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Effects of caffeine on central and peripheral fatigue
following closed- and open-loop cycling exercises
P.G. Couto
1
00
, M.D. Silva-Cavalcante
2
00
, B. Mezêncio
3
00
, R.A. Azevedo
1
00
, R. Cruz
1,4
00
, R. Bertuzzi
1
00
,
A.E. Lima-Silva
4
00
, and M.A.P.D. Kiss
1
00
1
Grupo de Estudos em Desempenho Aeróbio da USP, Escola de Educac¸ão Física e Esportes, Universidade de São Paulo,
São Paulo, SP, Brasil
2
Faculdade de Nutric¸ão, Universidade Federal de Alagoas, Maceió, AL, Brasil
3
Laboratório de Biomecânica, Escola de Educac¸ão Física e Esportes, Universidade de São Paulo, São Paulo, SP, Brasil
4
Grupo de Pesquisa em Performance Humana, Universidade Tecnológica Federal do Paraná, Curitiba, PR, Brasil
Abstract
We examined whether endurance performance and neuromuscular fatigue would be affected by caffeine ingestion during
closed- and open-loop exercises. Nine cyclists performed a closed-loop (4,000-m cycling time trial) and an open-loop exercise
(work rate fixed at mean power of the closed-loop trial) 60 min after ingesting caffeine (CAF, 5 mg/kg) or placebo (PLA,
cellulose). Central and peripheral fatigue was quantified via pre- to post-exercise decrease in quadriceps voluntary activation
and potentiated twitch force, respectively. Test sensitivity for detecting caffeine-induced improvements in exercise performance
was calculated as the mean change in time divided by the error of measurement. Caffeine ingestion reduced the time of the
closed-loop trial (PLA: 375.1±14.5 s vs CAF: 368.2±14.9 s, P=0.024) and increased exercise tolerance during the open-loop
trial (PLA: 418.2±99.5 s vs CAF: 552.5±106.5 s, P=0.001), with similar calculated sensitivity indices (1.5, 90%CI: 0.7–2.9 vs
2.8, 90%CI: 1.9–5.1). The reduction in voluntary activation was more pronounced (P=0.019) in open- (–6.8±8.3%) than in
closed-loop exercises (–1.9±4.4%), but there was no difference between open- and closed-loop exercises for the potentiated
twitch force reduction (–25.6±12.8 vs –26.6±12.0%, P40.05). Caffeine had no effect on central and peripheral fatigue
development in either mode of exercise. In conclusion, caffeine improved endurance performance in both modes of exercise
without influence on post-exercise central and peripheral fatigue, with the open-loop exercise imposing a greater challenge to
central fatigue tolerance.
Key words: Endurance performance; Neuromuscular fatigue; Central fatigue; Peripheral fatigue; Ergogenic aid
Introduction
The positive effects of caffeine ingestion (B5 mg/kg of
body mass) on exercise performance have been widely
investigated (1). Caffeine blocks the adenosine receptors
in the central nervous system, enhancing neural drive to
active muscles (2). Some evidence also suggests that
caffeine might act directly on skeletal muscles, increasing
contractile force (3,4). As a result of these central and
peripheral effects, caffeine increases performance in a
broad range of exercise tasks, including high-intensity
whole-body endurance exercise (5).
Surprisingly, even with these multiple effects of
caffeine on central and peripheral sites, only a few studies
have investigated the consequence of caffeine ingestion
on neuromuscular fatigue during a high-intensity whole-
body exercise (6–8). Neuromuscular fatigue can be
defined as a transitory exercise-induced reduction of the
muscle ability to generate power (9), which can be related
to failure of the central nervous system to voluntarily
activate the muscle (central fatigue) and/or processes
distal to or at the neuromuscular junction (peripheral
fatigue) leading to an attenuated response of the active
muscle to a given neural input (for a review see Weavil
and Amann (10)). One study reported that caffeine
increased total work in a 10-min cycling time trial (TT),
but exercise-induced reduction in evoked quadriceps
twitch force (a marker of peripheral fatigue) and voluntary
activation (a marker of central fatigue) were similar in
magnitude under both caffeine and placebo conditions (6).
It is important to highlight that post-exercise neuromus-
cular fatigue measurements in the mentioned study were
assessed 20 min after exercise cessation, when central
and peripheral fatigue might have been largely recovered
(11). Contrary to these findings, in a study measuring
post-exercise fatigue within one minute after exercise
Correspondence: A.E. Lima-Silva: <aesilva@utfpr.edu.br>
Received September 24, 2021 | Accepted December 21, 2021
Braz J Med Biol Res | doi: 10.1590/1414-431X2021e11901
Brazilian Journal of Medical and Biological Research (2022) 55: e11901, https://doi.org/10.1590/1414-431X2021e11901
ISSN 1414-431X Research Article
1/9
cessation, caffeine improved performance during a 4,000-
m cycling TT at the expense of a greater end-exercise
peripheral fatigue (7).
These aforementioned studies have assessed the
effect of caffeine on central and peripheral fatigue after a
high-intensity whole-body endurance exercise adopting a
‘closed-loop’model, in which the work rate can be
regulated throughout the trial in an attempt to complete
the task as quickly as possible (i.e., TT). Another approach
to assess endurance performance is by using an ‘open-
loop’design, in which the work rate is fixed and exercise is
performed until task failure. While it has been reported that
an open-loop exercise is as sensitive as a closed-loop
exercise for detecting changes in endurance performance
induced by a given manipulation (12), a constant-load trial
provokes greater physiological strain than a freely paced
exercise performed at the same average intensity (13). The
mechanism by which a constant-load trial provokes greater
physiological strain is not fully known, but it is assumed that
an enforced constant-load trial negates the self-managing
of the conscious signs of fatigue (13). During closed-loop
exercise, however, the individual can fluctuate pace based
on subconscious physiological feedback from an array of
peripheral receptors (13). Whether this higher physiological
strain results in greater central and/or peripheral fatigue
after open-loop rather than in closed-loop exercise is
unknown. In addition, it has been suggested that caffeine
has a significantly greater effect on endurance performance
measured during open-loop exercises than during closed-
loop exercises (14), but whether caffeine ingestion would
result in different end-exercise central and/or peripheral
fatigue after open- and closed-loop high-intensity whole-
body exercise is also unknown. It would be of interest,
therefore, to compare the degree of central and peripheral
fatigue after both closed- and open-loop high-intensity
whole-body exercise and to determine whether caffeine
affects central and peripheral fatigue after both modes of
exercises.
The aim of the present study was to compare the
degree of central and peripheral fatigue after a high-
intensity whole-body endurance exercise adopting closed-
(4,000-m cycling TT) and open-loop (task-to-failure trial
with work rate fixed at mean power of the 4,000-m cycling
TT) exercise modes and whether caffeine ingestion would
affect central and peripheral fatigue after both modes of
exercises. We also compared the sensitivity of the closed-
and open-loop exercises for detecting changes in endur-
ance performance caused by caffeine ingestion. Based on
an expectation of higher physiological strain during open-
loop exercise (13), our first hypothesis was that central
and/or peripheral fatigue would be greater after this mode
of exercise compared to closed-loop exercise. As caffeine
is much more likely to affect open-loop exercise (14), our
second hypothesis was that caffeine might induce greater
end-exercise central and/or peripheral fatigue in this mode
of exercise than in closed-loop exercise.
Materials and Methods
Participants
The required sample size was calculated using the
G-Power software (version 3.1.7). With an alpha of 0.05, a
desired power of 0.90, and a previously reported effect
size for the effect of caffeine on performance during a
4,000-m cycling TT (7) as well as on time to task failure
during a high-intensity exercise (15) (in both cases, effect
size=1.27), the total sample size necessary to achieve
statistical power was estimated to be nine participants.
Therefore, nine men with a mean (±SD) age of 32.3±6.0
years, body mass of 79.3±6.8 kg, height of 181.2±7.9
cm, peak power of 394±44 W (5.0±0.3 W/kg), respira-
tory compensation point (RCP) of 280±34 W (3.5±0.3
W/kg and 71.2±5.6% peak power), maximal oxygen
uptake of 4.3±0.7 L/min (55.2±5.7 mLkg
–1
min
–1
), and
habitual caffeine consumption of 85.5±71.3 mg/day were
recruited to participate in this study. Participants had B4.5
years of cycling experience, with approximately 300 km of
training per week, and were classified as trained cyclists in
accordance with De Pauw et al. (16). The study was
approved by the Ethics Committee for Human Studies of
the University of São Paulo (#807.005). A written informed
consent form was signed by each participant before the
beginning of the study.
Experimental protocol
Participants visited the laboratory nine times at least
48 h apart, within a 4-week period. In the first visit, the
participant’s health status was evaluated via a medical
screening and a resting electrocardiogram, followed by
anthropometric measurements. Then, participants per-
formed a maximal incremental exercise test on their own
bikes attached to a CompuTrainer (RacerMate4
s
, Com-
puTrainert, USA) to determine their maximal oxygen
uptake, maximal power output, and RCP. The maximal
incremental exercise test started with a 5-min warm up at
100 W, followed by increments of 30 W every minute until
task failure. Participants were instructed to maintain pedal
rotation between 80 and 90 rpm, with task failure defined
as a drop in pedal rotation below 80 rpm for more than 5 s,
despite verbal encouragement (7).
On visits 2 and 3, participants were familiarized with
the 4,000-m cycling TT and with neuromuscular function
assessment. On visits 4 and 5, using a crossover, double-
blind design, participants performed a 4,000-m cycling TT
one hour after ingestion of placebo (capsule containing
cellulose) or caffeine (capsule containing 5 mg/kg body
mass of caffeine anhydrous). The CompuTrainer was set
at a cadence-dependent mode and participants were free
to shift gear ratio and pedal frequency during the trials.
Constant feedback of covered distance was available on a
computer screen positioned in front of the participants, but
no other feedback, such as power, speed, or heart rate,
was provided. Neuromuscular function was assessed
Braz J Med Biol Res | doi: 10.1590/1414-431X2021e11901
Caffeine on central and peripheral fatigue after exercises 2/9
before supplementation (Baseline), 60 min after the
capsule ingestion (Pre-exercise), and 2 min after the
end of the exercise (Post-exercise).
On visits 6 and 7, participants were familiarized with
the task-to-failure trial. On visits 8 and 9, participants
performed the task-to-failure trial one hour after ingestion
of placebo or caffeine. The external work rate was fixed by
setting the CompuTrainer in a cadence-independent
mode, in which the selected target work rate is maintained
constant throughout the test. Mean power and pedal
cadence, measured from the 4,000-m TT of visits 2 and 3,
were used to set the work rate and pedal frequency
(313±41 W, 79±4% of peak power, 100±10 rpm). The
gear ratio was also fixed during the entire trial (i.e.,
50 14). Task failure was defined as a drop in pedal rota-
tion below 90% of individual target cadence for more than
5 s, despite verbal encouragement (17). The neuromus-
cular function was assessed as in TT (i.e., Baseline and
Pre- and Post-exercise).
Before all trials, the rear tire pressure was set at 110
psi and the CompuTrainer was calibrated according to
manufacturer’s instructions. Briefly, the rolling resistance
applied to the bicycle tire (1.96–2.0 lbs) was determined
by a calibration acceleration process performed before
and after a 10-min warm-up at 150 W. The calibration
acceleration consisted of an acceleration of the system up
to a speed of 25 mile/h immediately followed by free-
wheels for a standard calibration figure to be registered.
All calibration procedures were done by the same
researcher. When the recommended calibration proce-
dures are followed, the CompuTrainer presents an error of
measurement in power output inferior to 1% (18).
After the calibration procedures, participants per-
formed a 5-min warm-up at 150 W maintaining 90 rpm.
Participants were instructed to remain seated throughout
the trials. The trials were performed at the same time of
the day, and participants were instructed to abstain from
caffeine, alcohol, and strenuous physical exercise 24 h
before each trial. They were also asked to follow the same
diet during the 24 h before each trial and to have their last
meal at least two hours before the trials. Compliance with
these pretest instructions was checked by having partici-
pants fill out pre-test diet and exercise records. Partici-
pants were asked after each exercise trial about which
substance they thought they had ingested.
Neuromuscular function assessment
A Neuro-TES electric stimulator (Neurosoft, Russia)
was used to stimulate the femoral nerve and assess
neuromuscular function of the right quadriceps muscles,
as described in previous studies from our laboratory
(7,19,20). Briefly, participants were seated with the hip at
120° and the knee at 90° on a modified knee-extension
chair (Cefise, Brazil). The lever arm of the machine was
fixed to a force transducer (SML-500, Interface, USA)
and the right ankle attached to the lever arm by a
non-compliant cuff. Inelastic straps were used to hold the
participants on the chair. A cathode electrode was placed
on the femoral triangle and an anode electrode on the
gluteal fold. The optimal electrical stimulation intensity for
further use in the experimental trials was determined
by single pulse (1 Hz, 80 ms of duration) delivery to the
femoral nerve, starting at 100 V and progressively
increasing 30 V every 30 s until attainment of a plateau
in evoked twitch quadriceps force (Q
tw
) and muscle action
potential (M-wave) amplitude of vastus lateralis. The
electromyography activity of the right vastus lateralis
muscle was monitored by a bipolar Ag-AgCl surface
electrode (Hal, Brazil) with a sample rate of 1 kHz
(MyoTraceTM 400, Noaraxon, USA). To determine
M-wave amplitude, peak-to-peak amplitude of the electro-
myography signal induced by the electrical stimulation
was quantified.
To ensure maximal stimulation in the experimental
trials, the stimulation intensity was set at 120% of the
plateau in Q
tw
and M-wave. The plateau in Q
tw
and
M-wave was double-checked at the beginning of every
trial session. Before baseline assessments, a warm-up
was performed (5-s isometric contractions at 50, 60, 70,
80, and 100% of maximal voluntary contraction, with a 30-
s interval between contractions), and then six 5-s maximal
voluntary contractions (MVC) were performed, with visual
feedback of force provided on a computer screen
positioned in front of the participant. Participants were
asked to reach their maximum force rapidly and maintain it
for 5 s, with verbal encouragement provided during all
contractions. Electrical stimulus (1 Hz, 80 ms of duration)
was applied on the femoral nerve when the isometric force
reached a plateau (superimposed twitch) and 2 s after the
end of MVC in relaxed muscle (potentiated quadriceps
twitch force, Q
tw,pot
). During baseline and pre-exercise
phases, the first two measurements were discarded
to avoid the effects of potentiation on Q
tw,pot
; thus, the
average of the remaining four measurements was used for
further analysis (21). A single MVC with electrical
stimulation was performed 2-min post-exercise (19) and
later used to quantify exercise-induced neuromuscular
fatigue (see below).
The MVC was recorded as the highest value found
during each contraction (22). The Q
tw,pot
was recorded as
the evoked peak force (23). The voluntary activation (VA)
was calculated using a modified version of the super-
imposed twitch equation (24):
VAð%Þ¼100DFIB=MVCðÞ=Qtwpot
100 ðEq:1Þ
where, FIB is voluntary force immediately before super-
imposed twitch, D is the force difference between FIB and
maximum force evoked by the superimposed twitch, and
MVC is the maximal voluntary contraction.
Braz J Med Biol Res | doi: 10.1590/1414-431X2021e11901
Caffeine on central and peripheral fatigue after exercises 3/9
Between-day, within-subject coefficients of variation in
our laboratory were B5% for MVC, B2% for VA, and
B5% for Q
tw,pot
(7,20).
Physiological strain
Exercise-induced physiological strain was determined
by measuring total mechanical work, heart rate, oxygen
uptake, and pulmonary ventilation responses during the
trials. Total mechanical work was calculated by multiplying
mean power by exercise time. Heart rate was continually
recorded using a heart rate monitor (Polar FT1 Coded,
Finland), while oxygen uptake and pulmonary ventilation
were measured breath-by-breath using a pre-calibrated
metabolic cart (Cortex Metalyzer 3B, Cortex Biophysik,
Germany). Values of heart rate, oxygen uptake, and
pulmonary ventilation recorded in each trial were aver-
aged for further analysis.
Statistical analysis
Normal distribution of the data was confirmed using
the Shapiro-Wilk test. Performance during closed- and
open-loop exercises was compared between caffeine and
placebo using the paired t-test. Hedges’g effect size (ES)
and 95% confidence interval (95%CI) were calculated
using an online calculator (https://effect-size-calculator.
herokuapp.com/) from means and pooled standard devia-
tions to verify the magnitude of the effect of caffeine on
performance during closed- and open-loop exercises,
assuming values of 0.2, 0.6, 1.2, 2.0, 4.0, and 44.0 as
trivial, small, moderate, large, very large, and extremely
large, respectively (25).
The degree of sensitivity of the closed- and open-loop
exercises for detecting changes in endurance perfor-
mance with caffeine ingestion was determined by calcu-
lating a sensitivity index, as previously recommended
(26). Briefly, performance times were log-transformed, and
the sensitivity index was calculated by dividing mean
differences between placebo and caffeine by the error of
measurement. The error of measurement of a given trial
(closed- or open-loop trial) was calculated by dividing the
standard deviation of the differences between the two
familiarization trials by On–1 (26). The sensitivity index
was further corrected downwards for small-sample bias
using the following equation (27):
1n
p13=4n1ðÞ½fg2
pðEq:2Þ
The confidence limits of the sensitivity index were
derived using a macro to generate quantiles in an Excel
spreadsheet. Comparison of the sensitivity index for the
two modes of exercise was made by inspecting the
overlap of the closed- vs open-loop confidence intervals,
as previously described (12).
To check the existence of a potential order effect on
exercise performance, time to cover the 4,000-m cycling
TT and time to task failure during the first and second trials
were compared using a paired t-test. As no control trial
without supplementation was inserted in the experimental
design (28), a possible placebo effect was checked by
comparing time to cover the 4,000-m cycling TT and time
to task failure during the second familiarization with their
corresponding placebo trials using a paired t-test. The
blinding effectiveness was tested using the w
2
test.
As the preliminary analysis with the paired t-test
showed that oral supplementation alone had no effect
on neuromuscular function (i.e., baseline vs pre-exercise),
which is similar to the results of previous studies (7), three-
way within-subject repeated-measure ANOVA was further
used to determine the effect of supplement (caffeine vs
placebo), trial (closed- vs open-loop), and time (baseline
vs post-exercise) on MVC, VA, and Q
tw,pot
. If ANOVA
yielded a significant result, follow-up pair-wise compar-
isons were conducted using the Bonferroni correction.
Analyses were performed using SigmaStat 3.5 (Systat
Software, Inc., USA). All data are reported as means
±SD, and statistical significance was set at Po0.05.
Results
Reliability of exercise performance, order effect, and
blinding effectiveness
The typical error of measurement was 4.0 s (90%CI:
2.9–6.8) for time to covering the 4,000-m cycling TT
(coefficient of variation=0.9±0.5%). The corresponding
values for time-to-task failure trial were 39.6 s (90%CI:
28.5–67.8, coefficient of variation=9.4±4.1%). There was
no significant order effect for both the 4,000-m cycling TT
(trial 1: 371.6±16.2 s; trial 2: 371.8±14.2; P=0.965) and
the time-to-task failure trial (trial 1: 493.9±133.6 s; trial 2:
476.9±115.8 s; P=0.763). In addition, time to cover the
4,000-m cycling TT during the second familiarization
session (372.7±15.6 s) was not significantly different
from the placebo trial (371.6±16.2 s), and time to task
failure during the second familiarization session (453.2
±127.7 s) was not significantly different from the placebo
trial (418.2±99.6 s). The percent of correct identifications
of which supplement was ingested was not different from
that expected due to chance in both the 4,000-m cycling
TT (w
2
=0.22, P=0.637) and the time-to-task failure trial
(w
2
=2.80, P=0.089).
Overall performance
Mean power during the 4,000-m cycling TT in the
caffeine condition (323±40 W, 115.4±14% RCP) was
higher (P=0.029) than in the placebo condition (308±37
W, 110.3±13% RCP). Time to cover the 4,000-m cycling
TT (Figure 1A) was significantly faster under the caffeine
condition compared to the placebo condition (368.3±15.0
and 375.1±14.5 s, ES=0.42, 90%CI: 0.12–0.78,
P=0.024). Time to task failure (Figure 1B) under the
Braz J Med Biol Res | doi: 10.1590/1414-431X2021e11901
Caffeine on central and peripheral fatigue after exercises 4/9
caffeine condition took longer than the placebo condition
(552.6±106.6 and 418.2±99.6 s, ES=1.18, 90%CI:
0.59–1.96, P=0.001). The sensitivity index for detecting
placebo to caffeine changes was similar between closed-
(1.5, 90%CI: 0.7–2.9) and open-loop exercises (2.8, 90%
CI: 1.9–5.1).
Neuromuscular fatigue
Data of neuromuscular fatigue are shown in Table 1
and Figure 2. There were no interactions between factors
(PX0.05) or main effect of trial (P=0.679) or supplement
(P=0.137) for MVC. There was only a main effect of time
for MVC (P=0.001), with a reduction from baseline to post-
exercise for all trials and supplements. Similar results
were obtained for Q
tw,pot
, with no interactions (PX0.05) or
main effect of trial (P=0.552) or supplement (P=0.097).
There was only a main effect of time for Q
tw,pot
(P=0.001),
with a reduction from baseline to post-exercise for all trials
and supplements. There was a trial vs time interaction for
VA (P=0.019), with the open-loop exercise showing
greater exercise-induced reduction than the closed-loop
exercise. There was no main effect of supplement
(P=0.307) or any other interactions (PX0.05) for VA.
Physiological strain
Data of physiological strain are shown in Table 2.
There was a main effect of trial (P=0.001) and trial vs
supplement interaction (P=0.002) for total work, with
higher values in open- compared to closed-loop exercise
(P=0.001), and under the caffeine condition during the
open-loop exercise (P=0.005), but not during the closed-
loop exercise (P=0.139). There was a main effect of
trial for heart rate (P=0.047), with higher values in the
open-loop exercise. There was also a main effect of
supplement for heart rate (P=0.020), oxygen uptake
(P=0.008), and pulmonary ventilation (P=0.008), with
Figure 1. Time to complete 4,000 m cycling time trial (closed-loop
exercise) (A) and time to task failure (open-loop exercise) (B).
Data are reported as means±SD. *Po0.05 (paired t-test).
Table 1. Neuromuscular function before (baseline) and after a 4,000-m cycling time trial (closed-loop
exercise) and a time-to-task failure trial (open-loop exercise) with caffeine (CAF) and placebo (PLA)
ingestion.
Closed-loop exercise Open-loop exercise
PLA CAF PLA CAF
MVC (N)*
Baseline 678.0±134.3 687.5±141.9 677.5±157.4 681.7±151.8
Post-exercise 624.0±144.4 640.4±183.6 594.0±172.4 631.0±123.2
Q
tw,pot
(N)*
Baseline 187.2±31.5 181.8±23.9 181.9±28.9 179.1±26.2
Post-exercise 135.5±30.0 137.7±41.6 132.0±36.6 138.6±33.8
VA (%)
#
Baseline 92.5±2.7 92.6±2.7 91.7±4.2 89.7±5.9
Post-exercise 89.5±5.2 92.2±3.5 82.7±9.4 86.1±7.2
Data are reported as means±SD. *Main effect of time (lower values post-trial compared to baseline,
Po0.05).
#
Trial vs time interaction (greater reduction from baseline to post-trial in the open- than in the
closed-loop exercise, Po0.05). Three-way within-subject repeated-measure ANOVA. N: Newtons; MVC:
maximal voluntary contraction; Q
tw,pot
: potentiated quadriceps twitch force; VA: voluntary activation.
Braz J Med Biol Res | doi: 10.1590/1414-431X2021e11901
Caffeine on central and peripheral fatigue after exercises 5/9
higher values under the caffeine condition compared to
the placebo condition.
Discussion
The present study indicated that, for detecting caf-
feine-induced improvements in endurance performance,
the sensitivity of a closed-loop exercise is similar to that of
an open-loop exercise. However, the open-loop exercise
induced greater post-exercise central fatigue. Neverthe-
less, caffeine ingestion did not affect end-exercise central
or peripheral fatigue in either the closed- or open-loop
model.
Caffeine ingestion improved performance during the
4,000-m cycling TT (B1.8%), similar to what has been
previously reported for TT of similar distance and duration
(6,29). Caffeine also increased time to task failure during a
constant-load trial (B35%), a result that also corroborates
previous findings (15,30). While changes in time to task
failure resulting from experimental interventions are
expected to be greater than in TT performance (12), the
sensitivity for detecting performance changes seems to be
similar when the differences in error of measurement
between modes of exercise are taken into account
(12,25). Our data suggested, therefore, that caffeine was
ergogenic in different models of exercise, and that closed-
and open-loop exercises had similar sensitivity in detect-
ing ergogenic effects of caffeine. This is in accordance
with a previous report that demonstrated that both models
of exercise have comparable sensitivity for detecting
changes in endurance performance induced by hypoxia
and hyperoxia (12). As previously suggested (12), our
data reinforced that the choice between closed- and open-
loop exercises should be based on other considerations
rather than sensitivity.
Even though both models of exercise showed similar
sensitivity, total work done and mean heart rate were
greater in the open-loop exercise, suggesting an increased
physiological strain. As a result, exercise-induced reduction
Figure 2. Reduction (means±SD of percentage change from
baseline to post-trial) in (A) maximal voluntary contraction (MVC),
(B) evoked quadriceps twitch force (Q
tw,pot
), and (C) voluntary
activation (VA) after a 4,000-m cycling time trial (closed-loop
exercise) and a task-to-failure trial (open-loop exercise) with
caffeine and placebo ingestion. Trial vs time interaction, with a
greater reduction from baseline to post-exercise in the open- than
in the closed-loop exercise. Data are reported as means±SD.
*Po0.05 (three-way repeated-measure ANOVA).
Table 2. Total work and physiological responses during a 4,000-m cycling time trial (closed-loop exercise)
and task-to-failure trial (open-loop exercise) with caffeine (CAF) and placebo (PLA) ingestion.
Closed-loop exercise Open-loop exercise
PLA CAF PLA CAF
Total work (kJ)
w
120.6±9.9 124.6±10.4 149.7±26.6 191.3±20.9
Heart rate (bpm)*
ww
163±13 164±9 163±10 168±9
.
VO
2
(L/min)
ww
3.95±0.42 4.04±0.64 3.85±0.77 4.09±0.51
.
VE (L/min)
ww
136.5±16.2 144.6±15.1 134.2±17.5 144.0±9.1
Data are reported as means±SD. *Main effect of trial (higher values in the open-loop rather than in the
closed-loop exercise, Po0.05).
w
Trial vs supplement interaction (higher values in the caffeine than in the
placebo condition only for open-loop exercise, Po0.05).
ww
Main effect of supplement (higher values in the
caffeine than in the placebo condition, Po0.05). ANOVA. .
VO
2
: oxygen uptake; .
VE: pulmonary ventilation.
Braz J Med Biol Res | doi: 10.1590/1414-431X2021e11901
Caffeine on central and peripheral fatigue after exercises 6/9
in VA was more pronounced after the open-loop exercise.
Previous studies have suggested that during a 4,000-m
cycling TT performed above critical power (i.e., within the
severe-intensity domain) or a task-to-failure trial performed
at power of maximal oxygen uptake (also within the severe-
intensity domain), fatigue is predominantly of peripheral
origin (22,31,32). In the present study, mean power during
the 4,000-m cycling TT for both placebo and caffeine
trials was above the power corresponding to the RCP
(a surrogate of critical power), suggesting that the 4,000-m
cycling TT was performed within the severe-intensity
domain in both placebo and caffeine conditions. Conse-
quently, a significant amount of peripheral fatigue was
identified after both placebo and caffeine trials. It is,
however, not uncommon to report some degree of central
fatigue after an exercise of this intensity (7,8,19,31).
Although no previous study has compared exercise-
induced reduction in VA between closed- and open-loop
exercises, central fatigue seems to vary in an intensity-
dependent manner (31). A small reduction in VA has been
reported for exercise performed at power of maximal
oxygen uptake (31). A greater reduction in VA, however,
is found when the exercise is performed at the RCP, an
exercise intensity where time to task failure is longer than
when exercise is performed at power of maximal oxygen
uptake (31). Thus, the magnitude of central fatigue may rise
as exercise duration increases. As exercise time for the
open-loop was B40% longer than for the closed-loop
exercise, this longer exercise time may have induced the
greater reduction in VA after the open-loop exercise.
Although reduction in VA was more pronounced after
the open-loop exercise, VA was not influenced by caffeine
in either exercise model. Previous studies using a 4,000-m
cycling TT showed no effect of caffeine on exercise-
induced reduction in VA (7,33). To our knowledge, there is
no data of VA reduction after an open-loop exercise after
caffeine ingestion. Nevertheless, a study using a single-
leg, intermittent isometric knee extension contractions
performed until task failure found that caffeine ingestion
increased time to task failure and attenuated the rate of
decline in VA throughout the exercise without changes in
the VA at task failure (34). Although the same may have
occurred in our study, we were unable to measure the rate
by which VA declined during exercise. Thus, further
studies measuring VA throughout an open-loop, whole-
body exercise after caffeine ingestion are necessary to
test this hypothesis.
Different from VA, the degree of decline in evoked
twitch quadriceps force was similar for both exercise
models. These findings are in accordance with the ‘periph-
eral fatigue threshold concept’(35). A peripheral fatigue
threshold has been proposed to represent the maximal
level of peripheral fatigue attainable after an exercise (35).
It is assumed that the maximal level of end-exercise
peripheral fatigue is a fixed amount for a given individual
(35). It should be noted, however, that the peripheral
fatigue threshold is undoubtedly task-specific, as a greater
degree of end-exercise peripheral fatigue is attained
after isometric single-joint exercise than after whole-body
exercise (10). In the present study, although closed- and
open-loop exercises differ in relation to their mode of
execution (self-paced vs fixed work rate), each is a whole-
body exercise presumably recruiting the same amount
of muscle mass. Thus, our finding suggests that the
peripheral fatigue threshold concept is preserved during
different models of whole-body, high-intensity exercise.
There was also no effect of the supplement on the
level of decline in evoked twitch quadriceps force. It was
hypothesized that caffeine would affect the degree of end-
exercise decline in quadriceps twitch force, based on a
previous study showing that caffeine ingestion increases
performance during a 4,000-m cycling TT at the expense
of greater end-exercise locomotor muscle fatigue (7).
A more recent study has demonstrated, however, that
the caffeine-induced improvement on 4,000-m cycling TT
performance seems to be at the expense of greater
locomotor muscle fatigue in low- but not in high-perform-
ing cyclists (33). In fact, our cyclists performed the 4,000
cycling TT closer to the high-performing (B370 s) than to
the low-performing (B412 s) cyclists in the aforemen-
tioned study. This supports the assumption that caffeine
ingestion can improve performance in physically fit
cyclists without negatively affecting their end-exercise
peripheral fatigue. In relation to the open-loop exercise, no
previous study has investigated the effect of caffeine
ingestion on decline in evoked twitch force after this mode
of exercise. As reported for VA, one study noted that
caffeine expanded time to task failure without altering the
end-exercise quadriceps twitch torque during a single-leg,
intermittent isometric knee extension contraction (34). Our
findings add that the peripheral fatigue threshold was not
exceeded with caffeine ingestion during a whole-body
exercise performed in a closed- or an open-loop cycling
exercise model, at least when the peripheral fatigue
threshold is measured in cyclists with higher physical
fitness such as those recruited in the present study.
Together, our findings indicate that endurance perfor-
mance - measured as mean power during a closed-loop
exercise or time to task failure in an open-loop exercise -
improves with caffeine ingestion. This improvement was
not accompanied by changes in the amount of end-
exercise central or peripheral fatigue. However, the fact
that the same degree of end-exercise central and
peripheral fatigue was attained in placebo and caffeine
conditions even with caffeine condition presenting higher
power (closed-loop exercise) or duration (open-loop
exercise) suggests that caffeine might have reduced the
rate of central and peripheral fatigue development. During
closed-loop exercise, a lower rate of central and periph-
eral fatigue development might have enabled participants
to employ a higher power during the trial. During the open-
loop exercise, a lower rate of central and peripheral
Braz J Med Biol Res | doi: 10.1590/1414-431X2021e11901
Caffeine on central and peripheral fatigue after exercises 7/9
fatigue development might have enabled participants to
sustain exercise longer. Thus, the higher power/duration
with caffeine ingestion might have compensated the lower
rate of central and peripheral fatigue development induced
by caffeine ingestion, which resulted in similar end-
exercise central and peripheral fatigue between placebo
and caffeine conditions. Nevertheless, as we have not
measured the rate of decline in central and peripheral
fatigue, further studies are necessary to confirm this
assumption.
A limitation of the present study is that there was a
natural delay when moving from the cycle ergometer to
the knee extension chair, which might result in partial
recovery of both central and peripheral fatigue (36,37).
Although some fatigue recovery might occur within this
time, the magnitude of recovery might have been small
and similar between conditions, as the transition time was
maintained constant across the conditions (i.e., 2 min).
This transition time is also similar to several studies
investigating central and peripheral fatigue after whole-
body exercise (19,22,33,35). In addition, the lack of a
control condition precludes the verification of a potential
placebo effect (28). Nevertheless, we noted no difference
in exercise performance between the second familiariza-
tion session (without pill ingestion) and placebo trial (with
inert pill ingestion) for both closed- and open-loop
exercises, which suggests that a potential placebo effect
impacting our results is unlikely. Additionally, the number
of correct identifications of the ingested supplement
(caffeine or placebo) was not different from that expected
by chance, suggesting a successful blinding process.
Another factor that could influence the ergogenic effect of
caffeine was that participants were low-to-moderate
caffeine consumers and there was a 24-h caffeine
withdrawal before the trials. However, some evidence
suggests that habitual caffeine consumption (38) as well
as the presence or absence of a withdrawal period (39) do
not affect the ergogenicity of caffeine. Finally, our study
was conducted using high-intensity exercise trials per-
formed in the severe-intensity exercise domain. Whether
these results can be expanded to other exercise should be
further investigated.
In conclusion, caffeine ingestion improved endurance
performance, regardless of whether the endurance task
was performed with a closed- or an open-loop exercise
model. Caffeine-induced improvements in endurance
performance did not come at the expense of greater
central and peripheral fatigue in either exercise model.
However, the open-loop exercise resulted in a greater end-
exercise central fatigue than the closed-loop exercise.
Acknowledgments
This work was supported by the Brazilian National
Council for Scientific and Technological Development
(CNPq, Process numbers 406201/2013-7 and 470540/
2013-3), and in part by the Coordination for the Improve-
ment of Higher Education Personnel (CAPES, Brazil;
Finance Code 001). We thank Will G. Hopkins for his
support with the sensitivity index. The English text of this
paper has been revised by Sidney Pratt, Canadian, MAT
(The Johns Hopkins University).
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