The FASEB Journal • Research Communication
Hypoxia and exercise provoke both lactate release and
lactate oxidation by the human brain
Morten Overgaard,* Peter Rasmussen,*,1,2 Aske M. Bohm,* Thomas Seifert,*
Patrice Brassard,* Morten Zaar,* Pernille Homann,* Kevin A. Evans,†
Henning B. Nielsen,* and Niels H. Secher*
*Department of Anesthesia, The Copenhagen Muscle Research Center, Rigshospitalet, University of
Copenhagen, Copenhagen, Denmark; and †Neurovascular Research Laboratory, University of
Glamorgan, Pontypridd, UK
ABSTRACT Lactate is shuttled between organs, as
demonstrated in the Cori cycle. Although the brain
releases lactate at rest, during physical exercise there is
a cerebral uptake of lactate. Here, we evaluated the
cerebral lactate uptake and release in hypoxia, during
exercise and when the two interventions were com-
bined. We measured cerebral lactate turnover via a
tracer dilution method ([1-13C]lactate), using arterial to
right internal jugular venous differences in 9 healthy
individuals (5 males and 4 females), at rest and during
30 min of submaximal exercise in normoxia and hyp-
oxia (FiO2 10%, arterial oxygen saturation 72ⴞ10%,
meanⴞSD). Whole-body lactate turnover increased 3.5-
fold and 9-fold at two workloads in normoxia and
18-fold during exercise in hypoxia. Although middle
cerebral artery mean flow velocity increased during
exercise in hypoxia, calculated cerebral mitochondrial
oxygen tension decreased by 13 mmHg (P<0.001). At
the same time, cerebral lactate release increased from
0.15 ⴞ 0.1 to 0.8 ⴞ 0.6 mmol minⴚ1 (P<0.05), corre-
sponding to ⬃10% of cerebral energy consumption.
Concurrently, cerebral lactate uptake was 1.0 ⴞ 0.9
mmol minⴚ1 (P<0.05), of which 57 ⴞ 9% was oxidized,
demonstrating that lactate oxidation may account for
up to ⬃33% of the energy substrate used by the brain.
These results support the existence of a cell-cell lactate
shuttle that may involve neurons and astrocytes.—
Overgaard, M., Rasmussen, P., Bohm, A. M., Seifert,
T., Brassard, P., Zaar, M., Homann, P., Evans, K. A.,
Nielsen, H. B., Secher, N. H. Hypoxia and exercise
provoke both lactate release and lactate oxidation by
the human brain. FASEB J. 26, 3012–3020 (2012).
www.fasebj.org
Abbreviations: av, arteriovenous; CBF, cerebral blood flow;
CMRo2, cerebral metabolic rate for oxygen; Fio2, inspired
oxygen fraction; GC-MS, gas chromatography mass spectrom-
etry; MCA, middle cerebral artery; Paco2, arterial partial
pressure of carbon dioxide; Pao2, arterial partial pressure of
oxygen; Pmitoo2, mitochondrial oxygen tension; Pvco2, ve-
nous partial pressure of carbon dioxide; Pvo2, venous partial
pressure of oxygen; Ra/d, rate of lactate appearance and
disappearance; RPE, rating of perceived exertion; Sao2, arte-
rial oxygen saturation; Scapo2, average capillary oxygen satu-
ration; Svo2, venous oxygen saturation; Vmean, mean velocity
3012
Key Words: cerebral blood flow 䡠 cerebral metabolism 䡠 tracers
Cerebral metabolism requires a continuous supply
of glucose and oxygen, although there is plasticity in
regard to its energy supply. This is exemplified by the
cerebral uptake of both ketone bodies and lactate when
these substances are abundant in the bloodstream (1,
2). The ability of the brain to take up lactate manifests
both at rest and during exercise, when the lactate
uptake increases in proportion to the arterial concen-
tration (3–5) to an extent that can exceed cerebral
glucose consumption (3). Lactate taken up by the brain
is predominantly oxidized, since there is no accumula-
tion of lactate in brain tissue, as evaluated by magnetic
resonance spectroscopy, or in the cerebrospinal fluid
following exercise (6). Thus, at moderate arterial
concentrations, 85 to 100% of lactate taken up by the
brain is oxidized (5). However, the fate of lactate may
also be cataplerosis via ␣-ketoglutarate and gluta-
mate release (7, 8). In support of this hypothesis,
lactate taken up by the brain is not released from the
brain during recovery from exercise (4, 9), and there
is no significant release of a related compound (10).
Brain tissue not only takes up lactate but, as in other
tissue (11, 12), there is also a simultaneous indepen-
dent release of lactate. The source of lactate released
from the brain is probably brain glycogen (13–15) and
glucose taken up from the bloodstream (12). At rest,
brain lactate release is ⬃0.05 mmol min⫺1, which is
doubled during exercise, while at the same time, net
lactate release is turned into an uptake (5). Whether
cerebral lactate release progresses with increasing work-
load, and presumably elevated cerebral metabolic rate
for oxygen (16, 17), remains unknown. Rasmussen et al.
(17) provided evidence that cerebral lactate release
increases during intense exercise in hypoxia: the nor-
1
Current address: Department of Physiology, University of
Zurich, Winterthurerstrasse 190, CH8057 Zurich, Switzer-
land.
2
Correspondence: Rigshospitalet, AN2041, Blegdamsvej 9,
DK2100 Copenhagen, Denmark. E-mail: peter@prec.dk
doi: 10.1096/fj.11-191999
0892-6638/12/0026-3012 © FASEB
mal lactacemia-induced net cerebral lactate uptake was
eliminated, i.e., the arteriovenous difference was zero.
Two explanations were considered: hypoxia affected
cerebral uptake of lactate during exercise, or lactate
release from the brain was elevated to a similar extent
to lactate uptake. We considered the latter the more
likely explanation; however, the two processes repre-
sent different metabolic pathways. Organ-organ as well
as cell-cell lactate shuttling represents a carbon source
for oxidation and gluconeogenesis and a vehicle for
cell signaling via redox changes. Here, we test the
lactate shuttle hypothesis and the involvement of the
brain in this shuttle. We hypothesize cerebral lactate
uptake and release will increase in hypoxia and more so
during hypoxic exercise. Cerebral lactate turnover was
evaluated by tracer methodology ([1-13C]lactate) at rest
and during exercise in normoxia and hypoxia, at the
same absolute and relative workloads. At the same time,
we calculated the cerebral oxygen and glucose turnover
based on changes in middle cerebral artery (MCA)
mean flow velocity (Vmean) and the arteriovenous (av)
differences across the brain.
MATERIALS AND METHODS
Five males and 4 females (age: 26⫾6 yr, weight: 68⫾8 kg,
height: 167⫾11 cm; mean⫾sd) were recruited into the study.
Subjects were regularly physically active, and none was taking
any prescribed or over-the-counter medication or had any
history of disease. Subjects were informed both orally and in
writing about the purpose, risks, and discomforts associated
with the experimental protocol. All experimental protocols
were approved by a local ethical committee for Copenhagen
(KF-01287471), in accordance with the Declaration of Hel-
sinki. On a separate day prior to the experiment, subjects
were familiarized with the exercise protocol by incrementally
cycling to volitional exhaustion in order to determine their
physical capacity and maximal oxygen uptake. Following a
60-min resting period, a second 20-min bout of cycling in
normobaric hypoxia [inspired oxygen fraction (Fio2) 0.10]
was completed with the workload set at ⬃35% of the maximal
workload reached in normoxia. This enabled similar abso-
lute and relative workloads in normoxia and hypoxia to be
examined. A workload corresponding to 35% of maximal
normoxia work capacity (⬃119 W) corresponds to ⬃70%
of work capacity in hypoxia. Thus, a 70% normoxia trial
(⬃204 W) was included to compare same relative work-
loads. We refer to these workloads as low-intensity exercise
in normoxia, high-intensity exercise in normoxia, and
high-intensity exercise in hypoxia. Subjects were instructed
and verbally encouraged to complete as much work as
possible during each trial.
The first experimental day was held 7–14 d after the
familiarization trial. Cerebral metabolism was evaluated dur-
ing cycling in normoxia (d 1) and hypoxia (d 2), with a
minimum of 2 wk between experimental days. The order of
hypoxia and normoxia trials was randomly assigned. In nor-
moxia, subjects completed two 30-min cycling bouts at 35%
(low intensity) and 70% (high intensity) of maximal work-
load, as determined during the normoxic pretrial, with
exercise periods separated by 20 min of supine recovery. In
hypoxia, subjects rested supine for 30 min and then cycled for
30 min at 35% (high-intensity in hypoxia) of the maximal
workload achieved in normoxia (Fig. 1).
BRAIN LACTATE RELEASE AND UPTAKE
Figure 1. Flow scheme of the study with two experimental
trials. The first trial was conducted under normoxic condi-
tions (Copenhagen, sea level) at rest and during cycle ergom-
eter exercise at the same absolute (119 W) and relative
workload (204 W) as compared to the second trial, while
breathing a low-oxygen mixture (10% O2 in N2; 119 W). The
second trial in hypoxia started at rest, while breathing room
air, followed by breathing the low-oxygen mixture and 30-min
cycle ergometer exercise. Triangles and squares denote blood
sampling.
Subjects did not engage in planned physical exercise for
24 h and were instructed to abstain from caffeinated bever-
ages and alcohol for ⱖ12 h before study days. A light
breakfast before reporting to the laboratory at 8:00 AM was
advised. On arrival at the laboratory, subjects were placed on
a hospital bed tilted slightly head-down. Under local anesthe-
sia (2% lidocaine) and guided by ultrasound, a catheter (1.6
mm; ES-04706; Arrow International, Reading, PA, USA) was
inserted retrograde in the right internal jugular vein and
advanced to its bulb. A second catheter (1.1 mm) was inserted
in the left brachial artery for blood sampling, while a third
catheter (1.3 mm) was placed in a left antebrachial vein for
infusion of the tracer. After catheterization, subjects were
placed supine, and infusion of sodium [1-13C]lactate (Cam-
bridge Isotope laboratories, Andover, MA, USA) was started
(13 ␮mol kg⫺1 priming dose followed by 0.75 ␮mol kg⫺1
min⫺1). In addition, a bolus of labeled bicarbonate (H13CO3,
1.5 ␮mol kg⫺1) was used to prime the bicarbonate pool to
mitigate CO2 retention from 13C-lactate oxidation from
13
CO2 storage in bicarbonate and carbonic acid pools. Sub-
jects then rested for 2 h to offset the nociceptive stimuli
associated with catheterization and to allow distribution of
the tracer. The tracer infusion rate was increased 3-fold
during the low-intensity (35%) normoxic trial, 6-fold during
high-intensity (70%) normoxic and (35%) hypoxic trials, to
ensure enrichment (⬃5%). Resting blood samples were ob-
tained 30, 20, and 10 min before exercise, whereas exercising
blood samples were obtained after 5, 10, 20, and 30 min of
exercise (Fig. 1). Subjects were asked to express their rating
of perceived exertion (RPE) at the end of each exercise
workload (18).
Changes in cerebral blood flow (CBF) were identified by
transcranial Doppler-derived MCA Vmean through the poste-
rior temporal window (Multidrop X; DWL, Sipplingen, Ger-
many). After obtaining the optimal signal-to-noise ratio, the
probe was fixed by adhesive ultrasonic gel (Tensive; Parker
Laboratories, Fairfield, NJ, USA) and secured by a headband
(Marc 600 Spencer Probe Fixation System; Spencer Technol-
ogies, Seattle, WA, USA).
3013
Analytical procedures c ao 2 ⫺ c vo 2
Eo2 ⫽ (2)
c ao 2
Blood was collected in preheparinized syringes, kept anaero-
bic at room temperature, and analyzed within 30 min, for and as dissolved oxygen accounts for less than 2% of the
arterial and venous partial pressures of oxygen (Pao2 and arterial oxygen, Eqs. 1 and 2 can be simplified to Eq. 3:
Pvo2), oxygen saturation (Sao2, Svo2), and partial pressure of
carbon dioxide (Paco2, Pvco2), using a combined blood gas S aO2 ⫹ S vO2
ScapO2 ⫽ (3)
analyzer and cooximeter (ABL 725, Radiometer, Copenha- 2
gen, Denmark). Aterial and venous oxygen content (cao2;
cvo2) was subsequently calculated from hemoglobin concen- Solution of the Hill equation of O2 saturation yielded the
tration, Po2, and So2. For analysis of metabolites and tracer mean Pcapo2 (Eq. 4):

冑
enrichment, blood was stored on ice until centrifuged at 4°C
for 10 min, with plasma being stored at ⫺40°C. Concentra- ha Scap
PcapO2 ⫽ P50a (4)
tions of carbohydrates were analyzed using enzymatic meth- 1 ⫺ Scap
ods (glucose: Roche Unikit; Roche, Nuess, Germany; lactate
and pyruvate: Cobas Fara; Roche). where P50a is the Po2 when hemoglobin is half-saturated and
Lactate enrichment was measured by gas chromatography ha is Hill’s coefficient for arterial blood. P50 was estimated by
mass spectrometry (GC-MS; Automass II, Finnigan, France). the Radiometer ABL 725 machine, and ha and hv were
For GC-MS analysis, a trimethylsilyl derivative of lactate was subsequently calculated (17). As the brain lacks capillary
made. Ethanol (1 ml) was added to 200 ␮l of plasma and recruitment during activation, O2 diffusibility (L) was as-
centrifuged for 10 min; the supernatant was then transferred sumed to be stable (4.4 ␮mol 100 g⫺1 min⫺1 mmHg⫺1; ref.
to a new tube and evaporated to dryness under a stream of 25). Changes in mitochondrial oxygen tension (Pmitoo2)
nitrogen. The dried material was redissolved in 50 ␮l of relative to rest were then calculated (Eq. 5):
pyridine and 50 ␮l of N-(O-bistrimethylsilyl)-trifluoroacet- CMRO2
amide with 1% trimethylchlorosilan (Pierce, Rockford, IL, PmitoO2 ⫽ PcapO2 ⫺ (5)
USA) and incubated for 30 min at room temperature. Lactate L
enrichment was determined by split injection (ratio 1:25) of 1 The systemic lactate turnover at rest, Ra/d, was calculated
␮l into the GC-MS (GC column, CP-SIL 8CB; Chrompack, (Eq. 6):
Middelburg, The Netherlands). The isotopic enrichment was
determined using electron impact ionization. Ions at a mass- F
to-charge ratio (m/z) of 219 and 220 represented the molec- Ra ⫽ Rd ⫽ (6)
Ea
ular ions of unlabeled and labeled derivatives, respectively.
Samples of arterial and venous blood and expired air for where F is the isotope infusion rate (␮mol kg⫺1 min⫺1) and
measurement of 13CO2 enrichment were determined by gas Ea is the arterial enrichment of lactate in the tracer-to-tracee
chromatograph-isotope ratio mass spectrometry (GC-IRMS, ratio. The whole body rate of lactate appearance Ra and
Deltaplus; Finnigan MAT, Bremen, Germany). Expired air (10 disappearance during exercise was expressed using non-
ml) was collected in a Vacutainer (Becton Dickinson, Frank- steady-state equations (27) adapted for stable isotopes (28),
lin Lakes, NJ, USA), and the 13C- to 12C ratio was determined in Eqs. 7 and 8:
by split injection (ratio 1:4) of 20 ␮l of the expired air into the
GC-IRMS (GC column, poraplot Q; Chrompack). For the F ⫺ pV ⫻ [(Ca,2 ⫺ Ca,1) ⁄ 2] ⫻ [(Ea,2 ⫺ Ea,1) ⁄ (t2 ⫺ t1)]
Ra ⫽
determination of blood CO2 enrichment, 0.5 ml of 2.5 M [(Ea,2 ⫹ Ea,1) ⁄ 2 ⫻ body weight]
phosphoric acid was added to 0.5 ml of whole blood in a (7)
10-ml Vacutainer to release CO2, and the Vacutainer was
(Ca,2 ⫺ Ca2) ⁄ (t2 ⫺ t1)
brought to pressure with pure helium. The 13C to 12C ratio Rd ⫽ Ra ⫺ pV ⫻ (8)
was determined by a split injection (ratio 1:10) of 20 ␮l of the body weight
headspace on the GC-IRMS.
where E1 and E2 are the arterial isotope enrichments at
sample times 1 (t1) and 2 (t2) (min), respectively; Ca,1 and Ca,2
Calculations are the arterial concentrations at times t1 and t2 (mM),
respectively, and pV is the volume of distribution for lactate,
Changes in CBF, O2 delivery, cerebral metabolic rate for oxygen 0.1 L kg⫺1 (29). Although a pV of 0.1 L kg⫺1 has been used
(CMRo2), and carbohydrate (CMRCHO; glucose⫹½lactate) were for lactate kinetics with the assumption that this value is
derived from MCA Vmean, assuming an unchanged internal diam- appropriate for both rest and exercise, it is obviated by the
eter of the MCA (19, 20) with the resting CBF considered to be 46 presence of near steady-state conditions.
Lactate turnover was calculated combining the net balance
ml 100 g⫺1 min⫺1 (21). The contribution of pyruvate to CMRCHO
and the fractional extraction in Eqs. 9 and 10:
is in the range of ⬃0.5% (22) and disregarded, but the arterial
lactate-to-pyruvate ratio was calculated to evaluate its potential Net balance ⫽ (Ca ⫺ Cv) ⫻ CBF (9)
relevance as a redox signal for changes in CBF (22, 23).
To evaluate the influence of hypoxia and exercise on C aE a ⫺ C vE v
Fractional extraction ⫽ ⫻ 100 % (10)
cerebral oxygenation, the average capillary O2 saturation C aE a
(Scapo2) was calculated using Eq. 1 (24, 25):

冉 冊
where Ca and Cv are the arterial and venous concentrations of
E O2 lactate, and Ea and Ev are the arterial and venous enrichments
ScapO2 ⫽ SaO2 1 ⫺ (1) in the tracer-to-tracee ratio. Cerebral lactate uptake is then
2
found (Eq. 11):
assuming that the O2 extraction rises linearly with distance as blood Fractional extraction ⫻ Ca ⫻ CBF (11)
traverses the capillary network (26). The O2 extraction fraction
(Eo2) is expressed as Eq. 2: Net cerebral lactate balance is found by Eq. 12:

3014 Vol. 26 July 2012 The FASEB Journal 䡠 www.fasebj.org OVERGAARD ET AL.
TABLE 1. Systemic blood gas and metabolic variables

Exercise

Variable Hypoxia, ⫹/⫺ Rest 119 W 204 W

Glca (mM) ⫺ 6.23 ⫾ 0.73 5.88 ⫾ 0.84## 5.46 ⫾ 0.6##

⫹ 5.87 ⫾ 0.72 8.13 ⫾ 0.88*** ⫺
Laca (mM) ⫺ 1.00 ⫾ 0.24 1.6 ⫾ 0.52## 4.75 ⫾ 2.23***,##
⫹ 1.20 ⫾ 0.28 10.6 ⫾ 3.9*** ⫺
Lac Ra/d (mol kg⫺1 min⫺1) ⫺ 22.2 ⫾ 4.9 70.7 ⫾ 38.9‡ 227 ⫾ 123***,‡
⫹ 29.1 ⫾ 5.8 460 ⫾ 141*** ⫺
Pyra (␮M) ⫺ 103 ⫾ 39 99 ⫾ 27## 182 ⫾ 71**,##
⫹ 89 ⫾ 28 273 ⫾ 56*** ⫺
Pyrv (␮M) ⫺ 98 ⫾ 37 95 ⫾ 27## 165 ⫾ 66**,##
⫹ 94 ⫾ 29 285 ⫾ 48*** ⫺
Pao2 (kPa) ⫺ 13.5 ⫾ 0.4## 12.9 ⫾ 0.7## 12.6 ⫾ 1.0**,##
⫹ 4.7 ⫾ 0.67 4.37 ⫾ 0.43 ⫺
Sao2 (%) ⫺ 98.5 ⫾ 0.2## 97.8 ⫾ 0.6## 97.5 ⫾ 0.8##
⫹ 72.4 ⫾ 10.3 60.3 ⫾ 3.9*** ⫺
Paco2 (kPa) ⫺ 5.24 ⫾ 0.32## 5.19 ⫾ 0.39***,## 4.79 ⫾ 0.46***,##
⫹ 4.38 ⫾ 0.45 3.58 ⫾ 0.28*** ⫺

Values are expressed as means ⫾ sd. Glca, arterial glucose; Laca, arterial lactate; Lac Ra/d, lactate rate of appearance/disappearance; Pyra,
arterial pyruvate; Pao2, arterial partial pressure of oxygen; Sao2, arterial oxygen saturation; Paco2, arterial carbon dioxide tension. **P ⬍ 0.01,
***P ⬍ 0.001 vs. rest; ##P ⬍ 0.01 vs. hypoxia.

Net balance ⫽ lactate uptake ⫺ lactate release (12)
and cerebral lactate release then is equal to cerebral lactate
uptake minus the cerebral net balance (Eq. 13):
Lactate release ⫽ lactate uptake ⫺ net balance (13)
tion was observed (P⬍0.001; n⫽7), and linear regression
was used to calculate missing lactate oxidation percent-
ages.

Statistics RESULTS

Two-way repeated-measures ANOVA identified changes
between rest vs. exercise and normoxia vs. hypoxia. Fol-
lowing a significant F test, Tukey’s post hoc procedure was
used to identify pairwise differences. SAS 9.1 was used for
the analysis (SAS Institute, Cary, NC, USA), and values of
P ⬍ 0.05 were considered to represent a statistically
significant deviation. For correlation analysis, Pearson’s
product-moment was used. Data are presented as means ⫾
sd (median and range for RPE). During post hoc analysis, a
relationship between the lactate uptake and lactate oxida-
Resting systemic and cerebral variables are shown in
Tables 1 and 2, respectively. At rest, hypoxia resulted
in reduced arterial and venous O2 saturations
(P⬍0.001) and also in a 20% reduction in the
cerebral O2 av difference (P⬍0.01). Although MCA
Vmean increased during hypoxia (P⬍0.001), there was
a 10% decline in O2 delivery to the brain (P⬍0.05).
The CMRo2 did not change (113⫾34 vs. 112⫾35
␮mol 100 g⫺1 min⫺1, normoxia vs. hypoxia, corre-

TABLE 2. Cerebral blood gas and metabolic variables

Exercise

Variable Hypoxia, ⫹/⫺ Rest 119 W 204 W

MCA Vmean (cm s⫺1) ⫺ 51.0 ⫾ 9.3## 51.3 ⫾ 9.9## 51.3 ⫾ 8.8##
⫹ 64.0 ⫾ 19.3 65.9 ⫾ 13.4 ⫺
Oxygen delivery (␮mol 100 g⫺1 min⫺1) ⫺ 368 ⫾ 37# 387 ⫾ 63## 371 ⫾ 70
⫹ 332 ⫾ 85 304 ⫾ 71 ⫺
Scapo2 (mmHg) ⫺ 83.3 ⫾ 3.4## 82 ⫾ 4.5‡ 80.4 ⫾ 5.7##
⫹ 61.6 ⫾ 6.7 49.1 ⫾ 3.8***
Pcapo2 (mmHg) ⫺ 43.7 ⫾ 4.4## 44.3 ⫾ 5.9## 44.2 ⫾ 9.5##
⫹ 28.2 ⫾ 1.3 27.8 ⫾ 2.2 ⫺
OGI ⫺ 5.21 ⫾ 1.23# 5.25 ⫾ 1.05 4.77 ⫾ 1.42
⫹ 4.10 ⫾ 1.21 4.03 ⫾ 0.86 ⫺
OCI ⫺ 5.25 ⫾ 1.14 5.36 ⫾ 1.16# 4.36 ⫾ 1.37
⫹ 4.47 ⫾ 1.25 3.92 ⫾ 1.00 ⫺

Values are expressed as means ⫾ sd. MCA Vmean, middle cerebral artery mean flow velocity; Scapo2, capillary oxygen saturation; Pcapo2,
capillary partial pressure of oxygen; OGI, oxygen to glucose ratio; OCI, oxygen to carbohydrate ratio. ***P ⬍ 0.001 vs. rest; #P ⬍ 0.05, ##P ⬍
0.01 vs. hypoxia.

BRAIN LACTATE RELEASE AND UPTAKE 3015


Figure 2. Arterial glucose (A) and lactate (B) and systemic
lactate rate of appearance/disappearance (C) and arterial
pyruvate (D) concentration during control, normoxia, and
acute normobaric hypoxia (10% O2). Values are means ⫾
se (n⫽8).
Equally, systemic lactate turnover increased 3.5-fold
during low-intensity exercise and 9-fold during high-
intensity exercise, reaching ⬃200 ␮mol kg⫺1 min⫺1
(P⬍0.001). During both low- and high-intensity exer-
cise, MCA Vmean and O2 delivery remained similar to
rest, while CMRo2 increased to 135 ⫾ 51 ␮mol 100 g⫺1
min⫺1 (P⬍0.001, high intensity vs. rest). Yet, the Pcapo2
remained at 44 ⫾ 9 mmHg, and there was no signifi-
cant change in Pmitoo2.
During low-intensity exercise in normoxia (35%,
119 W), there was no significant change in cerebral
lactate uptake or release, and the net balance was
therefore unchanged. During high-intensity exercise
in normoxia (70%, 204 W), a substantial net lactate
uptake was observed in contrast to the net lactate
release at rest. Cerebral lactate uptake during high-
intensity exercise in normoxia increased markedly,
while lactate release only increased moderately (up-
take and release 0.46⫾0.60 and 0.37⫾0.41 mM
min⫺1, respectively). Cerebral lactate release during
high-intensity exercise in normoxia was similar to
that during the low-intensity exercise in normoxia
and 2-fold larger than rest.
Exercising in hypoxia had marked effects on O2 and

sponding to ⬃8.5 mmol ATP min⫺1), although,

Pcapo2 decreased to 27 ⫾ 2 mmHg (P⬍0.001), and
consequently, Pmitoo2 decreased by 11 ⫾ 11 mmHg
(P⬍0.001).
Arterial glucose, lactate, and pyruvate concentrations
were similar during normoxia and hypoxia trials at rest.
Within 10 min of inhaling a low O2 mixture at rest,
arterial lactate concentration increased to 1.0 ⫾ 0.2
mM (Fig. 2). This increase with hypoxia was supported by
an increase in the rate of lactate appearance in the
circulation (21⫾9, 23⫾6, and 29⫾6 ␮mol kg body mass⫺1
min⫺1 for rest, rest before induction of hypoxia, and rest
in hypoxia, respectively, P⬍0.05). In normoxia, resting
cerebral net lactate release was 0.05 ⫾ 0.01 mmol min⫺1;
however, within 10 min of inhaling the low O2 mixture,
net lactate release increased to 0.09 ⫾ 0.02 mmol min⫺1
with a tendency for a lower cerebral lactate release with
increasing duration of hypoxia (Fig. 3A), while cerebral
lactate uptake was similar. Cerebral lactate release was
0.13 ⫾ 0.02 and 0.18 ⫾ 0.03 mmol min⫺1 at normoxic rest
and hypoxic rest, respectively. As production of 1 mol of
lactate provides 1 mol of ATP, lactate, thus, yielded ⬃0.16
mmol min⫺1 of ATP or ⬃2% of energy production. A net
pyruvate release was observed after a resting period of 20
and 30 min in hypoxia. Furthermore, also the av-differ-
ence for pyruvate became negative in hypoxia (⫺7⫾21
␮M; P⫽0.05; Fig. 4).

Exercise

In normoxia, RPE increased and was 17 (14 –20) during Figure 3. Cerebral lactate kinetics during control, normoxia,
high-intensity exercise; Pao2 and Pvo2 remained un- and acute normobaric hypoxia (10% O2). A) Brain net lactate
changed, while arterial lactate increased ⬃2 and 5-fold release. B) Lactate uptake. C) Lactate release. Values are
during low- and high-intensity exercise, respectively. means ⫾ se (n⫽8).

3016 Vol. 26 July 2012 The FASEB Journal 䡠 www.fasebj.org OVERGAARD ET AL.
 release was observed similar in quantity to 30 min of
rest in hypoxia.
Cerebral lactate uptake followed the arterial lactate
concentration regardless of O2 tension (P⬍0.001,
Fig. 5, top panel). Across trials, Pcapo2 and cerebral
lactate release were correlated (P⬍0.01), but this was
not the case for Pmitoo2 and lactate release. Both at rest
and during exercise in hypoxia, MCA Vmean was related
to both the arterial lactate to pyruvate ratio (Fig. 6, top
panel) and to Pcapo2 (P⬍0.05).

DISCUSSION

Here, we confirm that from rest to exercise, a small

lactate release from the brain is turned to a remarkable
lactate uptake. Yet during exercise in hypoxia, the net
av-difference for lactate across the brain was less than
would be expected from the arterial lactate concentra-
tion (3), as previously observed (17). This study not
only confirms our earlier finding (17) but extends it by
showing that the amount of lactate released from the
brain in hypoxia increases markedly, to an extent that
almost matches the lactate uptake during exercise. The
most important finding of the study is that both hyp-
Figure 4. Cerebral net glucose (A) and pyruvate uptake (B) oxia and physical exercise increase cerebral nonoxida-
under control conditions, normoxia, and acute normobaric
hypoxia (10% O2). Values are means ⫾ se (n⫽8). tive glycolysis (i.e., glycolytic), as expressed by its lactate
release. Cerebral lactate release became ⬃5-fold
greater and indicates ⬃10% of the cerebral energy
substrate transport, while RPE was reported as 18 turnover stems from glycolytic energy pathways. Finally,
(15–20). Sao2 and Svo2 decreased to 63 ⫾ 6% and 40 ⫾
6%, respectively, and the av-difference for O2 was
reduced by ⬃20%. MCA Vmean supported an increase in
CBF with exercise, yet there was an 18% decrease in O2
delivery to the brain compared to rest (P⬍0.05). With
CMRo2 similar to rest, Pcapo2 decreased ⬃20 mmHg
(P⬍0.001) resulting in a decrease in Pmitoo2 by 13 ⫾ 11
mmHg (P⬍0.01).
Hypoxic exercise also caused substantially higher
glucose, lactate, and pyruvate concentrations compared
to low and high intensity normoxic trials. Both arterial
glucose and lactate increased (to 8.6⫾2.3 and 9.9⫾4.5
mmol l⫺1 respectively, P⬍0.001) and a large (19-fold)
increase in systemic lactate turnover was observed. No
significant changes were found for the cerebral net
glucose uptake. During high intensity exercise in hyp-
oxia the cerebral net glucose uptake tended to in-
crease.
High-intensity exercise in hypoxia increased cerebral
net lactate uptake, similar in quantity to that seen for
high-intensity exercise in normoxia. However, the ki-
netics were different as both lactate uptake and release
were higher in hypoxia compared to normoxia. The
cerebral lactate uptake increased to 1.0 ⫾ 0.9 mmol
min⫺1 and the release increased 5-fold (to 0.8⫾0.6
mmol min⫺1, P⬍0.05, equivalent to ⬃0.8 mmol min⫺1
ATP). The cerebral av-difference for glucose and pyru- Figure 5. Brain lactate uptake and oxidation. Top panel:
vate remained similar to rest in hypoxia. After 10 min of cerebral lactate uptake vs. arterial lactate. Bottom panel:
exercise, all individuals demonstrated a net pyruvate Percentage of cerebral lactate uptake that is oxidized vs.
uptake, whereas after 30 min of exercise, a net pyruvate cerebral lactate uptake. Values are expressed as means ⫾ se.

BRAIN LACTATE RELEASE AND UPTAKE 3017

Figure 6. CBF, mitochondrial oxygen tension,
and metabolism at rest and during exercise in
normoxia and hypoxia (10% O2 inspirate). Glc,
glucose; Pyr, pyruvate; Pmitoo2, mitochondrial
oxygen tension; L/P ratio, lactate to pyruvate
ratio;. Values are expressed as means ⫾ se
(n⫽9).***P ⬍ 0.001 vs. rest; †P ⬍ 0.05, ‡P ⬍
0.01 vs. normoxia.
we show that during high lactate concentrations, the
fraction of lactate oxidized decreases from ⬃90% at
rest (5) to ⬍60% as during intense exercise in hypoxia.
Whole-body lactate turnover increased ⬃3-fold and
9-fold at the same relative and absolute intensities
during normoxic exercise and 18-fold during hypoxic
exercise (Fig. 2). Lactate turnover increases as a func-
tion of exercise intensity, and we show that exercise in
acute hypoxia further increases lactate turnover. Al-
though working muscles are the major source of in-
creased lactate turnover during exercise, we demon-
strate that the brain contributes to increased whole-body
lactate metabolism. As suggested for skeletal muscles
(30, 31), increased cerebral metabolism is associated
with “leakage” of lactate to the bloodstream, probably
reflecting energy production from breakdown of glyco-
gen/glucose (13–15, 32). We show that whole-body
lactate metabolism is elevated from ⬃3- to 9-fold in
response to increases in exercise intensity but also that
decreased oxygen availability increased whole body
lactate appearance almost 20-fold during exercise (Fig.
2). Interestingly, at rest, hypoxia alone does not in-
crease lactate appearance. For the brain, we observed
that exercise and hypoxia both increase cerebral lactate
release. During high-intensity exercise, lactate release
was concurrent to an increase in CMRo2 (17, 33),
suggesting there was an increased glycolytic flux and,
therefore, lactate leakage into the blood. When mean
cerebral oxygenation decreases, there was also a
marked increase in cerebral lactate release. For skeletal
muscles, an elevated metabolic rate is considered the
major cause for an increase in lactate release to blood
(34). However, muscle desaturation is aggravated with
exercise in hypoxia (35), while, at the same absolute
work rates, lactate release is elevated in hypoxia com-
pared to normoxia. Although unknown for brain, it is
likely that lactate formation represents a limited ability,
perhaps by means of redox signaling by increasing
3018 Vol. 26 July 2012 The FASEB Journal 䡠 www.fasebj.org
lactate levels (30), of mitochondria to metabolize pyru-
vate and, thereby, eliminate lactate as brain metabolism
becomes elevated to control maximal exercise (16, 17).
Both of these considerations were substantiated, sug-
gesting there is a parallel between aerobic vs. nonaero-
bic metabolism in skeletal muscle and the brain. It may
be of importance that while mitochondria are abun-
dantly present in the soma of neurons, they are not in
axons. Accordingly, it could be that lactate formation
during intense neuronal activity reflects axonal rather
that somal glycolytic metabolism.
With a significant diffusion distance between capil-
laries and neurons, imposed by projections of the
astrocytes, the brain tolerates (compared to skeletal
muscle) only a small decrease in O2 tension, as exem-
plified by the O2 tension in its venous outflow. It is
critical for the brain to adjust its blood flow according
to metabolic demand. How this coupling is established
remains debatable. Redox signaling is a prominent
candidate, and the arterial lactate-to-pyruvate ratio is a
proposed link between blood flow and neuronal me-
tabolism (23). As observed during exercise (22, 36),
there was a relationship between MCA Vmean and the
arterial lactate to pyruvate ratio, indicating there may
be a coupling between muscle metabolism, with forma-
tion of lactate, and the ability of the brain to increase
flow to areas of importance for integration of the many
cerebral processes involved in exercise.
Lactate production and utilization are two distinct
biochemical processes occurring simultaneously (11),
as exemplified for the heart (12). This makes lactate a
prime candidate as an organ-to-organ energy currency,
and lactate organ-organ shuttling represents a carbon
source for oxidation and gluconeogenesis. Cell-cell
shuttling has been demonstrated for muscles and has
also been proposed within the brain by the astrocyte-
neuron lactate shuttle (37), or the alternative neuron-
astrocyte lactate shuttle (38), but here, we did not
OVERGAARD ET AL.
address which cells take up lactate or from where
lactate may be released. On the other hand, shuttling of
lactate from active muscles to the brain supports cell-
cell lactate communication. Lactate may be provided
directly to the neurons from the bloodstream for
oxidation and at modest arterial concentrations, lactate
taken up is almost fully oxidized (5). From rest to
hypoxic exercise, however, there was a decreasing frac-
tion of the lactate taken up by the brain that was
oxidized, reaching ⬍60% (Fig. 5), and other fates may
await lactate, such as cataplerosis via ␣-ketoglutarate
(7) and glutamate release (8). Here, we provide evi-
dence for cataplerosis in the brain by the reduction in
lactate oxidation. Thus, the carbon backbone of lactate
may find its way into a large number of substances (39),
as long as the cytosolic and/or mitochondrial NAD/
NADH ratio allows for conversion of lactate to pyruvate.
Finding 13CO2 in the jugular vein provides evidence
that this is energetically feasible, even during intense
cerebral activation or hypoxia. Accordingly, lactate
serves as a fuel in response to activation. Sixty percent
oxidation of the lactate uptake (⬃1.0 mmol min⫺1, Fig.
3B) corresponds to a lactate oxidation of ⬃0.6 mmol
min⫺1, which is approximately equivalent to glucose
oxidation (Fig. 4A). On a molar basis, cerebral lactate
uptake is therefore close to 50:50 in regard to glucose
uptake, but lactate yields only half the amount of
carbon. Thus, the implication here is that lactate serves
⬃33% of the carbohydrates needed for oxidative phos-
phorylation, and this value is in agreement with previ-
ous observations (3, 40).
Limitations
We used transcranial Doppler to estimate changes in
CBF, and an important assumption for interpretation
of the Doppler velocity data is an unchanged internal
diameter of the MCA. CBF is regulated distal to the
basal cerebral vessels (19, 41), and, hence, the MCA
diameter would not be expected to change. In support
of this, the increase in MCA Vmean during exercise
mirrors that in the carotid artery (42). Furthermore,
during exercise, changes in MCA Vmean are supported
by a near-infrared spectroscopy evaluation of cerebral
oxygenation (25) and paralleled by 133Xe-washout de-
termination of CBF (43). The assumptions underlying
calculation of Pmitoo2 have been detailed (24, 25).
There was a notable increase in arterial glucose
during exercise in hypoxia. Hyperglycemia is likely
induced by sympathetic activation, and there may also
be a contribution from the Cori cycle, caused by
elevated lactate. We did not measure circulating cat-
echolamines or any possible 13C (from lactate) incor-
poration into glucose to evaluate the respective contri-
bution to the glucemia. We acknowledge that part of
the recovered 13CO2 in the jugular vein may stem from
label transfer from lactate to glucose by the liver. This
labeled glucose would then be oxidized by the brain
and overestimate cerebral lactate oxidation. We con-
sider, however, that the cerebral metabolic rate for
BRAIN LACTATE RELEASE AND UPTAKE
glucose is unlikely to be affected by the increased
glucose availability since the av-differences for glucose
remained stable throughout exercise in hypoxia, de-
spite steadily increasing systemic levels of glucose.
CONCLUSIONS
Hypoxia alone increased cerebral lactate release and
hypoxic exercise provoked a 5-fold increase in cerebral
lactate release. Lactate production contributes ⬃2% of
cerebral energy turnover at rest and up to ⬃10%
during hypoxic exercise. At the same time, even during
hypoxic exercise, brain lactate uptake increases in
proportion to the arterial concentration, and in terms
of carbon, lactate uptake may become close to 50:50 in
regard to glucose uptake. The proportion of lactate
taken up by the brain being oxidized decreases from
⬃90% at rest to ⬃60% during exercise in hypoxia. This
demonstrates that lactate oxidation may account for up
to ⬃33% of the substrate used by the brain during
exercise. It remains to be established what the fate of
the surplus uptake of carbohydrate compared to oxy-
gen is. In summary, in humans, lactate production and
oxidation during cerebral activation by physical exer-
cise and also in hypoxia occur simultaneously support-
ing cell-cell shuttling of lactate, which may involve
neurons and astrocytes.
The skilled assistance by Gorm J. Ravn-Jonsen and Gerrit
van Hall is acknowledged. The authors were funded through
grants from Anti-Doping Denmark (P.R.), the Lundbeck
Foundation (P.R. and N.H.S.), and Fonds de la Recherche en
Santé du Québec (P.B.).
REFERENCES
1. Owen, O., Morgan, A., Kemp, H., Sullivan, J., Herrara, H., and
Cahill, G. (1967) Brain metabolism during fasting. J. Clin. Invest.
46, 1589 –1595
2. Quistorff, B., Secher, N. H., and Van Lieshout, J. J. (2008)
Lactate fuels the human brain during exercise. FASEB J. 22,
3443–3449
3. Rasmussen, P., Wyss, M. T., and Lundby, C. (2011) Cerebral
glucose and lactate consumption during cerebral activation by
physical activity in humans. FASEB J. 25, 2865–2873
4. Ide, K., and Secher, N. H. (2000) Cerebral blood flow and
metabolism during exercise. Prog. Neurobiol. 61, 397–414
5. van Hall, G., Stromstad, M., Rasmussen, P., Jans, O., Zaar, M.,
Gam, C., Quistorff, B., Secher, N. H., and Nielsen, H. B. (2009)
Blood lactate is an important energy source for the human
brain. J. Cereb. Blood Flow Metab. 29, 1121–1129
6. Dalsgaard, M. K., Quistorff, B., Danielsen, E. R., Selmer, C.,
Vogelsang, T., and Secher, N. H. (2004) A reduced cerebral
metabolic ratio in exercise reflects metabolism and not accumu-
lation of lactate within the human brain. J. Physiol. 554, 571–578
7. Des Rosiers, C., Labarthe, F., Lloyd, S. G., and Chatham, J. C.
(2011) Cardiac anaplerosis in health and disease: food for
thought. Cardiovasc. Res. 90, 210 –219
8. Maddock, R. J., Casazza, G. A., Buonocore, M. H., and Tanase,
C. (2011) Vigorous exercise increases brain lactate and Glx
(glutamate⫹glutamine): a dynamic 1H-MRS study. Neuroimage
57, 1324 –1330
9. Dalsgaard, M. K., and Secher, N. H. (2007) The brain at work:
a cerebral metabolic manifestation of central fatigue? J. Neurosci.
Res. 85, 3334 –3339
3019
10. Rasmussen, P., Nyberg, N., Jaroszewski, J. W., Krogh-Madsen, R.,
Secher, N. H., and Quistorff, B. (2010) Brain nonoxidative
carbohydrate consumption is not explained by export of an
unknown carbon source: evaluation of the arterial and jugular
venous metabolome. J. Cereb. Blood Flow Metab. 30, 1240 –1246
11. Brooks, G. A. (1999) Are arterial, muscle and working limb
lactate exchange data obtained on men at altitude consistent
with the hypothesis of an intracellular lactate shuttle? Adv. Exp.
Med. Biol. 474, 185–204
12. Chatham, J. C., Des Rosiers, C., and Forder, J. R. (2001)
Evidence of separate pathways for lactate uptake and release by
the perfused rat heart. Am. J. Physiol. Endocrinol. Metab. 281,
E794 –E802
13. Rasmussen, P., Vedel, J. C., Olesen, J., Adser, H., Pedersen,
M. V., Hart, E., Secher, N. H., and Pilegaard, H. (2011) In
humans IL-6 is released from the brain during and after exercise
and paralleled by enhanced IL-6 mRNA expression in the
hippocampus of mice. Acta Physiol. (Oxf.) 201, 475–482
14. Matsui, T., Ishikawa, T., Ito, H., Okamoto, M., Inoue, K., Lee,
M.-c., Fujikawa, T., Ichitani, Y., Kawanaka, K., and Soya, H.
(2012) Brain glycogen supercompensation following exhaustive
exercise. J. Physiol. 590, 607–616
15. Matsui, T., Soya, S., Okamoto, M., Ichitani, Y., Kawanaka, K.,
and Soya, H. (2011) Brain glycogen decreases during prolonged
exercise. J. Physiol. 589, 3383–3393
16. Seifert, T., Rasmussen, P., Secher, N. H., and Nielsen, H. B.
(2009) Cerebral oxygenation decreases during exercise in hu-
mans with beta-adrenergic blockade. Acta Physiol. (Oxf.) 196,
295–302
17. Rasmussen, P., Nielsen, J., Overgaard, M., Krogh-Madsen, R.,
Gjedde, A., Secher, N. H., and Petersen, N. C. (2010) Reduced
muscle activation during exercise related to brain oxygenation
and metabolism in humans. J. Physiol. 588, 1985–1995
18. Borg, G. (1975) Simple rating for estimation of perceived
exertion. In Physical Work and Effort (Borg, G., ed) pp. 39 –46,
Pergamon, New York
19. Bradac, G. B., Simon, R. S., and Heidsieck, C. H. (1976)
Angiographically verified transient alteration of intercranial
arteries and veins in dependence of different CO2 tension.
Neuroradiology 10, 257–262
20. Serrador, J. M., Picot, P. A., Rutt, B. K., Shoemaker, J. K., and
Bondar, R. L. (2000) MRI measures of middle cerebral artery
diameter in conscious humans during simulated orthostasis.
Stroke 31, 1672–1678
21. Madsen, P. L., Holm, S., Herning, M., and Lassen, N. A. (1993)
Average blood flow and oxygen uptake in the human brain
during resting wakefulness: a critical appraisal of the Kety-
Schmidt technique. J. Cereb. Blood Flow Metab. 13, 646 –655
22. Rasmussen, P., Plomgaard, P., Krogh-Madsen, R., Kim, Y. S., van
Lieshout, J. J., Secher, N. H., and Quistorff, B. (2006) MCA
Vmean and the arterial lactate-to-pyruvate ratio correlate during
rhythmic handgrip. J. Appl. Physiol. 101, 1406 –1411
23. Mintun, M. A., Vlassenko, A. G., Rundle, M. M., and Raichle,
M. E. (2004) Increased lactate/pyruvate ratio augments blood
flow in physiologically activated human brain. Proc. Natl. Acad.
Sci. U. S. A. 101, 659 –664
24. Gjedde, A., Johannsen, P., Cold, G. E., and Østergaard, L.
(2005) Cerebral metabolic response to low blood flow: possible
role of cytochrome oxidase inhibition. J. Cereb. Blood Flow Metab.
25, 1183–1196
25. Rasmussen, P., Dawson, E. A., Nybo, L., van Lieshout, J. J.,
Secher, N. H., and Gjedde, A. (2007) Capillary-oxygenation-
level-dependent near-infrared spectrometry in frontal lobe of
humans. J. Cereb. Blood Flow Metab. 27, 1082–1093
26. Kety, S. S. (1957) Determinants of tissue oxygen tension. Fed.
Proc. 16, 666 –671
3020 Vol. 26 July 2012 The FASEB Journal 䡠 www.fasebj.org
27. Steele, R. (1959) Influences of glucose loading and of injected
insulin on hepatic glucose output. Ann. N. Y. Acad. Sci. 82,
420 –430
28. Rosenblatt, J., Chinkes, D., Wolfe, M., and Wolfe, R. R. (1992)
Stable isotope tracer analysis by GC-MS, including quantifica-
tion of isotopomer effects. Am. J. Physiol. Endocrinol. Metab. 263,
E584 –E596
29. Stanley, W. C., Gertz, E. W., Wisneski, J. A., Morris, D. L., Neese,
R. A., and Brooks, G. A. (1985) Systemic lactate kinetics during
graded exercise in man. Am. J. Physiol. Endocrinol. Metab. 249,
E595–E602
30. Brooks, G. A. (2009) Cell-cell and intracellular lactate shuttles.
J. Physiol. 587, 5591–5600
31. Van Hall, G. (2010) Lactate kinetics in human tissues at rest and
during exercise. Acta Physiol. 199, 499 –508
32. DiNuzzo, M., Mangia, S., Maraviglia, B., and Giove, F. (2010)
Glycogenolysis in astrocytes supports blood-borne glucose chan-
neling not glycogen-derived lactate shuttling to neurons: evi-
dence from mathematical modeling. J. Cereb. Blood Flow Metab.
30, 1895–1904
33. Seifert, T., Rasmussen, P., Brassard, P., Homann, P. H., Wissen-
berg, M., Nordby, P., Stallknecht, B., Secher, N. H., and Nielsen,
H. B. (2009) Cerebral oxygenation and metabolism during
exercise following three months of endurance training in
healthy overweight males. Am. J. Physiol. Regul. Integr. Comp.
Physiol. 297, R867–R876
34. Richardson, R. S., Noyszewski, E. A., Leigh, J. S., and Wagner,
P. D. (1998) Lactate efflux from exercising human skeletal
muscle: role of intracellular PO2. J. Appl. Physiol. 85, 627–634
35. Rowell, L. B. (1986) Human Circulation: Regulation During Phys-
ical Stress, pp. 363–406, Oxford University Press, New York
36. Rasmussen, P., Madsen, C. A., Nielsen, H. B., Zaar, M., Gjedde,
A., Secher, N. H., and Quistorff, B. (2009) Coupling between
the blood lactate-to-pyruvate ratio and MCA Vmean at the onset
of exercise in humans. J. Appl. Physiol. 107, 1799 –1805
37. Pellerin, L., and Magistretti, P. J. (1994) Glutamate uptake into
astrocytes stimulates aerobic glycolysis: a mechanism coupling
neuronal activity to glucose utilization. Proc. Natl. Acad. Sci.
U. S. A. 91, 10625–10629
38. Mangia, S., Simpson, I. A., Vannucci, S. J., and Carruthers, A.
(2009) The in vivo neuron-to-astrocyte lactate shuttle in human
brain: evidence from modeling of measured lactate levels dur-
ing visual stimulation. J. Neurochem. 109(Suppl 1), 55–62
39. Boumezbeur, F., Petersen, K. F., Cline, G. W., Mason, G. F.,
Behar, K. L., Shulman, G. I., and Rothman, D. L. (2010) The
contribution of blood lactate to brain energy metabolism in
humans measured by dynamic 13C nuclear magnetic resonance
spectroscopy. J. Neurosci. 30, 13983–13991
40. Wyss, M. T., Jolivet, R., Buck, A., Magistretti, P. J., and Weber, B.
(2011) In vivo evidence for lactate as a neuronal energy source.
J. Neurosci. 31, 7477–7485
41. Giller, C. A., Bowman, G., Dyer, H., Mootz, L., Krippner, W.,
Loftus, C. M., and Muizelaar, J. P. (1993) Cerebral arterial
diameters during changes in blood-pressure and carbon-dioxide
during craniotomy. Neurosurgery 32, 737–742
42. Hellström, G., Fischer-Colbrie, W., Wahlgren, N. G., and
Jögestrand, T. (1996) Carotid artery blood flow and middle
cerebral artery blood flow velocity during physical exercise. J.
Appl. Physiol. 81, 413–418
43. Jørgensen, L., Perko, M., and Secher, N. H. (1992) Regional
cerebral artery mean flow velocity and blood flow during
dynamic exercise in humans. J. Appl. Physiol. 73, 1825–1830
Received for publication August 1, 2011.
Accepted for publication March 5, 2012.
OVERGAARD ET AL.