1 Exercise Physiology and Metabolism Laboratory, Department of Physiology, The University of Melbourne, Parkville, Victoria 3010; and 2 Department of Pathology and Immunology, Monash Medical School, Prahran, Victoria 3181, Australia
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ABSTRACT |
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To examine the effect of exercise and
adrenergic blockade on lymphocyte cytokine production, six men ingested
either a placebo (control) or an - (prazosin hydrochloride) and
-adrenoceptor antagonist (timolol malate) capsule (blockade, or BLK)
2 h before performing 19 ± 1 min of supine bicycle exercise
at 78 ± 3% peak pulmonary uptake. Blood was collected before and
after exercise, stimulated with phorbol 12-myristate 13-acetate and
ionomycin, and surface stained for T (CD3+) and natural
killer [NK (CD3
CD56+)] lymphocyte surface
antigens. Cells were permeabilized, stained for the intracellular
cytokines interleukin (IL)-2 and interferon (IFN)-
, and analyzed
using flow cytometry. BLK had no effect on the resting concentration of
stimulated cytokine-positive T and NK lymphocytes or the amount of
cytokine they were producing. Exercise resulted in an increase (P
< 0.05) in the concentration of stimulated T and NK lymphocytes
producing cytokines in the circulation, but these cells produced less
(P < 0.05) cytokine post- compared with preexercise.
BLK attenuated (P < 0.05) the elevation in the
concentration of lymphocytes producing cytokines during exercise;
however, BLK did not affect the amount of IL-2 and IFN-
produced.
These results suggest that adrenergic stimulation contributes to the
exercise-induced increase in the concentration of lymphocytes in the
circulation; however, it does not appear to be responsible for the
exercise-induced suppression in cytokine production.
T cells; natural killer cells; interleukin-2; interferon-
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INTRODUCTION |
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INTERLEUKIN
(IL)-2 and interferon (IFN)- are cytokines that are produced
primarily by T and natural killer (NK) lymphocytes, and they play an
important role in both humoral and cellular inflammatory responses
(7, 34). Exercise has been demonstrated to suppress T
(26, 43) and NK (29-31, 41) lymphocyte
function, and it is possible that it may compromise cytokine production
by these cells. The effect of exercise on IL-2 and IFN-
production
is, however, unclear. A decrease in the concentration of IL-2 and IFN-
in the supernatant of in vitro mitogen-stimulated blood has
often (1, 19, 28, 33, 41, 48), but not always (13), been observed post- compared with
preexercise. It is important to note that the suppression of
stimulated IFN-
production postexercise has been hypothesized to be
the prominent cause of a functional break in defense, resulting in an
increase in the risk of infection (28, 48). It is
possible, therefore, that this could provide a mechanism for the
increased risk of infection often reported following strenuous exercise
(25). Given this suggestion and the conflict in the
existing literature, the effect of acute exercise on IFN-
production
from NK and T lymphocytes at an individual cell level warrants further
investigation. The method employed in the current study measures
intracellular cytokine production at a single-cell level, allowing
determination of changes in the concentration of lymphocytes producing
the measured cytokine to be ascertained. In addition, a measurement of
the amount of cytokine produced by each cell can also be obtained.
Epinephrine and norepinephrine have been demonstrated to increase the
concentration of circulating lymphocytes (9, 10, 15, 16, 42,
47) but to decrease T (42) and NK (16) lymphocyte activity. Furthermore, epinephrine and norepinephrine have
been demonstrated to decrease in vitro stimulated IL-1, IL-6, and tumor
necrosis factor (TNF)- production by whole blood (4, 11, 36,
46). Catecholamines exert many of their effects through
- and
-adrenergic receptors. Binding of catecholamines to these receptors
increases the concentration of intracellular cAMP, leading to an
activation of protein kinase A that, in turn, phosphorylates other
intracellular enzymes, ultimately influencing cell function
(21). Lymphocytes have
- and
-adrenergic receptors on their surface membranes (18), and it is through these
receptors that epinephrine leads to an increase in lymphocyte
concentration in the circulation (17). Lymphocytes are
distributed in vivo in circulating and marginal pools that are in
dynamic exchange with one another (32). Administration of
catecholamines has been demonstrated to interfere with
-adrenergic
receptors on NK lymphocytes (3), thereby causing a
decrease in their adherence to the vascular endothelium. Because
lymphocytes have adrenergic receptors, and because catecholamines have
been demonstrated to decrease the production of cytokines predominantly
produced by monocytes, it is possible that these hormones also could
affect lymphocyte IL-2 and IFN-
production.
It has previously been demonstrated that the exercise-induced increase
in circulating NK lymphocytes (17) and lymphocyte concentration and function (24) is abolished by the
2-receptor antagonist propanolol. In addition,
incubation of blood samples with a
2-receptor antagonist
results in an increase in stimulated IL-2 production compared with
control samples (20, 22, 23). Together, these previously
reported data demonstrate that catecholamines can affect IL-2
production in basal (resting) blood samples when concentrations are
low. To our knowledge, no studies have examined the effect of
adrenergic receptor blockade on cytokine production during exercise.
This is important given the marked increase in sympathetic activity
during exercise.
The aims of the present study were, therefore, to examine the effect of
1) acute exercise on lymphocyte IL-2 and IFN- production on a single-cell level and 2) adrenergic blockade on
cytokine production at rest and during exercise. We hypothesized that
exercise would decrease cytokine production due to elevations in
epinephrine but that adrenergic blockade would attenuate these alterations.
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METHODS |
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Subjects
Six endurance-trained men [age 26 ± 5 yr, weight 71 ± 6 kg, peak pulmonary oxygen uptake (Experimental Procedures
At least 7 days before the first experimental trial,Subjects participated in two single-blind trials, conducted at least 1 wk apart. Subjects were supplied with food packages to consume for the 24 h preceding the trial, providing 15.6 MJ and comprising 71% CHO, 15% protein, and 14% fat. Subjects were instructed to abstain from alcohol, caffeine, and strenuous exercise. Subjects were also instructed to adhere to the diet but to consume water ad libitum.
Trials commenced at a set time (7:00 AM) to avoid circadian variations
in hormones. Subjects arrived in the laboratory after a 10- to 12-h
overnight fast to participate in the experimental trial. Subjects were
fitted with a three-lead electrocardiograph for continuous monitoring
of heart rate. An indwelling Teflon catheter (Ohmeda, Wiltshire, UK)
with an attached valve (Safe-site, Braun, PA) was positioned into the
brachial artery under local anesthetic (1% lidocaine) for collection
of arterial blood samples and continual measurement of blood pressure.
The catheter was kept patent by flushing with 0.5 ml NaCl after each
sample collection. Two hours before exercise commenced, an arterial
blood sample was collected (predrug), and subjects ingested either a
placebo capsule (control) or a capsule (blockade, or BLK) containing 5 mg of prazosin hydrochloride (an -adrenergic antagonist) and 5 mg of
timolol maleate (a
-adrenergic antagonist). Pilot data revealed that
subjects had variable tolerance to the BLK capsule with respect to
exercise; therefore, the BLK trial was always conducted first. Given
the effects of combined
- and
-adrenergic blockade, it was
necessary to use supine exercise on a modified cycle ergometer as the
mode of exercise. After the subjects had rested quietly for 2 h in
a supine position, a preexercise arterial blood sample was collected.
Subjects then commenced a 20-min supine cycling trial at a power output
eliciting 81.9 ± 2.5% O2 peak;
however, because of the effect of the drugs in the BLK, it was
necessary to decrease the power output to 73.4 ± 2.9%
O2 peak at 10 min. This workload was
maintained until the 20-min time point. Two subjects were unable to
complete the 20-min BLK trial, fatiguing at 16 and 19 min,
respectively. On average, subjects cycled for 19.2 ± 0.6 min at
78 ± 3%
O2 peak. The workload
and total cycling time for each subject were replicated in the
subsequent control trial.
Additional blood samples were collected after 10 min of exercise, at
the completion of exercise (postexercise), and 2 h into recovery
(2 h postexercise). Predrug as well as preexercise, postexercise, and
2-h postexercise samples were analyzed for alterations in leukocyte
counts, T lymphocyte IL-2 and IFN- production, and NK cell IFN-
production. Catecholamines were measured predrug, preexercise, at 10 min, and postexercise. Samples collected preexercise, at 10 min, and
postexercise were analyzed for cortisol. Heart rate was recorded at
5-min intervals during exercise.
Leukocyte Counts
Blood (3 ml) was placed into sterile EDTA vacutainer tubes and kept at room temperature until analysis for total and differential white blood cell (WBC) counts as routinely performed by the hematology laboratory at The Alfred Hospital. Thus, in addition to total WBC concentration, we determined neutrophil, monocyte, and lymphocyte concentrations for each blood sample.Intracellular Cytokines
Blood (2 ml) was placed in sterile sodium heparin vacutainer tubes and kept at room temperature until the end of the trial for measurement of lymphocyte intracellular IL-2 and IFN-Lymphocyte stimulation. Whole blood (1 ml) was incubated in 1.0 ml of RPMI 1640 medium (Life Technologies, Melbourne, Victoria, Australia) for 10 h and stimulated with 25 ng/ml phorbol 12-myristate 13-acetate (Sigma Aldrich, Castle Hill, New South Wales, Australia) and 1 µg/ml ionomycin (Sigma Aldrich) at 37°C and 5% CO2. Brefeldin-A (10 µg/ml) was added to all cultures at the commencement of the incubation to inhibit intracellular transport of proteins, thus retaining cytokines produced inside the cell.
Staining for T and NK lymphocyte IL-2 and INF- production.
Aliquots (200 µl) of stimulated and unstimulated blood were incubated
for 30 min with CD3 (peridinin chlorophyll protein) and CD56
(R-phycoerythrin; PE)-conjugated monoclonal antibodies (Becton
Dickinson, San Jose, CA) for staining of T (CD3+) and NK
(CD3
/CD56+) lymphocytes. Red blood cells were
lysed (0.15 M ammonium chloride, 10 mM potassium bicarbonate, and 1 mM
EDTA) for 10 min, and the samples were spun in a centrifuge (350 g) for 5 min. The supernatant was decanted, and the pellet
was resuspended in 500 µl of 4% paraformaldehyde for 20 min. Samples
were again spun (350 g) for 5 min, and the supernatant was
decanted. The fixed cells were permeabilized with 500 µl of
permeabilizing solution (Becton Dickinson) for 20 min, washed (1%
fetal calf serum, phosphate-buffered saline, and 0.02 M sodium azide),
and spun (350 g) for 5 min, and then the supernatant was
decanted. The cells were then incubated with IL-2 (PE), IFN-
(fluorescein isothiocyanate; FITC), or control
(
2aFITC/
1PE) monoclonal antibodies
(Becton Dickinson) for 30 min, making the final combinations of
antibodies CD3+/IL-2/IFN-
and
CD3
/CD56+/IFN-
. After the samples had been
washed and spun (350 g) for 5 min, the pellet was
resuspended in 500 µl of wash buffer. All incubations took place at
room temperature in the dark.
Analysis.
Analysis was performed using flow cytometry (FACScan; Becton
Dickinson). Lymphocytes were separately gated on a side scatter vs.
forward scatter cytogram. Data were acquired for 1 × 104 events within this gate. A subset of T cells expresses
CD56; therefore, only CD3/CD56+ cells were
collected for NK cell analysis. Analysis of collected samples was
performed using Cell Quest (Becton Dickinson) with gates for positive
staining set on isotype controls (<1% positive). Results are
expressed as the concentration of cytokine-producing cells in
CD3+ and CD3
/CD56+ populations in
the peripheral blood. To obtain these values, we first calculated the
concentration of T and NK lymphocytes in peripheral blood using the
percentage of T and NK lymphocytes (from the flow cytometer) and the
concentration of lymphocytes in the circulation (from the differential
WBC count). The concentration of cytokine-positive lymphocytes was then
determined by multiplying the percentage of cytokine-positive T and NK
lymphocytes by the concentration of T and NK lymphocytes in peripheral
blood. For quantification of the amount of cytokine within positive
cells, mean fluorescence intensity (FI) of positive events was obtained.
Hormones
Upon sampling, blood for analysis of cortisol was placed in lithium heparin tubes, and blood for catecholamine analysis was placed in tubes containing 30 µl of EGTA and reduced glutathione. Whole blood was separated by centrifugation (6,000 g for 4 min), and aliquots of plasma (~500 µl for each metabolite) were removed and stored atStatistical Analysis
A two-way (time × treatment) analysis of variance (ANOVA) with repeated measures was used to compare data. A Student-Newman-Keuls post hoc test was used to locate differences when the ANOVA revealed a significant interaction. A Statistica (StatSoft, Tulsa, OK) software package was used to compute these statistics. The level of significance to reject the null hypothesis was set at P < 0.05. ![]() |
RESULTS |
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In resting subjects, BLK had no effect on total and differential leukocyte concentration in the circulation or on the concentration of T and NK lymphocytes producing cytokines spontaneously or upon stimulation.
There was an increase (P < 0.01) in circulating
lymphocyte, monocyte, and neutrophil concentrations postexercise
compared with preexercise, resulting in an increase in total
circulating leukocyte concentrations (Table
1). Leukocyte concentrations remained
elevated 2 h postexercise (P < 0.01), and this
was due to maintained monocyte and neutrophil concentrations (Table 1). Lymphocyte concentration returned to preexercise levels postexercise (Table 1). Compared with the control, BLK suppressed (P < 0.05) the increase in circulating lymphocyte and monocyte
concentrations postexercise; however, neutrophil concentration was
elevated (P < 0.01) 2 h postexercise (Table 1).
As a result, the concentration of total leukocytes in the circulation
was less (P < 0.01) with BLK postexercise; however, at
2 h postexercise, it was higher (P < 0.01)
compared with the control (Table 1).
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There was an increase (P < 0.01) in the concentration
of T lymphocytes (CD3+) and NK lymphocytes
(CD3CD56+) in the circulation postexercise
compared with preexercise (Fig. 1). As a percentage of total
lymphocytes, NK lymphocytes increased (P < 0.01),
whereas T lymphocytes decreased postexercise. BLK resulted in a
decrease (P < 0.05) in the concentration of NK
lymphocytes in the circulation postexercise compared with the control
(Fig. 1). There was a treatment effect in that there were less
(P < 0.05) T lymphocytes in the circulation
postexercise in BLK compared with the control (Fig. 1).
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The concentration of stimulated T lymphocytes positive for IL-2 was
increased (P < 0.01) postexercise compared with
preexercise (Fig. 2) because of the
increase in T lymphocytes in the circulation at this time point.
Although there was an increase in the concentration of cells producing
IL-2 upon stimulation, there was a decrease (P < 0.05)
in the amount that these cells were producing postexercise compared
with preexercise (Table 2). There was a
treatment effect in that the concentration of stimulated T lymphocytes
positive for IL-2 was lower (P < 0.05) with BLK
compared with the control (Fig. 2) because the BLK caused a suppression
in the concentration of T lymphocytes in the circulation during
exercise. BLK had no effect on the amount of IL-2 produced by T
lymphocytes upon stimulation (Table 2).
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Exercise resulted in an increase (P < 0.01) in the
concentration (Fig. 3) of stimulated T
lymphocytes producing IFN- postexercise compared with preexercise
because more lymphocytes were in the circulation at this time.
Furthermore, cells produced less (P < 0.01) IFN-
postexercise compared with preexercise (Table 2). BLK resulted in a
decrease (P < 0.01) in the concentration of cells
producing IFN-
postexercise compared with the control (Fig. 3)
because the BLK caused a suppression in the concentration of T
lymphocytes entering the circulation during exercise. BLK had no effect
on the amount of IFN-
produced upon stimulation (Table 2).
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The concentration of NK lymphocytes producing IFN- upon stimulation
was elevated (P < 0.01) postexercise compared with
preexercise (Fig. 4) because these cells
entered the circulation. Once again, exercise resulted in a decrease
(P < 0.01) in the amount of INF-
produced per cell
postexercise (Table 2), and this suppression was maintained 2 h
postexercise. BLK resulted in a decrease (P < 0.05) in
the concentration of stimulated NK cells producing IFN-
postexercise
compared with the control (Fig. 4) because BLK reduced the
concentration of these cells in the circulation. There was a difference
in the amount of IFN-
produced by NK cells upon stimulation predrug
and preexercise between BLK and the control (Table 2), although the
cause of this was unclear.
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It is important to note that there was considerable variation in FI of
stimulated lymphocytes when BLK and control data were compared,
particularly at rest. To overcome any artifactual effect of these
variations, we also performed the statistical analyses on
log-transformed data for all FI analyses and on changes in FI from the
previous measurement point (e.g., preexercise predrug) (Table
2). Both analyses revealed no differences when BLK and control data
were compared (range: P = 0.21-0.77).
Plasma epinephrine and norepinephrine concentrations were elevated
(P < 0.01) after 10 min of exercise and postexercise
(Table 3). BLK resulted in greater
(P < 0.05) catecholamine levels at 10 min and greater
(P < 0.01) epinephrine levels postexercise (Table 3).
Cortisol concentration was increased (P < 0.01)
postexercise (Table 3), and BLK resulted in lower levels
(P < 0.05) at 10 min and postexercise (Table 3). BLK
resulted in a treatment effect of lowering (P < 0.05)
heart rate in response to exercise (Table 4).
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DISCUSSION |
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The results from the present study demonstrate that strenuous
exercise resulted in an increase in the concentration of stimulated T
lymphocytes producing IL-2 and of T and NK lymphocytes producing IFN-, but this increase was attenuated by adrenergic blockade, suggesting that adrenergic stimulation contributes to exercise-induced leukocytosis. In contrast, exercise caused a suppression in the amount
of IFN-
and IL-2 produced by stimulated lymphocytes, thereby providing a potential mechanism for the often-reported postexercise immunosuppression. However, since adrenergic blockade did not affect
the exercise-induced decrease in the amount of IFN-
and IL-2
production, it appears that adrenergic stimulation is not a mechanism
for this decrease.
Despite an increase in the concentration of cells producing cytokines,
stimulated lymphocytes produced less IL-2 and IFN- postexercise
compared with preexercise. This suppression in NK lymphocyte IFN-
production was maintained 2 h postexercise. These observations
support previous studies that have observed a decrease in supernatant
IL-2 and IFN-
concentrations after a strenuous bout of exercise
(1, 19, 28, 33, 41, 48). Given the marked exercise-induced
increase in circulating catecholamines and the fact that catecholamines
decrease in vitro stimulated monocyte IL-1, IL-6, and TNF-
production by whole blood (4, 11, 36, 46), it is
reasonable to suggest that adrenergic stimulation may provide a
mechanism for the current and previous (1, 19, 28, 33, 41,
48) observation. Adrenergic blockade did not, however, alter the
suppressive effect of exercise on cytokine production. To our
knowledge, this is the first study to investigate such a mechanism, and
our data provide strong evidence to suggest that the decrease in IL-2
and IFN-
produced by stimulated lymphocytes as a result of
strenuous exercise is not mediated by
- and/or
-adrenergic receptor stimulation.
As stated previously, suppression of stimulated IFN- production
postexercise has been hypothesized to cause an increase in the risk of
infection (28, 48). In the present study, exercise resulted in a decrease in the amount of cytokine produced by stimulated lymphocytes, providing a potential mechanism for the frequently reported postexercise immunosuppression. It is important to note, however, that exercise also resulted in an increase in the
concentration of lymphocytes within the circulation. The overall impact
on immune function, as well as whether cytokine production is a
limiting factor in immune protection postexercise, is complex. From
data in the present study, it cannot be determined whether having more lymphocytes in circulation is beneficial, since these cells cannot respond to stimuli optimally.
The elevated concentrations in plasma epinephrine and norepinephrine
during BLK, compared with the control, support previous investigations
(12, 38-40) and are most likely to be caused by decreased clearance by -receptors (5, 6). These
elevated levels of catecholamines, therefore, suggest successful
blockade of the adrenergic receptors. It is possible, however, that
complete blockade of the adrenergic receptors was not achieved, because the exercise-induced elevation in heart rate and lymphocyte
concentration was not completely suppressed in BLK. If complete
blockade was not achieved, then a lesser amount of epinephrine could
have bound to circulating lymphocytes, and it is possible that this may
have resulted in the reduced amount of cytokine produced by stimulated lymphocytes. If this occurred, then further suppression in stimulated cytokine production may not be observed during the control trial. It is
possible, however, that complete blockade of the adrenergic receptors
was achieved and that other factors caused lymphocyte concentration and
heart rate to increase during exercise. Previous studies reported
similar reductions in heart rate with
-blockade during strenuous
exercise as observed in the present study (14, 39).
Furthermore, Murray et al. (24) also observed elevations in lymphocyte concentration during exercise with adrenergic blockade. It is important to note, however, that three other studies did report
complete suppression in NK lymphocyte concentration with
-blockade
after mental stress (3), parachute jumping
(2), and head-up tilt (17).
Plasma cortisol concentration was increased during exercise, and
cortisol has been reported to suppress stimulated IL-1, IL-6, and
IFN- production by monocytes (8). Therefore, it is
possible that elevated cortisol levels may have caused the suppression in the amount of IL-2 and IFN-
produced by stimulated lymphocytes. Cortisol concentration was higher in the control compared with the BLK
trial; however, we did not observe any treatment effect on the amount
of cytokine produced by stimulated lymphocytes, indicating that the
different cortisol concentrations did not alter cytokine production.
Once again, however, it is possible that the cortisol levels observed
during BLK were enough to cause a suppression in cytokine production so
that augmented levels in the control had no further suppressive effect.
The decreased cortisol levels during BLK compared with the control were
a surprising and unexpected result. Previous studies that have examined
the effect of adrenergic blockade on cortisol secretion during exercise observed either no change (35, 45) or an increase
(12, 44). Therefore, it is unclear why
- and
-blockade resulted in a decrease in cortisol concentration in the
present study; however, administration of
-adrenergic antagonist has
been shown to decrease plasma cortisol levels in resting humans
(37).
In conclusion, the decrease in mitogen-activated cytokine production by
lymphocytes provides a mechanism for the immunosuppressive effect of
strenuous exercise. Because the increased concentration of T
lymphocytes producing IL-2 and of T and NK lymphocytes producing IFN- upon stimulation was attenuated by adrenergic blockade, it
appears that sympathoadrenal activity mediates, in part, the exercise-induced increase in cell concentration. However, because
- and/or
-adrenergic blockade did not affect the
exercise-induced amount of IL-2 and IFN-
produced by stimulated
lymphocytes, it is unlikely that adrenergic receptor stimulation
mediates this response.
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ACKNOWLEDGEMENTS |
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We thank the subjects for their participation and Kirsten Howlett, Matthew Watt, and Mark Hargreaves, School of Health Sciences, Deakin University, Melbourne, Australia, for assistance with experimental trials and analysis. In addition, we thank Bronwyn Kingwell and staff at The Baker Medical Research Institute, The Alfred Hospital, Melbourne, Australia, for medical support and assistance with experimental trials. We also acknowledge Andrew Garnham, School of Health Sciences, Deakin University, for medically screening subjects before their participation.
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FOOTNOTES |
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This study was supported by The Australian Research Council.
Address for reprint requests and other correspondence: M. A. Febbraio, Exercise Physiology and Metabolism Laboratory, Dept. of Physiology, The Univ. of Melbourne, Parkville, Victoria 3010, Australia (E-mail: m.febbraio{at}physiology.unimelb.edu.au).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 5 April 2001; accepted in final form 7 June 2001.
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