowski & Lardy, 1977;
NADH was oxidized in the presence of external La− , Dawson, 1979). Usually, some irreversible step is necessary
and this oxidation was inhibited by the monocarboxylate within a shuttle system in order to maintain these separate

redox states (Milkowski & Lardy, 1977; Dawson, 1979); Bonen, 2001; Juel, 2001) have been published in recent
such a step has not been identified in the spermatozoan years. The study of La− transport was stimulated
lactate shuttle. An obvious question is raised: Why does by the serendipitous cloning of the first transporter
an ‘intracellular’ lactate shuttle appear to operate in (MCT1) by Garcia et al. (1994). They were studying a
spermatozoa but perhaps not in muscle, based on the mutant allele that encoded a transporter protein that
evidence to date? transported mevalonate, an intermediate in cholesterol
Intriguingly, the enzyme activities of the metabolic synthesis, in Chinese hamster ovary cells. Subsequently
pathways (glycolysis versus TCA cycle) of germ cells appear they found that the mevalonate wild-type gene coded for a
to change during the differentiation and maturation monocarboxylate transporter. Shortly thereafter, Jackson
process (Bajpai et al. 1998). Although the physiological et al. (1995) reported the independent cloning of MCT1
significance of these changes is not clear, on the whole from rat skeletal muscle. Since then, in rapid succession,
it appears that the germ cells are more dependent on a a family of nine MCTs, MCT1–MCT9, has been cloned
direct supply of La− as a fuel than are mature spermatozoa. (Halestrap & Price, 1999). At present, there is active
For example, numerous studies have reported that La− investigation into the factors that determine MCT density
is a preferred, and perhaps essential, substrate for in membranes as well as the possible role of MCTs in
spermatocytes and spermatids (see Nakamura et al. 1984; metabolic regulation.
Grootegoed et al. 1984 and references therein). Recently
it was reported that spermatogenesis is improved by
Lactate in injury, sepsis, and haemorrhage
intratesticular infusion of La− into the adult cryptorchid
rat testis (Courtens & Plöen, 1999). In this context, the fluid Lactate is an important intermediate in the process
of seminiferous tubules is reported to be rich in La− but low of wound repair and regeneration, a role that may
in glucose and pyruvate (see Bajpai et al. 1998; Courtens not be generally familiar to researchers in the area of
& Plöen, 1999 and references therein). Further, Sertoli energy metabolism. As early as 1964, Green & Goldberg
cells that line the seminiferous tubules and extend to the (1964) reported that collagen synthesis is increased almost
lumen actively metabolize glucose with the majority being twofold when [La− ] rises to 15 mm in cultured fibroblasts.
converted to La− (e.g. see Grootegoed et al. 1986; Bajpai Notably, healing wounds produce and accumulate La−
et al. 1998). Whether or not the germ cells metabolize with concentrations sometimes rising to the range of
the La− provided by the Sertoli cells via the same lactate 10–15 mm (Hunt et al. 1978; Gibson et al. 1997).
shuttle as spermatozoa is unclear, but it would seem to be Significantly, La− is not simply a sequel to hypoxia in
a reasonable hypothesis. Provision of La− by Sertoli cells wounds (Trabold et al. 2003). In fact, it is well-established
to the germ cells adds a cell-to-cell aspect that may not be that oxygen level has a relatively small effect on wound
present in the spermatozoan lactate shuttle. [La− ] (Constant et al. 2000; Sheikh et al. 2000; Ghani
et al. 2003; Trabold et al. 2003). Wound La− is raised
only marginally by hypoxaemia (Hunt et al. 1978) and
Lactate transport
hyperoxia leaves wound [La− ] essentially unchanged
Shuttling of La− among neighbouring cells, among tissues, (Sheikh et al. 2000). So what is the source of La− in wound
between tissues and blood, and among intracellular tissue and fluid? While some cells in wounds shift towards
compartments raises important questions concerning La− production in hypoxia, other cells are heavily reliant
how and at what rates La− is able to cross the on aerobic glycolysis regardless of O2 level (Ghani et al.
membranes of cells and organelles. Definitive evidence 2003; Trabold et al. 2003). For example, large amounts of
of carrier-mediated transport of La− came from studies La− are produced in rapidly multiplying cells in a process
of sarcolemmal vesicles by Roth & Brooks (1990a,b). that is not fully understood, the Warburg effect. Perhaps
They demonstrated that sarcolemmal La− transport most importantly, the ‘oxidative burst’ of leucocytes is
was concentration dependent, saturable, stereospecific, powered largely by aerobic glycolysis because leucocytes
competitively inhibited by other monocarboxylates, contain few mitochondria. This ‘oxidative burst’ produces
blocked by known inhibitors of monocarboxylate superoxide and is a key component of wound immunity.
transport, sensitive to temperature, and stimulated by Oxidant production by leucocytes accounts for about 98%
[H+ ] gradients. Since these pioneering studies, there has of the O2 consumed by activated cells and is dependent
literally been an explosion of research on membrane on P O2 up to approximately 600 mmHg. Accordingly,
transport of La− . Several excellent reviews (e.g. Halestrap La− production by leucocytes increases with increased
& Price, 1999; Juel & Halestrap, 1999; Brooks, 2000; oxygenation apparently offsetting any decrease in La−

production by fibroblasts due to the alleviation of hypoxia may promote wound healing by increasing O2 supply
(Sheikh et al. 2000; Trabold et al. 2003). to wounds because La− is a pH-independent vasodilator
What is the proposed role for La− in wound healing? (Mori et al. 1998; Trabold et al. 2003).
−
La enhances both collagen deposition and angiogenesis Trabold et al. (2003) postulated that La− effects on
(see Constant et al. 2000; Trabold et al. 2003). Hunt’s San the ADP-ribosylation pathway as described for wound
Francisco team has proposed two separate mechanisms healing may be applicable to the angiogenesis and collagen
to explain the stimulation of collagen synthesis by La− in deposition that follow exercise. This novel proposal
fibroblasts (see Ghani et al. 2003; Trabold et al. 2003 for deserves consideration and data collection.
review and references). First, La− provokes an increase Clinically, the classical explanation for increased blood
in collagen promoter activity leading to an increased [La− ] (hyperlactataemia) has been anaerobic glycolysis
procollagen mRNA production and collagen synthesis. due to insufficient O2 delivery (e.g. Mizock & Falk,
Second, La− activates prolyl hydroxylase independently 1992) and patients have been managed accordingly.
of its enhancement of collagen transcription; this enzyme Recently, James et al. (1996, 1999a,b) have offered evidence
converts proline into hydroxyproline in collagen peptide. that hyperlactataemia following injury and sepsis may
Apparently the underlying mechanism for both of in fact be the result of an adrenaline surge that
these mechanisms is the same, down-regulation of stimulates sarcolemmal Na+ –K+ -ATPase activity and
ADP-ribosylation. ADP-ribosylation is a widespread type coupled aerobic glycolysis. Persistent hyperlactataemia
of post-translation modification of proteins; in this process in the face of haemodynamic stability may reflect
the source of adenosine diphosphoribose (ADPR) is adrenaline-stimulated aerobic glycolysis rather than tissue
nicotinamide adenine dinucleotide (NAD+ ). The ADPR hypoxia (James et al. 1999a). As reviewed by James et al.
moiety can be enzymatically transferred onto certain (1999a), plasma adrenaline can be elevated for prolonged
acceptor proteins, thus modifying their structures and periods in patients who are in shock due to sepsis, trauma,
activities. In nuclei, numerous ADPR moieties can or haemorrhage. Adrenaline binds to β 2 -adrenoceptors,
be added to target amino acid residues of proteins activating adenylate cyclase, which catalyses the conversion
to form polyADPR (pADPR). In the case of wound of ATP to cAMP. In turn, cAMP activates protein
healing, it is hypothesized that pADPR down-regulates kinase A, which triggers a conformational change in the
collagen gene transcription in fibroblasts and that in Na+ –K+ -ATPase; i.e. the Na+ –K+ -ATPase is activated
a similar but separate process, ADPR inhibits prolyl (Clausen, 2003).
hydroxylase in the cytoplasm. These inhibitory effects of Central to the relationship between Na+ –K+ -ATPase
ADP-ribosylation are reversed by elevated [La− ] in the activation and increased blood [La− ] is the notion that the
following manner. High [La− ] shifts the equilibrium of ATPase pump derives its energy heavily from glycolysis that
the LDH reaction away from La− plus NAD+ and towards is compartmentalized in association with the pump (James
pyruvate plus NADH. The resulting decline in the NAD+ et al. 1999a). Such compartmentalization of glycolysis has
pool down-regulates NAD+ -mediated pADPR and ADPR, been reported for red blood cells (Parker & Hoffman,
and collagen synthesis and deposition are promoted. 1967), smooth muscle (Paul et al. 1989), and sarcoplasmic
NADH is not a substrate for the ribosylation enzymes. reticulum (Entman et al. 1980; Xu et al. 1995). In support
In the case of La− -stimulated angiogenesis in wounds, of such a scenario for the skeletal muscle Na+ –K+ -
the major pathway appears to be enhanced vascular ATPase pump, James et al. (1996) reported that aerobically
endothelial growth factor (VEGF) production in incubated muscles from septic or endotoxin-treated rats
macrophages (Constant et al. 2000; Sheikh et al. 2000; displayed an increased rate of La− production that
Ghani et al. 2003; Trabold et al. 2003). Similarly to the was partially inhibited by the Na+ –K+ -ATPase blocker,
case for collagen synthesis above, it appears that pADPR ouabain. In further studies, both adrenaline- and amylin-
inhibits the transcription and synthesis of VEGF and stimulated glycolysis and glycogenolysis by aerobically
that the activity of VEGF released from macrophages incubated rat muscles was found to be closely linked
is inhibited by covalently bound ADPR (Constant et al. to stimulation of the muscles’ Na+ –K+ -ATPase activity
2000; Ghani et al. 2003; Trabold et al. 2003). Again, it (James et al. 1999b). Finally, in a recent study (Bundgaard
is proposed that elevated [La− ] diminishes the NAD+ et al. 2003), endotoxaemia was induced in a group
pool and decreases the inhibitory effects of pADPR on of healthy human subjects. In response, both plasma
VEGF synthesis and of mono-ADPR on VEGF activity [adrenaline] and [La− ] were increased; the increased [La− ]
(Constant et al. 2000; Ghani et al. 2003; Trabold et al. was associated with a measured increase in La− release
2003). In addition to the ADP-ribosylation pathway, La− by the legs. Activation of Na+ –K+ -ATPase was suggested

by a significant decrease in plasma [K+ ] and a relative an end result of cell damage. In the same time frame,
increase in K+ uptake by the legs. There was no evidence of Myers & Yamaguchi (1977) reported the serendipitous
hypoperfusion or hypoxia. discovery that pre-ischaemic hyperglycaemia resulted in
The Cincinnati group (Luchette, James et al.) has an increase in post-ischaemic brain damage. This finding
also presented evidence that adrenaline-stimulated was easily incorporated into the lactic acidosis hypothesis;
Na+ –K+ -ATPase activity may be an important contributor more glucose provided more fuel for ischaemic glycolysis
to increased blood [La− ] during haemorrhage. In one causing higher tissue HLa levels, more severe acidosis and
study (McCarter et al. 2001), rats were bled to a mean greater nerve cell damage (Schurr, 2002). This finding
arterial blood pressure of 40 mmHg; one group of has been repeated in numerous experiments in many
these haemorrhaged rats was also administered the animal models since its initial report. This oft-verified
adrenergic blockers, propranolol and phenoxybenzamine. result became known as ‘the glucose paradox of cerebral
This adrenergic blockade significantly reduced muscle ischaemia’. The primary brain energy pathway during
La− accumulation and plasma [La− ]. In haemorrhaged ischaemia is, of necessity, glycolysis from glucose (and
rats without the blockers, the intracellular Na+ : K+ glycogen); the paradox is that an increased supply of fuel
ratio was decreased, implying an increase in Na+ –K+ (glucose) at a time when it is most needed, would also
pump activity. The intracellular Na+ : K+ ratio was higher cause greater post-ischaemic brain damage.
in the haemorrhaged rats that received the adrenergic This paradox is currently undergoing serious
blockers, suggesting that the blockade reduced pump re-examination, largely because of a series of findings
activity and thereby La− production. In a second study from Shurr’s laboratory at the University of Louisville.
(Luchette et al. 2002), microdialysis catheters were placed First, it was reported that both glucose and lactic acidosis
in the muscle of both thighs of anaesthetized rats. Rats protect neuronal tissue against hypoxia in vitro (Schurr
were then either haemorrhaged or treated with a local et al. 1987, 1988). Later studies (see Schurr & Rigor,
perfusion of adrenaline; both of these conditions caused 1998) demonstrated that La− is used as an aerobic energy
an increase in dialysate [La− ]. Local administration of the substrate by neural tissue immediately following hypoxia
Na+ –K+ -ATPase blocker, ouabain, reduced the dialysate in vitro. Even more recently, La− was found to be a critical
[La− ] response to both haemorrhage and adrenaline. The oxidative energy substrate immediately post-ischaemia
important implication is that a significant portion of in rat brain in vivo (Schurr et al. 2001). Clearly, as also
the increased La− production during haemorrhage may be outlined above with regard to the ANLSH, far from being
due to an elevated adrenaline concentration that stimulates simply a noxious agent to neural tissue, La− is often a
Na+ –K+ -ATPase pump activity and compartmentally valuable neuronal energy substrate.
associated glycolysis. Tissue hypoperfusion, hypoxia and The history of the glucose paradox of cerebral
resulting anaerobic glycolysis are probably not the only ischaemia illustrates the danger of equating correlation
causes of increased La− production during shock. with causality; post-ischaemic neural damage was almost
In summary, there is now strong evidence that without fail associated with elevated brain La− levels,
clinical hyperlactataemia can be the result of adrenaline- with more severe damage corresponding to higher La−
stimulated Na+ –K+ -ATPase activity that is fuelled by concentrations. If La− in fact is not the culprit in
coupled aerobic glycolysis. The fact that Na+ –K+ -ATPase hyperglycaemic post-ischaemic cerebral damage, what is?
activity is activated during exercise, probably by both Schurr’s laboratory has provided provocative evidence that
an increased intramuscular [Na+ ] (Nielsen & Clausen, a corticosteroid, corticosterone in rats and possibly cortisol
2000) and by increasing adrenaline concentration, invites in humans, may be the causative factor in hyperglycaemic
investigation of the possible role of pump-associated post-ischaemic damage. First, a disregarded result of the
aerobic glycolysis in the progressive increase in blood [La− ] original experiments of Myers & Yamaguchi (1977) was
during incremental exercise. brought to light (Payne et al. 2003). Myers & Yamaguchi
(1977) had reported that glucose infusion prior to cardiac
arrest caused greater post-ischaemic brain damage when
The glucose paradox of cerebral ischaemia
the infusion was terminated shortly before the cardiac arrest.
In the 1970s and early 1980s, a lactic acidosis hypothesis What was ignored was the additional result that there
of cerebral ischaemic damage was developed (Siesjo, 1981; was no aggravated brain damage when the glucose infusion
Schurr, 2002). The paradigm is simple; ischaemia leads to a was terminated 90 min prior to the cardiac arrest. Schurr
lack of O2 with resulting stimulation of glycolysis, followed et al. (2001) followed this lead with experiments in a rat
by an accumulation of HLa and concomitant acidosis with model of cardiac-arrest-induced transient global cerebral

ischaemia (TGI). They found that hyperglycaemia that was by a functionally linked aerobic glycolysis. Extra damage
induced 120–240 min prior to TGI actually reduced post- caused by hyperglycaemia preceding cerebral ischaemia
TGI neuronal damage as compared to normoglycaemia. may be the result of a corticosteroid surge instead
However, when hyperglycaemia was induced 15–60 min of lactic acidosis. Essentially unanimous experimental
pre-TGI, post-TGI neuronal damage was significantly support for the cell-to-cell lactate shuttle, along with
increased. Interestingly, brain La− levels in both mounting evidence for astrocyte–neuron, lactate–alanine,
hyperglycaemic conditions were similar and significantly peroxisomal and spermatogenic lactate shuttles strongly
higher than in the normoglycaemic condition; in other suggest that La− is an important intermediary in numerous
words, the enhanced post-TGI damage was independent metabolic processes, a particularly mobile fuel for aerobic
of the brain [La− ]. Both hyperglycaemic conditions metabolism, and perhaps a mediator of redox state among
triggered a significant increase in blood corticosterone various compartments both within and between cells.
concentration with the peak increase occurring 15–30 min La− can no longer be considered the usual suspect for
after the glucose loading and a return to baseline metabolic ‘crimes’, but is instead a central player in
concentration by 60–120 min. Pre-TGI administration of cellular, regional and whole body metabolism. Overall,
an inhibitor of corticosterone synthesis reduced post- the cell-to-cell lactate shuttle has expanded far beyond
TGI neuronal damage in both hyperglycaemic (glucose its initial conception as an explanation for muscle and
loading 15 min pre-TGI) and normoglycaemic animals. exercise metabolism to now subsume all of the other
In a subsequent study, administration of corticosterone shuttles as a grand description of the role(s) of La− in
in the same rat model of TGI caused neuronal damage numerous metabolic processes and pathways. In the words
that was comparable to that caused by glucose loading of Thomas Kuhn (1970), paradigms must be ‘sufficiently
15 min pre-TGI even though plasma glucose levels were unprecedented to attract an enduring group of adherents
normoglycaemic and not different from control levels away from competing modes of scientific activity’, and
following the corticosterone injection (Payne et al. 2003). ‘sufficiently open-ended to leave all sorts of problems
On the whole, current evidence suggests that hypotheses for the redefined group of practitioners to resolve’, an
to explain the glucose paradox of cerebral ischaemia apt description of the present state of research in La−
should now focus on the elevation of plasma cortico- metabolism.
sterone (cortisol) concentration elicited by pre-ischaemic
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J Physiol 558.

Lactate metabolism: a new paradigm

to determine which of these phosphagens might be the

Table 1. Causes of increased lactate accumulation with increasing exercise intensity

Figure 2. Illustration of a simpler intracellular (intramuscular) lactate shuttle hypothesis originally

Figure 3. Illustration of the putative astrocyte–neuron lactate shuttle

Figure 5. Illustration of the proposed peroxisomal lactate shuttle

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