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The Journal of Physiology - 2021 - Brooks - Lactate in Contemporary Biology A Phoenix Risen

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J Physiol 600.

5 (2022) pp 1229–1251 1229

TOPICAL REVIEW

Lactate in contemporary biology: a phoenix risen

George A. Brooks , Jose A. Arevalo, Adam D. Osmond, Robert G. Leija, Casey C. Curl
and Ashley P. Tovar
Exercise Physiology Laboratory, Department of Integrative Biology, University of California, Berkeley, CA, USA

Edited by: Ian Forsythe & Lykke Sylow

Cell signaling
Cell fueling

Microbiome Adaptation
The Journal of Physiology

Metabolic flexibility Reproduction

Satiety regulation Resuscitation

Lactate

Burn Anaerobic Fatigue Acid

Cramps threshold Waste
O2 debt Metabolic agent
product
poison

Abstract After a century, it’s time to turn the page on understanding of lactate metabolism
and appreciate that lactate shuttling is an important component of intermediary metabolism
in vivo. Cell-cell and intracellular lactate shuttles fulfil purposes of energy substrate production
and distribution, as well as cell signalling under fully aerobic conditions. Recognition of lactate

George A. Brooks is Professor of Integrative Biology at the University of California, Berkeley and
Docteur Honoris Causa de l’Université Montpellier. Dr Brooks has received Honor Awards from
the American College of Sports Medicine and the Exercise and Environmental Physiology Section
of the American Physiological Society. His research interests involve bioenergetics, mitochondrial
morphology, energetics and biogenesis, and the regulation of energy substrate partitioning. His work
on the lactate shuttle has influenced thinking in fields as diverse as brain and cancer metabolism.
When not in the laboratory, his focus centres on interests of family and friends. José Arevalo is a
3rd year PhD student at the University of California Berkeley investigating ageing mitochondrial fragmentation and what drives mitochondrial
dysfunction with age progression in skeletal muscle. José was born in Guatemala and grew up in the Boyle Heights neighbourhood of East Los
Angeles, California. José received his master’s degree in kinesiology from California State University Fullerton. When not in the laboratory, his
interests are football, rugby, trail running, and lifting weights.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution
and reproduction in any medium, provided the original work is properly cited.
14697793, 2022, 5, Downloaded from https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP280955 by Schweizerische Akademie Der, Wiley Online Library on [10/11/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1230 G. A. Brooks and others J Physiol 600.5

shuttling came first in studies of physical exercise where the roles of driver (producer) and
recipient (consumer) cells and tissues were obvious. Moreover, the presence of lactate shuttling as
part of postprandial glucose disposal and satiety signalling has been recognized. Mitochondrial
respiration creates the physiological sink for lactate disposal in vivo. Repeated lactate exposure
from regular exercise results in adaptive processes such as mitochondrial biogenesis and other
healthful circulatory and neurological characteristics such as improved physical work capacity,
metabolic flexibility, learning, and memory. The importance of lactate and lactate shuttling in
healthful living is further emphasized when lactate signalling and shuttling are dysregulated as
occurs in particular illnesses and injuries. Like a phoenix, lactate has risen to major importance
in 21st century biology.
(Received 5 November 2020; accepted after revision 21 January 2021; first published online 10 February 2021)
Corresponding author G. A. Brooks: 5101 Valley Life Sciences Building, Exercise Physiology Laboratory, Berkeley, CA
94720-3140, USA. Email: [email protected]

Abstract figure legend: Roles of lactate in physiology and metabolism elaborated as: cell fuelling (the preferential use
of lactate over other fuel energy substrates such as glucose, fatty and keto acids in cardiac and red skeletal muscle
and brain for cognition); cell signalling (the mechanisms by which lactate affects metabolism via effects on cell redox,
ROS production, lactylation and covalent binding); microbiome (the role of fermentation in health and disease and
the possibility of a gut-soma lactate shuttle); satiety (the role of lactate on the arcuate nucleus of the hypothalamus
and gut-hypothalamic signalling); adaptation (the role of lactate in expression of glycolytic and metabolic enzymes and
insulin sensitivity, the latter by TGF-β); reproduction (roles of lactate in sperm mitochondrial energetics, developing
a favourable microenvironment for blastocysts and secretion of VEGF for uterine angiogenesis), and resuscitation
(treatments of dehydration, acidosis, dengue, pancreatitis and hepatitis, myocardial infarction and wound healing).

Introduction a certain extent despite obvious evidence to the contrary.

Commencing with work of early 20th century Nobel prize
The story of lactate and its role in physiology and medicine winners (Hill, 1914; Meyerhof, 1920), the role of lactate
may be a century old, but has changed dramatically in in metabolism has been misunderstood and perpetuated.
the last three decades (Brooks, 1986, 2002, 2018; Gladden, Even as their cell and tissue cultures incubated in air
2004). No longer conceived of as a dead-end metabolite, often turned acidic overnight, textbook authors (e.g.
a fatigue agent, or metabolic poison, in contemporary Lehninger, 1970) perpetuated the myth of oxygen-limited
physiology, lactate is seen as a major metabolic inter- metabolism giving rise to lactate formation despite the
mediate that has wide ranging impacts in energy substrate fact that the partial pressure of oxygen in air over their
utilization, cell signalling, and adaptation; simply, lactate mitochondrial preparations and culture dishes was 3–5
is at the fulcrum of metabolic integration (Brooks, 1984, times higher than in vivo (Brooks et al. 2019). Hence, a
1986, 2020a). Now, rather than regarded as an oddity of reckoning of minds in biology is necessary to understand
exercise metabolism (Gladden, 2004; Chen et al. 2016; human and mammalian metabolism in a contemporary
Hui et al. 2017; Brooks, 2018; Ferguson et al. 2018), context.
the presence of lactate shuttling is recognized in fields Take for instance conflations of terms ‘glycolysis’ and
as diverse as wound healing (Hunt et al. 2007), cancer ‘fermentation.’ In mammalian tissues, glycolysis (i.e.
biology (San-Millan & Brooks, 2017), insulin secretion conversion of glucose and glycogen to lactate) is very
(Rutter et al. 2015), management of sepsis (Garcia-Alvarez different from aerobic fermentation of sugar to alcohol
et al. 2014a), learning and memory (Suzuki et al. 2011; El by yeast, or the production of swamp gases by anaerobic
Hayek et al. 2019), and treatment of traumatic brain injury bacteria as occurs in the colon, at wound sites or in rotting
(TBI) (Brooks & Martin, 2014). Hence, in contemporary (Brooks, 2018, 2020c; Ferguson et al. 2018). Conflation
biology, the role of lactate in metabolism needs to be of the terms perpetuates the myth of lactate poisoning
understood and viewed as a ‘phoenix risen’ (Brooks, 2002, and thus handicaps understanding of basic biology and
2018) in contrast to a remnant of (1988) early 20th century its translation. Fortunately, textbook authors are noting a
biology (Rabinowitz & Enerback, 2020). distinction between glycolysis as occurs in animals in vivo,
As scholars we have our limitations and, as a and fermentation processes that occur in microbes giving
consequence, in formal education we rely on tradition to rise to ethanol and foul gases (Urry et al. 2020).

© 2021 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society
14697793, 2022, 5, Downloaded from https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP280955 by Schweizerische Akademie Der, Wiley Online Library on [10/11/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
J Physiol 600.5 Lactate, phoenix risen 1231

Lactate shuttling: roles of driver and recipient cells beds. For instance, during exercise, fast white fibres can
provide oxidizable substrate to red, oxidative fibres in the
Like other metabolites, lactate flux between cells and
same tissue bed (Baldwin et al. 1972; Hooker & Baldwin,
tissue beds depends on concentration and hydrogen
1979). Conversely, postprandial glucose uptake in red
ion (pH) differences. Lactate exchanges between and
fibres can provide substrate to the body corpus as in the
among cells are facilitated by the presence of cell
glucose paradox (Foster, 1984). Also, working muscle can
membrane lactate transport proteins termed mono-
fuel the beating heart (Gertz et al. 1981), brain (Suzuki
carboxylate transporters (MCTs) (Garcia et al. 1994,
et al. 2011; Glenn et al. 2015a; Steinman et al. 2016) and
1995); MCTs are bidirectional symporters (Roth &
provide gluconeogenic substrates to the splanchnic organs
Brooks, 1990a,b; Brown & Brooks, 1994) sensitive to
(Bergman et al. 2000; Gerich et al. 2001).
trans-stimulation by lactate and hydrogen ion gradients.
Lactate exchanges among muscle, heart, liver and
Hence, we have the concept of glycolytic lactate producing
kidneys are obvious examples of lactate shuttling.
(driver) and lactate consuming (recipient) cells (Fig. 1).
However, are other organs involved? Some might argue
From first observations on dog gracilis muscle pre-
that the integument is the largest organ in the body,
parations that showed net lactate release at rest, an
and it is known to produce lactate under sympathetic
increased release when contractions started followed by
stimulation (Johnson & Fusaro, 1972). Hence, is there
net lactate uptake as contractions continued (Stainsby &
a skin-muscle lactate shuttle during exercise (Brooks,
Welch, 1966), the concepts of lactate driver and recipient
2018)? Similarly, the gut, the only organ of fermentation
cells could have been predicted. Subsequently, similar
in the body, produces lactate because of the presence of
results of net lactate release from resting muscle, followed
bacteria and dietary fibre in the colon may release lactate
by increased release and switch to uptake during exercise
into the systemic circulation. Hence, we can speculate
were confirmed in human muscles (Stanley et al. 1985;
on the presence of a gut to soma lactate shuttle (Brooks,
Bergman et al. 1999b). Again, from such results, the pre-
2018). As there are no obvious venous drainage vessels to
sence of lactate driver and recipient cells as part of lactate
catheterize, other methods to detect lactate exchange in
shuttling could be inferred. Not surprisingly, we now
the integument and gut will need to be found to quantify
know not only that driver and recipient cells can switch
their roles in lactate shuttling under various conditions.
roles depending on conditions, but that some cells can
exchange lactate through the interstitium and vascular

Contributions from muscle and exercise physiology

The lactate shuttle: Lactate the autocrine, (the cell-cell and intracellular lactate shuttles)
paracrine and endocrine link between glycolytic and
oxidative metabolism The cell-cell lactate shuttle. As is often the case, it is
difficult to identify a seminal moment of discovery or
publication, but from this perspective, it was results
on dog muscles made to contract in situ (Stainsby &
Welch, 1966). At rest, those highly red, richly perfused
muscles always released lactate. Then, at the onset of
contractions, lactate release increased, but then switched
to net uptake as contractions continued and oxygen
consumption rose (vide supra). So, in a kernel, we
have it, muscle lactate production under fully aerobic
conditions followed by uptake as oxygen consumption
Glycolytic Oxidative rises to meet metabolic demand. Subsequently, using
metabolism metabolism
NADH fluoroscopy, investigators (Jöbsis & Stainsby, 1968)
Lactate
verified that working muscles were not oxygen limited.
Later efforts to study working muscle lactate metabolism
(Honig et al. 1992) using myoglobin cryomicroscopy
again showed ‘aerobic glycolysis’ in working muscle.
Importantly, Gladden and associates determined effects
Figure 1. The concept of lactate shuttling between producer of exercise intensity, blood lactate concentration, O2
(driver) cells and tissues and consumer (recipient) consumption and pH on lactate production and disposal
By this mechanism lactate has autocrine-, paracrine- and
endocrine-like influences on metabolism that fulfil at least three
using arterial-venous differences ((a-v)), blood flow and
14
purposes. Lactate is: (1) a major energy source; (2) the major C-lactate measurements on resting and contracting
gluconeogenic precursor; and (3) a signalling molecule. Revised from canine muscles in situ (Gladden, 1991; Gladden et al.
Brooks (2018). 1994; Kelley et al. 2002). In their studies investigators

showed lactate turnover (production and disposal) in well above the threshold for decreased ATP production
resting and contracting, fully oxygenated and circulated (0.80 mmHg) (Kreutzer & Jue, 1995). Thus, while there
canine muscle (for reviews see Gladden, 2004; Rogatzki is no singular value that would imply a threshold for
et al. 2015). increased lactate production in human muscle or rat heart,
The advent of radiotracers and their use in physio- it is certain that lactate is formed under fully aerobic,
logy and metabolism soon showed continuous lactate normoxic conditions (Connett et al. 1990).
production under fully aerobic conditions in dogs Complimentary to determinations of lactate disposal
(Depocas et al. 1969) and rats (Freminet et al. 1974; via oxidation were those determining lactate disposal
Donovan & Brooks, 1983), with disposal during exercise via gluconeogenesis in resting postabsorptive humans.
by oxidation and conversion to glucose (Brooks & Hence, it is fair to state that while most lactate disposal
Donovan, 1983). Moreover, in studies on rats recovering is accomplished via oxidation, with a minority of
from exercise, the so called ‘oxygen debt’ (now referred to lactate disposal accomplished via gluconeogenesis under
as EPOC: Gasser & Brooks, 1984) period showed oxidative postabsorptive resting conditions, lactate is the most
disposal (4/5) predominating over gluconeogenesis and important gluconeogenic precursor during rest and
glyconeogenesis (1/5) (Brooks et al. 1973; Brooks & exercise (Stanley et al. 1988; Bergman et al. 2000; Gerich
Gaesser, 1980; Gaesser & Brooks, 1980). Compared to et al. 2001)
the classic results of Meyerhof on isolated frog muscle In sum, the above-cited work shows continuous aerobic
preparations ex vivo (Meyerhof, 1920), results on rats in (not oxygen-limited) lactate turnover (production and
vivo upended the long-held idea that after exercise 4/5 of disposal) in humans and mammalian model systems.
the lactate produced during contractions was restored to Further, the work shows two of three features of the lactate
muscle glycogen in situ. shuttle – lactate production in driver cells and disposal in
Initial efforts to study lactate-glucose interactions in recipient cells and tissues; signalling being a third feature
humans involved (a-v) and blood flow measurements of the lactate shuttle (Brooks, 2000, 2002, 2018). Hence,
across working muscle and splanchnic tissue beds we now realize that lactate produced in working muscle is
(Ahlborg & Felig, 1982; Wahren & Ekberg, 2007). a major fuel energy source (Stanley et al. 1986; Bergman
Such experiments are highly invasive and difficult to et al. 1999b), but also that lactate release from working
conduct and interpret. Nonetheless, the significance muscle fuels other organs such as the heart (Gertz et al.
of the technologies employed and lessons learned 1988; Bergman et al. 2009b) and brain (Glenn et al. 2015a)
from those difficult experiments showing inter-organ normally, but also in illness and following injury (Marik
metabolite exchanges in resting and exercising humans & Bellomo, 2013; Brooks & Martin, 2014; Garcia-Alvarez
are noteworthy. et al. 2014b). Moreover, lactate released from working
The advent of stable, non-radioactive tracers and their muscles (Stanley et al. 1986; Bergman et al. 1999b) and
use in physiology and metabolism soon replicated what other driver cells such as the integument is the major
was shown in mammalian models (Stanley et al. 1985, gluconeogenic precursor (Stanley et al. 1988; Bergman
1986; Mazzeo et al. 1986). Subsequently, combined use et al. 2000) (Fig. 2).
of (a-v) differences and blood flow, as well as iso-
topic tracers, showed simultaneous lactate production and
oxidative disposal within resting and working human The intracellular lactate shuttle (ICLS). The above-cited
skeletal muscles (Stanley et al. 1986; Bergman et al. 1999b). studies using infused 13 C-lactate and observing 13 CO2
More recently, the same technologies have been employed excretion from resting and working muscles show
to show lactate turnover (production, net uptake and simultaneous lactate uptake, production, and oxidation
oxidative disposal) in the heart (Gertz et al. 1981, 1988; in vivo (Stanley et al. 1986; Bergman et al. 1999b).
Bergman et al. 2009b) and brain (Glenn et al. 2015a).In However, those studies do not provide information on
their studies of muscle lactate metabolism Richardson the intracellular path of lactate oxidation. Hence, studies
and colleagues made ingenious use of repeated studies of on isolated mitochondria (Brooks et al. 1999c, 1999d;
muscle net balance ((a-v) and blood flow) and nuclear Dubouchaud et al. 2000; Hashimoto et al. 2006, 2008;
magnetic resonance (NMR) to determine intracellular PO2 Atlante et al. 2007; Passarella et al. 2008, 2014) and
from the myoglobin spectrum (Richardson et al. 1998). muscles (Park et al. 2015) were called for.
Their results showed lactate production in, and release To understand mitochondrial lactate oxidation in
from, resting and exercising muscle when intracellular vivo, one needs to appreciate that the cellular respiratory
PO2 was significantly above the critical mitochondrial apparatus is composed not of discrete vesicles (i.e.
oxygen tension as previously determined (Wilson et al. mitochondria), but rather an extensive network, a
1988). Similarly, with their MRS experiments on rat heart mitochondrial reticulum (Bakeeva et al. 1978; Kirkwood
preparations, Kreutzer and Jue demonstrated myocardial et al. 1986, 1987) that extends from the sub-sarcolemmal
lactate formation above an intracellular PO2 that was domain to deep within fibres, that represents an ‘energy

highway’ (Glancy et al. 2015). To oxidize energy products

of glycolysis, the reticulum contains both lactate (mMCT)
(Brooks et al. 1999c) and pyruvate (mPC) transporters
(Bricker et al. 2012; Herzig et al. 2012). Importantly,
because the product of glycolysis is lactate, not pyruvate
(Rogatzki et al. 2015), mitochondrial uptake and oxidation
far exceeds that of pyruvate. Hence, studies of muscle
lactate oxidation led to discovery of the mitochondrial
Brain lactate oxidation complex (mLOC) in vivo.
In terms of functionality, the mLOC contains several
essential components of lactate oxidation: an MCT, its
membrane chaperone Basigin (BSG or CD147), lactate
Mixed venous
(Pulmonary artery) Lac Gluc dehydrogenase (LDH), and cytochrome oxidase (COx) as
seen in muscle (Hashimoto et al. 2006), liver (De Bari
et al. 2004; Passarella et al. 2014), and brain (Hashimoto
et al. 2008), and various model systems such as brain slices
Lungs (Schurr, 2008), primary neuronal cultures (Atlante et al.
2007; Hashimoto et al. 2008), normal breast and trans-
formed breast cancer cells (Hussien & Brooks, 2011), and
tumours (Sonveaux et al. 2008). Colocalization of MCTs,
LDH and COx has been seen in muscles (Hashimoto et al.
Pulmonary 2005, 2007, 2013), brain (Hashimoto et al. 2008), lung
vein
(Systemic (Johnson et al. 2012), and cancer cells (Hussien & Brooks,
Heart
arterial) 2011).
Confirmation of the preference of mitochondrial lactate
over pyruvate oxidation comes from studies of hyper-
Lac Gluc
Lac Gluc polarized lactate in muscles in situ (Park et al. 2015). So
Coronary Lac Gluc far as mitochondrial pyruvate transport and oxidation are
sinus Lac Gluc concerned, it is known that the putative mPC colocalizes
Lac with mitochondrial MCT1 in L6 myocytes. In preliminary
studies, colocalization analysis of mMCT1 and mPC1
Liver
using Imaris software revealed that both MCT1 and mPC
Gluc Lac are co-localized to the mitochondria (r2 = 0.8) (Brooks,
2020c). However, because muscle lactate concentration
Glycogen exceeds that of pyruvate by one (10×) to two (200–400×)
Lac Lac Gluc orders of magnitude in resting and exercising human
muscles, respectively (Henderson et al. 2004), lactate
Lactate Glycogen + Glucose
oxidation is dominant in vivo.
Integument and muscle As will be discussed in more detail later, an important
feature of lactate shuttling is that it affects cell redox
in both driver and recipient cells, and between cell
compartments. At present there is discussion over
whether the ICLS functions independently of or
cooperatively with longer established malate-aspartate
and glycerol phosphate shuttles (Kane, 2014). Given
Figure 2. Illustration of lactate shuttling during exercise (the redundancies in physiological control systems, it may be
cell-cell lactate shuttle) that cytosolic-to-mitochondrial shuttles work in parallel
Lactate released from muscles, skin and other driver cells provides to manage the lactate load and balance cell redox during
energy for working muscles (Stanley et al. 1986; Bergman et al. exercise and other conditions. Using CRISPR knockout
1999b), heart (Gertz et al. 1981, 1988; Bergman et al. 2009b) and
brain (Glenn et al. 2015a). Moreover, lactate released from working
technology in mouse or other mammalian models may
muscles (Stanley et al. 1986; Bergman et al. 1999b) and other driver provide missing data on the relative uses of specific
cells such as adipose tissue is the major gluconeogenic precursor intracellular redox shuttles under particular physiological
(Stanley et al. 1988; Bergman et al. 2000) and brain fuel, even after circumstances (Kane, 2014).
injury when lactate supplementation may be efficacious (Brooks &
Martin, 2014). Revised from Brooks (2018).

Lactate shuttling as a basis for the lactate threshold glycogen synthesis is to be contrasted with the ‘direct’
in physical exercise. It has been half a century since pathway in which dietary glucose from the gut is taken up
introduction of the concept of oxygen-limited metabolism and converted to liver glycogen on first circulatory pass
producing an ‘anaerobic threshold’ (AT), that is, O2 (Fig. 3).
limited metabolism during exercise of a particular The initial concept developed from studies on lab
intensity. The subject has been recently reviewed (Poole animals has been replicated in human subjects showing
et al. 2021). With 1541 citations (Web of Science, 27th both indirect and direct liver glycogen synthesis in healthy,
September, 2020) the paper of (Wasserman & McIlroy, postprandial humans. However, the balance of indirect
1964) is the eighth most cited paper of all time in the and direct glucose conversion appears to be species
Journal of Applied Physiology. As recited in the recent related. Results of Gerich and colleagues in human sub-
review (Poole et al. 2021), in a letter from Karlman jects confirm that glycolysis is the main initial post-
Wasserman to this author, the concept of an ‘anaerobic prandial fate of glucose, accounting for ≈66% of over-
threshold’ was based on the assumption that ‘failure of all disposal, while oxidation and storage each accounted
the heart to transport O2 adequately would result in for ≈45%. However, the majority of hepatic glycogen
lactic acidosis’, an event that would trigger ventilatory synthesis in postprandial humans (≈73%) was formed via
compensation. Subsequently, concepts of anaerobic, the direct pathway (Woerle et al. 2003). In the near future
lactate, ventilatory and other related thresholds (e.g. it should be possible to better understand the issue of
OBLA) are pervasive in the literature and have represented influences of diet and other factors on the balance of direct
key concepts in basic and applied physiology, sports and vs. indirect liver and muscle glycogen synthesis in humans
pulmonary medicine. These thresholds are determined using 13 C-tracers and magnetic resonance spectrometry
by turnpoints in the rise in blood lactate concentration, (Stender et al. 2020).
pulmonary minute ventilation, and heart rate during While considered to be a homogenous ‘organ system,’
graded exercise. In a PubMed (National Library of muscle is in fact a heterogeneous tissue containing
Science) search on 20th October, 2020 the term ‘anaerobic different types of muscle fibres, and circulatory and
threshold’ elicited 5902 citations. In their review, Poole connective tissue networks, all with different metabolic
et al. explain that while the basic tenant of the AT (i.e. characteristics (Barnard et al. 1970, 1971). Postural
oxygen-limited metabolism) in exercise is no longer muscles (e.g. soleus, erector spinae) are alternatively
acceptable, use of the ‘gas exchange threshold’ (GET) termed intermediate (i.e. pink, not red or white), or Type
in graded exercise possesses significant importance I fibres. In many species deep vastus and lateral gastric are
for cardio-pulmonary and other types of evaluation in bright red and termed red or Type IIA fibres. In contrast
patients (Poole et al. 2021). white, fast twitch fibres are termed Type IIX (in humans)
In sum, intracellular lactate disposal is accomplished or IIB (in rodents). Hence, results of the above-cited
by a transport mechanism for direct mitochondrial studies on the glucose paradox are complimented by
uptake and oxidation that involves a mLOC which results of studies showing greater postprandial perfusion
probably works in parallel with malate-aspartate, and glucose uptake in muscles containing predominantly
glycerol-phosphate and other shuttles to balance cell oxidative Type I and IIA fibres than in muscles containing
redox and manage the lactate load from glycolysis under predominantly Type IIB/X fibres (James et al. 1985, 1986).
normal and stressful conditions (Brooks, 2020c). Redundancy of terminology in science is confusing, but
the glucose paradox can also be thought of as a post-
prandial lactate shuttle.
Contributions from studies of postprandial
metabolism: the glucose paradox (indirect pathway
of liver glycogen synthesis) and the postprandial Phasic lactate shuttling: lessons from the heart. Tracer
studies allow us to know that the heart produces lactate
lactate shuttle
even as it acts as a lactate sink displaying net uptake
The glucose paradox. Studies of postprandial glucose from the arterial circulation (Gertz et al. 1988; Bergman
metabolism on rodent models and humans show what has et al. 2009b). Assessing cardiac metabolism in humans is
been termed the ‘glucose paradox,’ or ‘indirect pathway difficult at best and is complicated by the cardiac cycle.
of hepatic glycogen synthesis’ (Foster, 1984). This concept If it is true that even in a healthy heart systole interrupts
states that dietary glucose released into the hepatic portal coronary blood flow, especially in the endocardium, then
vein initially bypasses the liver and goes to the periphery, the presence of a phasic intra-cardiac lactate shuttle is
where glycolysis converts glucose to lactate that is sub- indicated. Assuming a resting heart rate of 60 bpm, then
sequently released into the central venous circulation and systole followed by diastole occurs once per second. This
taken up from the arterial circulation by liver for glycogen could mean that there occurs 200 ms of stopped flow
synthesis. This, paradoxical, ‘indirect’ pathway of hepatic during the isometric phase of systole which is powered

Brain

Lac Gluc

Postprandial
mixed venous
(Pulmonary artery)

Lungs

Pulmonary vein
(Systemic arterial)
Heart
Lac Gluc
Lac Gluc

Coronary
Lac Gluc
sinus
Lac Gluc
Lac
Gluc Gut Glucose
Liver

Gastrointestinal
tract
Glycogen Lac

Lac

Lactate Glycogen + Glucose

Gluc
Integument and muscle

Figure 3. Illustration of lactate shuttling after consuming dietary carbohydrate: the postprandial period
(the postprandial lactate shuttle)
Depending on liver glycogen content some dietary glucose bypasses liver and enters the systemic circulation. From
there glucose is taken up by non-contracting muscles, particularly red and intermediate fibres (James et al. 1985,
1986). Glycolysis in these and other driver tissues results in lactate release into the central venous circulation
and uptake by the recipient liver from the arterial circulation. Paradoxically, this circuitous, ‘indirect pathway,’ is
preferred over glucose for hepatic glycogen synthesis (Foster, 1984). In contrast, glucose from dietary consumption
or digestion or carbohydrate in the GI tract can be taken up by liver on the first circulatory pass for ‘direct’ glycogen
synthesis. Again as indicated in Fig. 2, lactate released from driver cells and tissues supports cerebral metabolic
needs (Glenn et al. 2015a,b) and functions such as glutamatergic signalling (Pellerin & Magistretti, 1994). Similarly,
systemic lactate and fatty acids from digestion serve as an energy source for the heart (Bergman et al. 2009a,b).
Figures 2 and 3 illustrate the extent of lactate shuttling under diverse conditions.

by glycolysis, followed by 800 ms of diastole for oxidative prandial splanchnic lactate release in humans following
recovery and lactate clearance. Then heart rate increases the ingestion of one carbohydrate energy source, fructose.
during exercise, and time for the T-P interval decreases, so In sum, like the event of physical exercise in which
also does the time for restoration of myocardial blood flow lactate plays a prominent role in energy substrate
and intra-cardiac oxidative metabolism decrease. Again, production and disposal, lactate also plays an important
as with the hypothesis of gut lactate shuttling, the pre- role in carbohydrate distribution and disposal after
sence of an intra-cardiac lactate shuttle would be difficult eating. Hence, whether after a meal when glycogen
to prove because even coronary sinus sampling would be storage is prominent, or during post-absorptive exercise
insufficient to determine phasic events. Hopefully in the when glycaemia is supported by hepatic glycogenolysis
future, hyperpolarized MRS (Park et al. 2015) or other and gluconeogenesis, lactate plays important roles in
technologies will allow for detection of lactate production, carbohydrate (CHO) energy substrate distribution
net uptake and oxidative disposal within a cardiac cycle. (Brooks, 2020b). The issue of GI lactate production is
For the present, perhaps the best evidence of a phasic, addressed further in the section on the microbiome
intra-cardiac lactate shuttle may come from the lactate below.
threshold/turn point field in which a steep rise in blood
lactate occurs at 90% of maximal heart rate (Hofmann Lower gut: the microbiome. The possibility of
et al. 1994). Even in the healthy hearts of athletes with participation of the gut microbiome in lactate shuttling
high heart rates, there simply may be inadequate time for and a gut-soma lactate shuttle has previously been
intra-myocardial lactate disposal plus a burden of systemic suggested (Brooks, 2018, 2020a), but we are in the early
blood lactate clearance. stages of discovery. Support for the idea is to be found
in diverse sources. From epidemiology, we know that
regular physical exercise is beneficial for reducing risks
Can the splanchnic bed be a source of lactate? of many common cancers including those of the colon
(Powell et al. 2018). Also, from nutrition science we know
Upper gut: the liver. Classically, the liver removes lactate
that pre- and pro-biotic dietary components favourably
from the circulation and converts it to glucose for release affect gut fermentation and health (Hill et al. 2014) and
into the systemic circulation (Cori & Cori, 1946), or data indicate relationships between microbiota and the
converts lactate to liver glycogen (Nilsson & Hultman, prevalence of insulin resistance and metabolic syndrome
1974). But, can the liver, or splanchnic bed as a whole (Vrieze et al. 2012). The concentration of lactate in
contribute lactate to the systemic circulation? Evidence for human faeces is relatively low (< 5 mm) because of
splanchnic lactate production is sparse. the presence of bacteria that convert lactate to butyrate
Hepatic release from dog liver under glucagon (Duncan et al. 2004). More recently, we have learned that
stimulation was not seen (Wasserman et al. 1984). physical exercise and physical fitness encourage diversity
However, after glucose ingestion in rats with indwelling of species including those that act to convert lactate to
portal vein catheters, a porto-peripheral lactate gradient butyrate (Estaki et al. 2016, 2020). Recently also, the pre-
was present, reflecting the production of lactate in or by sence of ‘performance-enhancing’ gut microbes, members
the intestine (Smadja et al. 1988). Unfortunately, because of the genus Veillonella, in the stools of marathon runners
studies on humans would involve hepatic portal vein (Scheiman et al. 2019) have been found. Unfortunately,
catheterization, an invasive procedure not known to be those investigators were unaware of the importance of
associated with any disease state, and hence probably lactate shuttling during exercise, and did not consider a
ethically unjustified, we know of no report of hepatic scenario in which the gut supplies lactate, a fermentation
or splanchnic net release during postprandial exercise. product that is exported via sodium-mediated mono-
However, because the phenomenon of splanchnic lactate carboxylate transporters (sMCT) (Coady et al. 2004;
release has not been observed, it doesn’t necessarily follow Teramae et al. 2010), thus supporting athletes’ efforts by
that the phenomenon fails to exist. fuelling working muscles as opposed to clearing lactate
In addressing the issue of upper gastrointestinal from the circulation.
(GI) lactate production in humans, consideration of
the carbohydrate energy form may be helpful. Using
combinations of glucose, fructose and lactate tracers to Lactate controls lipid metabolism: the role of lactate
evaluate the use of oral carbohydrate energy sources in
in metabolic flexibility and the crossover concept
sports drinks investigators in the Tappy lab (Lecoultre
et al. 2010; Theytaz et al. 2014) observed carbon Lactate from working muscle (Bergman et al. 1999b) or
atoms from an orally ingested fructose tracer appearing other tissues such as the integument (Johnson & Fusaro,
in the systemic circulation as labelled lactate. Hence, 1972) has short-term effects on lipid metabolism by down-
counter to classic thought, there is evidence for post- regulating both lipolysis and mitochondrial free fatty

acid entry and oxidation. In contrast, chronic exercise Lactate shuttling and metabolic signalling
exposure, as with endurance training, improves capacities
The effects of increases in cell work and lactate production
to maintain glycaemia and lipid oxidation by improving
on redox, reactive oxygen species (ROS), allosteric
the ability to clear lactate by oxidation (Bergman et al.
binding, and histone lactylation have been recently
1999b) and gluconeogenesis (Bergman et al. 2000), as well
reviewed (Brooks, 2020a). Briefly, cell work leads to lactate
as acting as a pseudo-myokine (Takahashi et al. 2019)
production and changes in the cellular lactate/pyruvate
(vide infra). The role of lactate in affecting energy substrate
ratio (Henderson et al. 2007) that accompanies changes
partitioning in exercise and other conditions is imbedded
in the cellular NAD+ /NADH ratio and subsequent
in concepts of ‘crossover’ (Brooks & Mercier, 1994) and
metabolic and regulatory effects in driver and recipient
metabolic flexibility (Kelley et al. 1999; Goodpaster &
cells (vide supra). Importantly also, additional lactate
Sparks, 2017; San-Millan & Brooks, 2018). In the case of
signalling mechanisms have been revealed.
lactate and lipolysis in adipose tissue, during hard exercise
inverse relationships between blood lactate and plasma
free fatty acid concentration [FFA] in humans (Brooks Cell redox. As described above, muscle contraction
& Mercier, 1994) and other mammals (Issekutz & Miller, causes major changes in the L/P and NADH/NAD+ ratios.
1962; Rodahl et al. 1964) have long been recognized. Also, In driver cells that change allows glycolysis to proceed
lactate infusion into running dogs caused the circulating via providing NAD+ for GAPDH, but also by reducing
[FFA] to decline (Issekutz & Miller, 1962; Gold et al. 1963; pyruvate to lactate in the cytosol, which creates a driving
Miller et al. 1964). In those investigations an effect of force for mitochondrial substrate oxidation. In contrast,
lactate on circulating [FFA] could be clearly observed, in recipient cells uptake of lactate raises the NADH/NAD+
but whether the mechanisms involved hydrogen ions or ratio, thus downregulating glycolysis. This preferential use
lactate anions was not assessed. of lactate over endogenous cellular energy sources reduces
The mechanism by which lactataemia suppresses oxidation of glucose in muscle (Miller et al. 2002a,b) and
circulating FFAs is now known to be due to suppression of heart (Wisneski et al. 1987; Gertz et al. 1988; Bergman
adipose lipolysis by lactate binding to hydroxycarboxylic et al. 2009a).
acid receptor 1 (HCAR-1), formerly known as G-protein Moreover, aside from the major effects of muscle
coupled receptor 81 (GPR-81), independently of changes contraction and glycolysis on energy substrate
in pH (Cai et al. 2008; Ge et al. 2008; Liu et al. 2009; Ahmed partitioning, glycolysis leading to lactate production
et al. 2010). Signalling effects of lactate on HCAR-1 are and resulting change in cytosolic NADH/NAD+ also
further discussed below. effects the status of other redox couples such as the ratio
of reduced to oxidized glutathione (GSH/GSSG) (Gohil
Lactate and pyruvate as inhibitors of mitochondrial et al. 1988; Viguie et al. 1993).
β-oxidation. When glycolysis is accelerated during
muscle contraction, lactate (L) and pyruvate (P) ROS. Lactate can raise cellular production of ROS via
concentrations rise and increase the L/P ratio, (Bergman mitochondrial respiration (Powers et al. 1999; Passarella
et al. 1999b; Henderson et al. 2004) reducing cytosolic et al. 2008) and non-enzymatically via lactate-iron inter-
redox (Brooks, 2020a). At rest, the L/P ratio in muscle actions that are capable of generating ROS (Wagner et al.
and venous effluent from a muscle bed approximates 10, 2004). Another way in which lactate can affect ROS
but the ratio rises more than an order of magnitude (≥ production is via generation of hydrogen peroxide (H2 O2 )
30×) during moderate intensity exercise (Henderson (Passarella et al. 2008). The latter mechanism involves
et al. 2004). By mass action the monocarboxylate generation of H2 O2 via a flavine-dependent lactate oxidase
pair floods into the mitochondrial reticulum (Saddik located in the mitochondrial intermembrane space (de
et al. 1993; Brooks et al. 1999b; Passarella et al. 2008), Bari et al. 2010).
giving rise to acetyl-CoA and, thereby, malonyl-CoA
formation. The rise in malonyl-CoA inhibits the entry of Sirtuins. Sirtuins are deacetylases regulated by the
activated FFAs into the mitochondrial matrix by inhibiting equilibrium between nicotinamide (NAM) and NAD+ .
carnitine-palmitoyl transferase-1 (CPT1) (McGarry et al. Sirtuin activation is accomplished via changes in cell redox
1977; Saddik et al. 1993). As well, the effect of glycolysis (i.e. the NAD+ /NADH) through the concentration of
driving an accumulation of acetyl-CoA downregulates NAM and the activity of the enzyme NAM phosphoribosyl
β-ketothiolase, the terminal and rate-limiting enzyme transferase (Nampt). Many investigators are concerned
of the mitochondrial β-oxidation pathway. Hence, by with how the subtle changes in cell redox affect cell
mass action, allosteric binding and effects on cell redox, homeostasis as occur in apoptosis, inflammation, and
lactate acts to prevent entry of activated fatty acids into other processes. However, more obvious are changes
the matrix of the mitochondrial reticulum, thus limiting in cell redox with increments in cell work as occur in
β-oxidation of fatty acid derivatives. exercise. At present, data are lacking on the change

in Nampt activity in working muscle or non-working lactate transporter 2 (Mrs2). Investigators observed
recipient tissues in which changes in NAD+ and NADH that a surge in mitochondrial Mg2+ uptake promotes
concentrations are likely to affect sirtuin regulation in inflammation and organ failure by interfering with
vivo. mitochondrial energetics. In contrast, suppression
of the mMg2+ surge alleviates inflammation-induced
Hydroxycarboxylic acid receptor 1 (HCAR-1). The multi-organ failure. Together, these findings reveal that
mechanism by which lactataemia suppresses circulating lactate mobilizes intracellular Mg2+ and links the mMg2+
FFAs is now known to be due to suppression of adipose transport machinery with major metabolic feedback
lipolysis (Ahmed et al. 2010). Independently of pH, circuits and mitochondrial bioenergetics (Daw et al.
lactate inhibits lipolysis in fat cells through activation of 2020). Hence, on the basis of the work by Daw et al., it is
HCAR-1 (vide supra). In studies of mouse, rat, and human apparent that, in addition to mass action, redox control,
adipocytes, HCAR-1 appears to act as a lactate sensor and ROS generation, lactate may affect mitochondrial
with the inhibitory effect on lipolysis operating through energetics in other ways such as by Mg2+ release from
cyclic AMP (cAMP) and cAMP response element binding endoplasmic reticulum.
(CREB) (Ahmed et al. 2010; Bergersen, 2015). The purported effects of lactate signalling HCAR-1,
TGF-β2, Nampt, mMg2+ and lactylation of histones
observed in rodent and cell models await validation in
Transforming growth factor beta 2 (TGF-β2). The
humans. However, for the present, it is certain that lactate
effects of lactate on inter-organ signalling and dual
both inhibits lipolysis and mitochondrial FFA oxidation
or multiple effects of lactate signalling is illustrated by the
in the short-term and in the long-term stimulates
recent discovery that transforming growth factor beta 2
mitochondrial biogenesis and glucose tolerance and lipid
(TGF-β2) is secreted from adipose tissue in response to
oxidation in in vivo (Takahashi et al. 2019). Therefore, the
lactate released from working muscle (Takahashi et al.
new results are encouraging as the signalling patterns are
2019). Because TGF-β2 improved glucose tolerance
consistent with what is known about the roles of lactate in
in mice, the authors concluded that exercise training
physiology and metabolism.
improves metabolic regulation through an inter-organ
(adipose to liver) communication via a ‘lactate-TGF-β2
signalling cycle.’ If validated on studies of human subjects,
A plethora of lactate shuttles and diverse roles in
TGF-β2 could be classified as an ‘adipokine,’ and lactate
physiology and metabolism
could be thought of as a ‘pseudo myokine’ and the value
of enhancing lactate clearance during exercise by end- Since recognition of the presence of lactate shuttling
urance training further emphasized (Donovan et al. 1983; within and among various cells, tissues and organs such
Bergman et al. 1999b; Messonnier et al. 2013). In this as muscle, heart and liver (Brooks, 1984, 1985, 1986, 2002,
context both short- and long term-effects are illustrated 2018), the concept has been extended to include other
because lactate is known to suppress lipolysis in adipose cells, tissues and organs such as brain (Pellerin et al. 1998;
via HCAR-1 and CREB (vide supra). Liu et al. 2017), lung (Johnson et al. 2011, 2012), sperm
(Storey & Kayne, 1977; Boussouar & Benahmed, 2004),
Lactylation of histones. Regulation of gene expression adipose tissue (Cai et al. 2008; Liu et al. 2009; Ahmed et al.
by lactylation of 28 lysine residues on histones has 2010), and peroxisomes (McClelland et al. 2003). The pre-
been demonstrated (Zhang et al. 2019). The addition sences of multiple lactate shuttles with diverse functions in
of lactate in addition to phosphate, methyl and acetyl physiology has been recently summarized (Brooks, 2009),
tags to histones is yet another epigenetic way by which but for completeness the following are mentioned.
the genome and intermediary metabolism are regulated.
As noted above, lactate release from driver cells into The astrocyte-neuron lactate shuttle and brain
the circulation, as occurs in physical exercise and other functioning. Lactate shuttling between astrocytes and
stressful conditions, has the potential for epigenetic neurons linked to glutamatergic signalling was recognized
modifications in diverse cells around the body during and by Pellerin, Magistretti and colleagues who used the term
after physical exercise. ‘astrocyte-neuron lactate shuttle’ (ANLS) (Magistretti
et al. 1999). Since its introduction and further exposition
Lactate, endoplasmic reticulum Mg2± release and (Pellerin & Magistretti, 2012), the concept has remained
mitochondrial function. Recently, Daw et al. in the controversial (Patel et al. 2014). However, subsequent
Madesh lab (Daw et al. 2020) showed that lactate is an studies show wide expression of brain MCTs (Pellerin
activator of Mg2+ release from endoplasmic reticulum et al. 2005) and support the presence of an ANLS.
(ER). ER Mg2+ release facilitates mitochondrial Mg2+ While cerebral lactate flux may be related to
(mMg2+ ) uptake, a process facilitated by magnesium glutamatergic signalling (Pellerin & Magistretti, 1994),

there are other processes that are related to lactate downregulates Toll like receptor induction of the pyrin
shuttling. For instance, in health and after injury (Glenn domain-containing protein 3 (NLRP3) inflammasome
et al. 2015a), as well as during physical exercise (van Hall and production of IL1beta, via Arrestin beta 2 (ARRβ2)
et al. 2009; Hashimoto et al. 2018), the brain takes up and and HCAR-1, was the mechanism by which lactate
oxidizes lactate from the systemic circulation. In such suppressed inflammation in patients with acute organ
cases, the lactate shuttle concept holds true and explains injury. Because of the above, the science and translation of
the exchange between muscle lactate driver and brain lactate shuttling in inflammation needs further attention.
recipient cells.
Characteristics of cellular lactate uptake such as
The peroxisomal lactate shuttle and β-oxidation.
stereo-specificity, concentration and pH dependence,
Peroxisomes are cellular organelles found in virtually
saturation, trans-stimulation and inhibition by
all eukaryotic cells that are involved in catabolism of
competitive and non-competitive inhibitors were
substances such as very long chain (i.e. C22 and longer)
recognized early on (Watt et al. 1988; Roth & Brooks,
fatty acids, branched-chain fatty acids, d-amino acids,
1990a,b; Brown & Brooks, 1994). Since MCT iso-
polyamines, and reactive oxygen species such as hydrogen
forms were cloned and sequenced (Garcia et al. 1994,
peroxide (H2 O2 ) (Gladden, 2004). While it was known
1995; Price et al. 1998) and then studied in vitro, it
that β-oxidation of very long-chain fatty acids occurred
has been appreciated that MCTs facilitate movement
in mammalian peroxisomes (Lazarow & De Duve,
of monocarboxylates other than lactate (e.g. pyruvate,
1976), in the absence of enzyme systems such as exist
β-hydroxybutyrate and acetoacetate) across biological
in the mitochondrial matrix, it was not understood how
membranes. However, for at least two sets of reasons,
β-oxidation could occur in peroxisomes. Key findings
these other monocarboxylates are of lesser physiological
were those of Baumgart et al. (1996), who showed the
importance in terms of carbon-energy transfer. First,
presence of peroxisomal LDH isoforms, and McClelland
other monocarboxylates do not compete as well as lactate
et al. (2003), who confirmed the presence of peroxisome
for exchange by MCTs because of Michaelis-Menten
LDH and further demonstrated that rat liver peroxisomal
kinetic properties (Roth & Brooks, 1990a,b). Secondly,
membranes contained MCT1 and MCT2. From there,
physiological levels of lactate exchange competitors are far
it was possible to hypothesize that peroxisomal redox
less abundant (Zinker et al. 1990; Bergman et al. 1999b;
control necessary to support β-oxidation involved a
Henderson et al. 2004). Importantly, from a physio-
lactate-pyruvate shuttle. Discovery of the peroxisomal
logical standpoint, MCTs do not create the conditions for
lactate shuttle involving pyruvate-lactate conversion
lactate exchange; rather, MCTs facilitate carbon exchange
linked to changes in the NADH/NAD+ redox couple
between loci of driver processes such as glycolysis and
emphasizes the critical importance of redox changes in all
glycogenolysis and recipient loci where processes such
forms of lactate shuttles.
as mitochondrial respiration and gluconeogenesis are
responsible for lactate consumption (Brooks, 1984, 2002).
Hence, it is appropriate to recognize the importance of Spermatogenic and Sertoli-germ cell lactate shuttles.
MCTs in cerebral lactate shuttling in cognition, learning, It has been known for decades that mammalian
memory and other executive functions (Holloway et al. spermatozoa use lactate as an aerobic energy source
2007; Suzuki et al. 2011; Steinman et al. 2016; Hashimoto (Storey & Kayne, 1977). Noteworthy also is that in their
et al. 2018; El Hayek et al. 2019). seminal papers on the discovery of MCT1 and MCT2
Garcia et al. (1994, 1995) observed high expression of
Lactate and inflammation. Other than acknowledging MCT1 in sperm heads as they entered the epididymis,
its complexity, the role of lactate in promoting or followed by lower expression of MCT1 expression as
suppressing inflammation is incompletely understood at sperm coursed through the epididymis. It was also noted
present. As mentioned above, Daw et al. have provided that lactate stimulates respiration in ejaculated bovine
evidence that lactate-induced Mg2+ release from ER sperm (Halangk et al. 1985), and further that lactate
affects mitochondrial energetics and could be involved in maintains bovine sperm motility when maintained ex
cell death and organ systems failure (Daw et al. 2020). vivo (Inskeep & Hammerstedt, 1985). By analogy, just as
In contrast, others have provided evidence that -lactate fast twitch-glycolytic driver muscle fibres fuel adjacent
containing solutions have efficacy as resuscitation fluids slow twitch-oxidative muscle fibres, Sertoli cells in testes
for use in a variety of conditions including metabolic secrete lactate to fuel sperm motility in vivo. In effect
acidosis (Brooks, 2018), acute pancreatitis (Wu et al. 2011; then, the Sertoli-sperm cell relationship is the primal
Hoque et al. 2014), hepatitis (Hoque et al. 2014), sepsis demonstration of cell-cell lactate shuttling. In sperm, the
(Garcia-Alvarez et al. 2014b) and dengue fever (Somasetia mitochondrial reticulum is elaborate, large and spiral
et al. 2014). In terms of mechanism, Hoque and colleagues shaped, located at the midpiece (Storey & Kayne, 1977)
(Hoque et al. 2014) found that lactate binding to HCAR-1 at the base of the sperm head. The ability of sperm

mitochondria to oxidize exogenously supplied lactate the TCA cycle (Bertocci & Lujan, 1999). Also, using
31
(Jones, 1997) is analogous to capacities for mitochondrial P MRS to study muscle metabolism in patients with
lactate oxidation in other tissues (Baba & Sharma, 1971; McArdle disease, a knock-out experiment of Nature
Kline et al. 1986; Brandt et al. 1987; Brooks et al. 1999a; involving phosphofructokinase (PFK) deficiency, lactate
De Bari et al. 2004). infusion was shown to improve muscle force output and
energy status in terms of higher phosphocreatine (PCr)
Not a few, but many observers and lower adenosine diphosphate (ADP) and inorganic
phosphate (Pi ) levels (Bertocci et al. 1993). Thus, by
Readers may note that the contemporary literature on means of exogenous lactate infusion investigators were
the role of lactate in exercise physiology and metabolism able to bypass the enzymatic block at PFK. Subsequently,
comes from only a few laboratories (Brooks, 2018; in studies using vascular infusion of [1-13 C]lactate
Ferguson et al. 2018), but such is not the case if a wider and arterial-venous difference measurements across
perspective is taken, when it is apparent that support for resting and exercising legs of McArdle disease patients,
the biological roles of lactate come from diverse scientific investigators concluded that ‘lactate formation is
and clinical fields in which solutions to many problems are mandatory for muscle energy generation during exercise.’
addressed utilizing a variety of technologies. In addition In part those results could have been predicted based
to the above identified lactate shuttles, the importance on results of studies on electrically stimulated isolated
of lactate in contemporary biology is illustrated in the rat muscles in which lactate addition to the incubation
following examples. bath helped maintain cell membrane chemical-electrical
gradients and ward off fatigue (de Paoli et al. 2007).
The glycogen shunt. Shulman and colleagues used
proton (1 H) and 13 C magnetic resonance spectroscopy Lactate metabolism in injuries and illnesses. This issue
(MRS) to explain the rapid rate of metabolic transitions has been addressed in recent reviews (Brooks, 2018,
in brain after stimulation; consequently, a glycogen shunt 2020a), but there appear to be both positive and negative
was proposed (Shulman et al. 2001). By this model, aspects to lactate metabolism in illnesses and injuries
shunting a portion of glucose from the circulation into (Table 1).
glycogen with subsequent glycogenolysis provides for
lactate production by two parallel pathways, traditional Positive effects – lactate or supplemental lactate
glycolysis from glucose and glycolysis from glycogen.
treatment
Although ATP energy from the glycogen shunt is
energetically less efficient than glycolysis from glucose, Lactate treatment can be involved in resuscitation
the shunt allows cell energy storage and glial energy to following environmental stresses (dehydration and
be provided in milliseconds for rapid neurotransmitter acidosis), inflammation (hepatitis and pancreatitis),
release when needed. Enlarging on their work on cerebral infectious (Dengue and sepsis) and non-infectious
energy needs, Shulman and colleagues expanded the diseases (hypoglycaemia) and traumatic conditions
model to include the energetics of working skeletal (brain injury, myocardial infarction, burns and wound
muscle (Shulman & Rothman, 2001) The hypothesis is healing).
a forceful reminder of the immediate role of glycogen
over glucose in supplying energy via glycolysis, leading Negative effects – overabundance of lactate
to lactate production in rodents (Brooks & Donovan,
production and accumulation
1983; Donovan et al. 1983) and humans (Bergman et al.
1999a,b). The idea of a glycogen shunt is also a reminder Cancer. Seminal studies have shown that lactate
that everything, including glycogen, turns over during production and accumulation occur in cancer cells
exercise (Azevedo et al. 1998) and that reduced glycogen incubated under fully aerobic condition (Warburg &
depletion in exercising muscle is due, in part, to a Minami, 1923, 1927). Subsequently, accelerated glycolysis
reduction in turnover. leading to lactate production in cancer cells has been
implicated in many stages in carcinogenesis (San-Millan
Muscle lactate disposal and energy status. Bertocci, & Brooks, 2017). More recently, blocking of MCTs in
Haller and colleagues have used MRS and 13 C-lactate driver (glycolytic) and oxidative (recipient) tumour
tracers to evaluate the role of lactate in muscle energy cells can minimize lactate exchange, in effect killing
transduction. By tracking the conversion of 13 C-lactate both cell types by pickling the drivers and starving the
into glutamate in a rat muscle preparation, a TCA cycle recipients, thus arresting tumour development (Semenza,
intermediate in equilibrium with α-ketoglutarate, it was 2008; Sonveaux et al. 2008). To date, however, the use
confirmed that lactate is readily oxidized by skeletal of pharmacological agents to block MCTs in cancer is
muscle during rest and contraction, and directly enters contraindicated because of the ubiquitous expression of

Table 1. Potential for lactate treatment for illness and injury (from Brooks, 2020a)

Resuscitation (fluid, electrolytes, energy) (Azevedo et al. 2007; Garcia-Alvarez et al. 2014a; Marik & Bellomo, 2016)
Acidosis (exogenous lactate infusion has an alkalotic effect) (Miller et al. 2005; Wu et al. 2011; Marik & Bellomo, 2016)
Regulation of glycaemia (lactate is the major gluconeogenesis (GNG) precursor) (Meyer et al. 1998, 2002; Gerich et al. 2001; Marik,
2009)
Traumatic brain injury (lactate is brain fuel and anti-inflammatory) (Glenn et al. 2015a)
Inflammation (via GPR81 binding down stream signalling lactate inhibit the inflammasome) (Hoque et al. 2014)
Acute pancreatitis and hepatitis (lactate is an energy substrate, a GNG precursor and anti-inflammatory agent) (Hoque et al. 2014)
Myocardial infarction, cardiac surgery and acute heart failure (lactate is heart fuel) (Shapiro et al. 2005; Bergman et al. 2009b)
Burns (lactate is an energy substrate, a GNG precursor and anti-inflammatory agent) (Spitzer, 1979)
Sepsis (lactate incorporation in resuscitation fluids can support maintenance of blood pressure and circulation, and help deliver
antibiotics, as well as being an energy substrate, a GNG precursor and have an anti-inflammatory effect) (Garcia et al. 1995; Marik
& Bellomo, 2016)
Dengue (lactate is an energy substrate, a GNG precursor and anti-inflammatory agent) (Wu et al. 2011; Somasetia et al. 2014)
Cognition (lactate readily crosses the blood-brain barrier, fuels neurons and stimulates secretion of brain-derived neurotrophic
factor (BDNF), improves executive function and memory) (Rice et al. 2002; Holloway et al. 2007; Hashimoto et al. 2018)
Wound healing (Hunt et al. 2007) and muscle regeneration after injury (Tsukamoto et al. 2018; Ohno et al. 2019).

MCTs in most cell types and negative consequences for central role in physiology. Consider for instance several
the host. Additionally, blocking or deleting HCAR-1 leads of the topics discussed above that have been studied
to a reduced transcription of cancer-regulated genes, thus separately, but seldom investigated in an integrated
diminishing cancer cell proliferation in animal and cell fashion. Seemingly, there is need for a more integrative
culture models (Brown et al. 2020; Xie et al. 2020). At pre- approach to develop models of physiological organization.
sent there are no definitive data indicating that aberrant Seemingly also, we may learn from, or contribute to,
lactate metabolism causes cancer, but it has been observed research in other fields of science and medicine. Some
that lactate accumulation is associated with upregulation examples follow.
of cancer promoting genes and downregulation of cancer
suppressor genes (San-Millan et al. 2020).
Nutrition, digestion, muscle physiology and the micro-
Errors in the ability to transport or exclude lactate may
biome. For instance, consider that the consumption of
have serious consequences. For instance, embryologic
deletion of the lactate transporters (monocarboxylate dietary CHO elicits neuroendocrine signals to splanchnic
transporters, MCTs) is lethal. For glucoregulation when tissues and brain. In the upper GI tract, entry of
blood lactate is elevated as in exercise or other conditions, glucose for CHO digestion is disposed of via direct and
MCTs must be excluded from insertion into pancreatic indirect pathways as described in the glucose paradox.
β-cell plasma membranes (Pullen et al. 2010; Rutter Glucose released into the systemic circulation via the
et al. 2015). While MCTs are present on plasma and hepatic portal vein is taken up by red muscle where
mitochondrial membranes of most cells and tissues, glycogen synthesis and glycolysis are stimulated. Sub-
exclusion of MCTs from pancreatic β-cell plasma sequently, in the GI tract glucagon-like peptide-1 (GLP-1)
membranes keeps extracellular lactate from entering and glucose-dependent insulinotropic polypeptide (GIP)
and affecting intracellular redox, thus interfering with are released from enteroendocrine cells in response to
glucose sensing and insulin secretion (Bender et al. 2006). nutrient ingestion and the presence of glucose and
Noteworthy in this regard is that individuals experiencing lactate. GLP-1 receptors (GLP-1Rs) on enteric neurons,
failed suppression of pancreatic β-cell MCT expression including intrinsic afferent neurons, and extrinsic spinal
become hypoglycaemic during hard exercise leading to and vagal sensory afferents, have potentially numerous
lactataemia because the combination of high insulin and effects including enhancement of insulin secretion and
increased glucose disposal through metabolism causes mediation of satiety signalling, via effects on the hypo-
profound hypoglycaemia (Otonkoski et al. 2007). thalamic arcuate and paraventricular nuclei.
It goes without citation that short- and long-term
nutrition and blood glucose regulation is heavily tied to
Lactate shuttling into the future: unresolved issues hunger and satiety signalling. The biochemistry behind
appetite regulation is a complicated and active area of
and future directions
research (Gale et al. 2004; Murphy & Bloom, 2006).
The more lactate shuttling is studied, the more is revealed Suffice it to state that in the arcuate nucleus of the hypo-
about the expansive nature of lactate metabolism and its thalamus effects of the appetite stimulating (feeding)

(neuropeptide y (NPY)) centre are balanced Jones and colleagues observed that metabolically
against those of the appetite inhibitory (satiation) inflexible subjects had an increased fasting plasma lactate
[pro-opio-melanocortin (POMC)] centre. Hormones compared to aged matched controls (Jones et al. 2019).
that inform the hypothalamic centres that regulate Similarly, San-Millán and Brooks observed that diabetic
appetite include insulin, ghrelin, leptin, peptide YY and obese subjects showed increased circulating lactate
(PYY), glucagon like peptide-1 (GLP-1) and others and decreased lipid oxidation during rest and exercise
(Ghosal et al. 2013). Results of classic studies relating compared to age matched lean and highly trained athletes
physical activity level and diet (Mayer et al. 1956), as well (San-Millan & Brooks, 2018). Further research is needed
as practical experience, indicate that maximal exercise has to determine the mechanisms by which lactataemia
an appetite inhibiting effect. For instance, few are hungry limits metabolic flexibility in sedentary, obese and older
immediately after maximal exercise to exhaustion. The individuals. Elaboration of those mechanisms could
suppressive effect of lactate on appetite (Schmid et al. lead to behavioural and pharmacological treatments for
2008; Schultes et al. 2012; McCarthy et al. 2020) is metabolic inflexibility in illnesses and ageing.
consistent with data showing that lactataemia suppresses
ghrelin secretion (Islam et al. 2017; Vanderheyden
Epigenetic modifications by lactylation of histones and
et al. 2020). The ghrelin receptor (growth hormone
other potential mechanisms. Glis family zinc finger
secretagogue receptor (GHSR-1α)) is a G-protein coupled
(Glis1) is a transcription factor known to be involved in
receptor expressed throughout both the stomach and GI
cell reprogramming, such as transformation of somatic
tract. Recently, it was found that lactate, short chain fatty
to pluripotent cells. In somatic cells Glis1 binds to
acids and other bacterial excretions in the GI tract are
glycolysis genes to open them and promote transcription
able to attenuate ghrelin mediated signalling through
(Li et al. 2020). This activates glycolysis, without affecting
the GHSR-1α (Torres-Fuentes et al. 2019). Hence, in
OXPHOS, thus increasing lactate and acetyl-CoA levels
combination with lactate produced by gut microbiota,
that result in an increase in histone lactylation and
the high blood lactate of exercise can enter the bowel
acetylation. Further, histone lactylation in some (Pan Kla
via sodium-mediated monocarboxylate transporters
and H3K18la), but not all (H3K9me3 and H3K27me3)
(sMCT) and attenuate ghrelin receptor signalling, perhaps
cultured tumour cells increased substantially after Glis1
revealing how hard exercise attenuates hunger.
overexpression and decreased after Glis1 knockdown.
Continuing with the course of chyme down the
Taken together, the results offer the possibility that Glis1
GI tract, microbiota give rise to lactate that is either
modulates histone acetylation and lactylation during cell
converted to butyrate, released into the systemic
reprogramming. Given these hints in the literature, it
circulation, or excreted (vide supra). However, it is
may be worthwhile to learn from progress in regenerative
clear that more research is needed to better understand
medicine and cancer biology to expand our knowledge of
how upper and lower bowl processes are regulated and
the effects of diet and exercise on histone modulation in
integrated in vivo. Consider for instance, the physiology
disease and ageing processes.
of someone consuming a sports drink during exercise.
Notwithstanding the organoleptic effects of cool beverage
consumption (Jeukendrup & Chambers, 2010), we would Fertilization in vivo and in vitro. It is recognized by
benefit from the development of an overarching model workers in some fields of science (e.g. sepsis: Marik
of nutrient consumption and disposal during rest and & Bellomo, 2016) that progress in understanding
exercise. the biological roles of lactate is attributable to the
contributions of exercise physiology summarized above
and previously (Brooks, 2018; Ferguson et al. 2018).
Clearly all can benefit from greater understanding,
Metabolic flexibility and lactataemia
including those in the fields of in vitro fertilization
Lactataemia limits lipid oxidation by blocking lipolysis (IVF) in which the classic antagonism between glycolytic
and oxidation of FFAs (vide supra). From the fields of and oxidative metabolism is on display. In describing
obesity, diabetes and exercise physiology research come lactate shuttles above, the relationship between lactate
the concepts of metabolic flexibility (Kelley et al. 1999) and secreting Sertoli and sperm cells was described as the
crossover (Brooks & Mercier, 1994). Metabolic flexibility ‘primal demonstration’ of cell-cell lactate shuttling. The
describes the ability of individuals to switch between key ‘good thing, bad thing’ dichotomy of lactate carries
fuel energy substrates in response to changing physio- over to the field of IVF, which is typically conducted
logical conditions such as obesity and diabetes. The cross- on blastocysts in culture media exposed to air, in
over concept additionally considers the effect of metabolic which the PO2 is 5× greater than in vivo. Therefore,
rate on energy substrate partitioning. With regard to an the consequences of hyperoxic ROS generation are a
effect of lactataemia on energy substrate partitioning, major concern because of the potential effects of ROS

on mitochondrial morphology and function in the homeostasis by oxidative phosphorylation of ADP and
embryos (Belli et al. 2020). Similarly, because a disrupted creatine (Hashimoto et al. 2006). Hence, mitochondrial
microenvironment can lead to problems in postnatal respiration creates the physiological sink for lactate
development (Feuer et al. 2017), high lactate and low pH disposal in vivo. As research progresses important facets
have been matters of concern. Much like the Warburg of lactate shuttling are becoming recognized with regard
effect of high rates of aerobic glycolysis in cancer cells to cell signalling and metabolic regulation (Brooks,
and working muscles, mammalian blastocysts exhibit 2020a). In diverse tissues lactate acts by mass action, cell
high capacities for aerobic glycolysis and lactate secretion redox regulation, ROS generation, allosteric binding and
that may create a favourable microenvironment for lactylation of histones. By inhibiting lipolysis in adipose
uterine implantation and invasion. Beyond providing an tissue, via HCAR-1 binding and CREB activation, and
energy supply, glycolysis in blastocysts creates a micro- muscle mitochondrial fatty acid uptake, via malonyl-CoA
environment around the embryo to contribute to the and CPT1, lactate controls lipid oxidation and overall
disaggregation of uterine tissues to facilitate trophoblast energy substrate partitioning. Repeated lactate exposure
invasion. Further, as in wound healing, it may be that from regular exercise results in adaptive processes
lactate acts as a signalling molecule to elicit vascular end- such as mitochondrial biogenesis and other healthful
othelial growth factor (VEGF) recruitment from uterine circulatory and neurological characteristics such as
cells to promote angiogenesis in the uterus. It has also improved physical work capacity, metabolic flexibility
been suggested that the region of high lactate created by (Brooks, 2018), memory and cognition (Suzuki et al.
the blastocyst modulates the activity of the local immune 2011; El Hayek et al. 2019). The importance of lactate and
response, thereby promoting immune tolerance (Gardner, lactate shuttling in healthful living is further emphasized
2015). Moreover, lactate produced during delivery may when lactate signalling and shuttling are dysregulated
reduce post-partum uterine inflammation via the lactate as occur in cancer (San-Millan & Brooks, 2017) and
receptor HCAR-1 (Madaan et al. 2017). As discussed other conditions such as following traumatic brain injury
above, several sets of independent studies indicate a role (Glenn et al. 2015b), metabolic syndrome (Brooks,
of lactate in mitigating inflammation. Because of the role 2018; San-Millan & Brooks, 2018), inappropriate insulin
of inflammation in chronic diseases, it seems that focused signalling (Rutter et al. 2015) and sepsis (Garcia-Alvarez
efforts on the role of lactate in reducing inflammation et al. 2014a). While much has been done to determine
may be of importance. energetic regulation in steady and transient states of
metabolism, the importance of measuring the dynamics
of metabolism beyond stagnant use of ‘metabolomics’, by
assessing physiological, environmental and age-related
Summary
effects on the turnover rates of lactate, glucose, fatty and
Time is overdue to turn the page on understanding amino acids as well as structural and metabolic proteins
lactate metabolism and consider lactate shuttling as and membranes (i.e. ‘fluxomics’), are research challenges
an important component of intermediary metabolism for the new millennium.
in vivo. Lactate shuttling between producer (driver) Like a phoenix, lactate has again risen to major
and consumer (recipient) cells requires the presence importance in 21st century biology.
of cell-cell and intracellular lactate shuttles that fulfil
at least three purposes; lactate is: (1) a major energy
source, (2) the major gluconeogenic precursor and (3)
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Xie Q, Zhu Z, He Y, Zhang Z, Zhang Y, Wang Y, Luo J, Peng for authorship, and all those who qualify for authorship are
T, Cheng F & Gao J (2020). A lactate-induced Snail/STAT3 listed.
pathway drives GPR81 expression in lung cancer cells.
Biochim Biophys Acta 1866, 165576.
Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, Liu W, Funding
Kim S, Lee S, Perez-Neut M, Ding J, Czyz D, Hu R, Ye Z,
He M, Zheng YG, Shuman HA, Dai L, Ren B, Roeder RG, Supported by NIH 1 R01 AG059715-01, Pac-12 Conference
Becker L & Zhao Y (2019). Metabolic regulation of gene Grant No. 3-02-Brooks-17 and the UCB Centre for Research
expression by histone lactylation. Nature 574, 575–580. and Education on Aging (CREA) to G.A.B. There are no other
Zinker BA, Britz K & Brooks GA (1990). Effects of a 36-hour funding sources.
fast on human endurance and substrate utilization. J Appl
Physiol 69, 1849–1855.
Acknowledgements

Additional information Michael Horning and Andrea Salvador Pascual are thanked for
reading and commenting on the manuscript.
Competing interests
The authors have no competing interests. Keywords
exercise, fibre type, gene adaptation, gluconeogenesis,
Author contributions glycogenolysis, indirect pathway, lactate shuttle, lactate
All authors contributed to writing of the paper and approve signalling, microbiome, muscle, postabsorptive metabolism,
of the final version. All persons designated as authors qualify postprandial metabolism, satiety

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The Journal of Physiology - 2021 - Brooks - Lactate in Contemporary Biology A Phoenix Risen

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The Journal of Physiology - 2021 - Brooks - Lactate in Contemporary Biology A Phoenix Risen

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J Physiol 600.

5 (2022) pp 1229–1251 1229

Lactate in contemporary biology: a phoenix risen

Edited by: Ian Forsythe & Lykke Sylow

Metabolic flexibility Reproduction

Satiety regulation Resuscitation

Burn Anaerobic Fatigue Acid

Introduction a certain extent despite obvious evidence to the contrary.

Contributions from muscle and exercise physiology

highway’ (Glancy et al. 2015). To oxidize energy products

Lactate Glycogen + Glucose

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