J Physiol 586.

1 (2008) pp 161–173 161

Locomotor muscle fatigue modifies central motor drive

in healthy humans and imposes a limitation to exercise
performance
Markus Amann and Jerome A. Dempsey
University of Wisconsin Medical School, John Rankin Laboratory of Pulmonary Medicine, Madison, WI, USA

We asked whether the central effects of fatiguing locomotor muscle fatigue exert an inhibitory
influence on central motor drive to regulate the total degree of peripheral fatigue development.
Eight cyclists performed constant-workload prefatigue trials (a) to exhaustion (83% of peak
power output (W peak ), 10 ± 1 min; PFT83% ), and (b) for an identical duration but at 67% W peak
(PFT67% ). Exercise-induced peripheral quadriceps fatigue was assessed via changes in potentiated
quadriceps twitch force (ΔQtw,pot ) from pre- to post-exercise in response to supra-maximal
femoral nerve stimulation (ΔQtw,pot ). On different days, each subject randomly performed
three 5 km time trials (TTs). First, subjects repeated PFT83% and the TT was started 4 min later
with a known level of pre-existing locomotor muscle fatigue (ΔQtw,pot −36%) (PFT83% -TT).
Second, subjects repeated PFT67% and the TT was started 4 min later with a known level of
pre-existing locomotor muscle fatigue (ΔQtw,pot −20%) (PFT67% -TT). Finally, a control TT was
performed without any pre-existing level of fatigue. Central neural drive during the three TTs
was estimated via quadriceps EMG. Increases in pre-existing locomotor muscle fatigue from
control TT to PFT83% -TT resulted in significant dose-dependent changes in central motor drive
(−23%), power output (−14%), and performance time (+6%) during the TTs. However, the
magnitude of locomotor muscle fatigue following various TTs was not different (ΔQtw,pot of
−35 to −37%, P = 0.35). We suggest that feedback from fatiguing muscle plays an important
role in the determination of central motor drive and force output, so that the development of
peripheral muscle fatigue is confined to a certain level.
(Received 30 July 2007; accepted after revision 23 October 2007; first published online 25 October 2007)
Corresponding author M. Amann: The John Rankin Laboratory of Pulmonary Medicine, 4245 Medical Science Center,
1300 University Avenue, Madison, WI 53706, USA. Email: amann@wisc.edu

We have postulated, based on correlative evidence, that
endurance exercise performance is determined to a
significant extent by the feedback effects of exercise-
induced peripheral muscle fatigue on central motor
output (Amann et al. 2006a, 2007a,b; Romer et al.
2007). The key data supporting this postulate were
obtained in studies that altered inspired O2 fraction (FI,O2 )
(and arterial O2 content) during endurance exercise and
used supra-maximal stimulation of the femoral nerve to
determine the amount of quadriceps fatigue incurred as
a result of the exercise (Amann et al. 2006a,b, 2007b).
The consistent finding was that alterations in arterial
O2 content caused significant changes in central motor
drive (i.e. quadriceps EMG) and power output during
the exercise and consequently exercise performance time,
but the amount of peripheral quadriceps fatigue incurred
at exercise termination was identical. Accordingly, we
postulated that peripheral locomotor muscle fatigue was
a tightly regulated variable during exercise, such that
central motor drive and therefore locomotor power output
would be ‘adjusted’ by the performer so as to prevent
peripheral muscle fatigue from rising above a critical
threshold, beyond which the level of sensory input would
not be tolerated (Gandevia, 2001).
Our present study used an interventional approach
to provide a further test of this hypothesis. We
prefatigued the locomotor muscles to varying degrees
prior to the performance of a 5 km cycling time trial (TT)
and quantified the magnitude of peripheral fatigue via
supra-maximal magnetic stimulation of the motor nerve.
We then observed if these varying levels of ‘prefatigue’
would influence the central motor output during exercise,
the performance of a 5 km TT, and the eventual level of
locomotor muscle fatigue achieved at end-exercise.


C 2008 The Authors. Journal compilation 
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162 M. Amann and J. A. Dempsey
Methods
Subjects
Eight competitive male cyclists volunteered to participate
in the study (age 22.7 ± 1.9 years, body mass 71.1 ± 2.8 kg,
stature 1.79 ± 0.07 m, maximal O2 consumption ( V̇O2 ,max )
63.1 ± 3.5 ml kg −1 min−1 ). Written informed consent was
obtained from each participant. All procedures conformed
to the standards set by the Declaration of Helsinki and the
protocol was approved by the institution’s human subjects
committee.
Exercise responses
Ventilation and pulmonary gas exchange were measured
breath-by-breath at rest and throughout exercise using an
open circuit system including two pneumotachographs
(model 3800; Hans Rudolph, Shawnee, KS, USA)
(inspiration, expiration) and two Perkin-Elmer mass
spectrometer (model 1100; Waltham, MA, USA) for the
analysis of mixed expired and end-tidal gases (Harms
et al. 1998). Arterial O2 saturation was estimated (Sp,O2 )
using a pulse oximeter (N-595; Nellcor, Pleasanton, CA,
USA) with adhesive forehead sensors. Heart rate was
measured from the R-R interval of an electrocardiogram
using a three-lead arrangement. Ratings of perceived
exertion for dyspnoea and limb discomfort were obtained
at rest and every minute during exercise using Borg’s
modified CR10 scale (Borg, 1998). Arterialized (Finalgon;
Boehringer Ingelheim, Germany) capillary blood samples
were collected from an earlobe at rest, every 3 min during
the constant-workload trials and every kilometre during
the TTs for determination of total whole blood lactate
concentration ([La− ]B ) using an electrochemical analyser
(YSI 1500 Sport; YSI Life Sciences, Yellow Springs, OH,
USA).
Neuromuscular function
Electromyography. Quadriceps EMGs were recorded
from the right vastus lateralis (VL), vastus medialis (VM)
and rectus femoris (RF) using monitoring electrodes
with full-surface solid adhesive hydrogel (H59P; Kendall,
Mansfield, MA, USA), with on-site amplification. Electro-
des were placed in a bipolar electrode configuration over
the middle of the respective muscle belly. The active
electrode was placed over the motor point of the muscle.
The recording electrode was moved along the muscle
until a good configuration – confirmed by a ‘maximal’
M-wave shape – was achieved. The reference electrode
was placed over an electrically neutral site. The position
of the EMG electrodes was marked with indelible ink
to ensure that they were placed in the same location at
subsequent visits. Proper electrode configuration was
checked before the beginning of every experiment. To
minimize movement artifacts, electrode cables were
J Physiol 586.1
fastened to the subject’s quadriceps using medical adhesive
tape and wrapped in elastic bandage. The VL, VM and RF
electrodes were used to record: (a) magnetically evoked
compound muscle action potentials (M-waves) to evaluate
changes in membrane excitability; and (b) EMG for VL
throughout exercise to estimate fatigue and central neural
drive. The M-wave properties included conduction time,
peak amplitude and area (Caquelard et al. 2000; Sandiford
et al. 2005; Katayama et al. 2007). Membrane excitability
was maintained from pre- to post-exercise in all trials
as indicated by unchanged M-wave characteristics. This
suggests that the observed changes in potentiated twitch
force (Qtw,pot ) are mainly due to changes within the
quadriceps and that peripheral failure of electrical trans-
mission might be excluded.
Raw EMG signals from VL, VM and RF corresponding
to each muscle contraction during the exercise trials
and the pre- and post-exercise MVC manoeuvres were
recorded for later analysis. The EMG signals were amplified
and filtered by a Butterworth band pass filter (BMA
−830; CWE, Ardmore, PA, USA) with a low pass cut-off
frequency of 10 Hz and a high pass cut-off frequency of
1 kHz. The slope of the filters was −6 dB octave−1 . The
filtered EMG signals were sampled at 2 kHz by a 16-bit A/D
converter (PCI-MIO-16XE-50; National Instruments,
Austin, TX, USA) with custom software (Labview 6.0;
National Instruments). A computer algorithm identified
the onset of activity where the rectified EMG signals
deviated by more than two standard deviations above the
baselines for at least 100 ms. Each EMG burst was visually
inspected to verify the timing identified by the computer.
For data analysis, the integral of each burst (integrated
EMG, iEMG)
 t was calculated using the formula iEMG
[|m(t)|] = 0 |m (t)|dt where m is the raw EMG signal.
A 1024 point fast Fourier transform was used to
compute a power spectrum periodogram. The mean power
frequency (MPF) was calculated using the formula
f
f Sm ( f ) d f
MPF = 0 f
Sm ( f ) d f
0
where Sm (f ) is the power density spectrum of the EMG
signal.
Magnetic stimulation. For a detailed description we refer
the reader to previous studies from our laboratory (Amann
et al. 2006b, 2007b; Romer et al. 2006). Briefly, subjects
lay semirecumbent on a table with the right thigh resting
in a preformed holder, the knee joint angle set at
1.57 rad (90 deg) of flexion and the arms folded across
the chest. A magnetic stimulator (Magstim 200; The
Magstim Company, Wales, UK) connected to a double
70 mm coil was used to stimulate the femoral nerve.
The evoked quadriceps twitch force was obtained from a
calibrated load cell (model SM 1000; Interface, Scottsdale,

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J Physiol 586.1 Locomotor muscle fatigue and exercise performance
AZ, USA) connected to a noncompliant strap, which was
placed around the subject’s right leg just superior to the
ankle malleoli. To determine whether nerve stimulation
was supramaximal, three single twitches were obtained
every 30 s at 50, 60, 70, 80, 85, 90, 95 and 100% of
maximal stimulator power output. A near plateau in
baseline Qtw and M-wave amplitudes with increasing
stimulus intensities was observed in every subject,
indicating maximal depolarization of the femoral nerve.
The Qtw,pot is more sensitive for detecting fatigue than
the nonpotentiated twitch, particularly when the degree
of fatigue is small (Kufel et al. 2002). Furthermore,
Qtw,pot is more valid for comparing differences in fatigue
when levels of post-activation potentiation are unequal,
as was expected to occur in the present study where the
exercise durations differed (Rassier & Macintosh, 2000).
Accordingly, we measured quadriceps twitch force 5 s
after a 5 s maximal voluntary contraction (MVC) of the
quadriceps and repeated this procedure six times such
that six Qtw,pot were obtained (Kufel et al. 2002). Like
others (Kufel et al. 2002), we found that the degree of
potentiation was slightly smaller after the first and, to a
lesser extent, after the second MVC; therefore, we discarded
the first two measurements. Activation of the quadriceps
during the MVCs was assessed using a superimposed
twitch technique (Merton, 1954; Strojnik & Komi, 1998).
Briefly, the force produced during a superimposed single
twitch on the MVC was compared with the force produced
by the potentiated single twitch delivered 5 s afterward.
The assessment procedure was performed before exercise
(∼20 min) and at 4 min after exercise, which represented
the duration of the break between the prefatigue trials and
the subsequent TTs (see below). Peak force, contraction
time (CT), maximal rate of force development (MRFD),
one-half relaxation time (RT0.5 ), and maximal relaxation
rate (MRR) were analysed for all Qtw,pot (Lepers et al. 2002;
Sandiford et al. 2005).
Protocol
At preliminary visits to the laboratory, subjects were
thoroughly familiarized with the procedures used to assess
neuromuscular functions. All participants performed a
practice 5 km cycling TT, a practice constant-workload
trial to the limit of exhaustion, and a maximal incremental
exercise test (20 W + 25 W min−1 ; Amann et al. 2004)
on a computer-controlled electromagnetically braked
cycle ergometer (Velotron, Elite Model; Racer Mate,
Seattle, WA, USA) for the determination of peak power
output (W peak ) and V̇O2 ,max . The following two visits
were used to evaluate the degree of locomotor muscle
fatigue induced via constant-load cycling at two different
exercise intensities (prefatigue trials, PFTs). First, all
subjects cycled to exhaustion (Amann et al. 2007b)
at 83 ± 1% of W peak (PFT83% ) (resulting in a pre- to
post-exercise change in Qtw,pot (Qtw,pot ) of −36 ± 2%)

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163
(see Fig. 1). Second, exercise was repeated for the identical
duration (10.1 ± 0.5 min) but at a lower exercise intensity
(67 ± 1% of W peak ; PFT67% ) (resulting in Qtw,pot of
−20 ± 1%) (Fig. 1). During these PFTs, subjects used
visual and verbal feedback in order to maintain their
self-selected pedal cadence (105 ± 2), as inferred from
the practice trials. Next, on separate days and in random
order, all participants performed three 5 km cycling TTs
(performance trials) (Fig. 1). The first performance trial
was carried out in a ‘fresh’ state without pre-existing
locomotor muscle fatigue (Ctrl). The second performance
trial (PFT83% -TT) was started following a 4 min rest
period which was preceded by the PFT83% prefatigue trial;
hence, the PFT83% -TT performance trial was launched
with a known level of pre-existing locomotor muscle
fatigue (Qtw,pot of −36%). The third performance trial
(PFT67% -TT) was started following a 4 min rest period
which was preceded by the PFT67% prefatigue trial; hence,
the PFT67% -TT performance trial was launched with a
known level of pre-existing locomotor muscle fatigue
(Qtw,pot of −20%).
All of the exercise trials were preceded by a 10 min
warm-up at 1.5 W (kg body mass)−1 and the subjects
remained seated throughout exercise. To avoid initial peak
force outputs in the performance and the PFTs, subjects
were instructed to slowly pick up their pace, the
recording period started after the mean power output
and pedal cadence, adopted from the practice trials, was
reached (within 10 s). Neuromuscular functions were
assessed before and 4 min after exercise (Fig. 1). The
subjects were naive to the purpose of the study and the
expected outcomes. Each exercise session was separated
by at least 48 h and was completed at the same time of day.
Subjects were instructed to refrain from caffeine for 12 h,
and stressful exercise for 48 h, before each exercise trial.
Ambient temperature and relative humidity were not
different between conditions.
The exercise time in both PFTs was 10.1 ± 0.5 min. The
group mean power output during PFT83% was 347 ± 14 W
(equals 83 ± 1% W peak or 98 ± 1% V̇O2 ,max ) which was
individually chosen based on the mean power output from
the practice 5 km TT. The power output during PFT67% was
276 ± 14 W (equals 67 ± 1% W peak or 75 ± 2% V̇O2 ,max )
which was based on the intention to induce a lesser
degree of end-exercise locomotor muscle fatigue compared
with PFT83% (see below). The effects of various PFTs on
physiological responses during the final minute of exercise
are represented in Table 1 and Fig. 2. All variables indicate
a significantly lower exertion at end-exercise in PFT67%
versus PFT83% .
Reliability, reproducibility and technical
considerations
Magnetic femoral nerve stimulation. For between-day
reliability, the subjects repeated the magnetic stimulation
164 M. Amann and J. A. Dempsey J Physiol 586.1

Table 1. Physiological response to the final 30 s of constant work rate (prefatigue trials) and 5 km time trial (performance
trials) exercise

Prefatigue trial (PFT) 5 km time trials (TT)

PFT83% PFT67% Ctrl PFT83% -TT PFT67% -TT

Power output (W) 347 ± 14 276 ± 10∗ 347 ± 14a 298 ± 14a † 332 ± 18a †,‡
Power output (% of W peak ) 83 ± 1 67 ± 1∗ 83 ± 1 72 ± 2 † 80 ± 2†,‡
Exercise time (min) 10.1 ± 0.5 10.1 ± 0.5 7.3 ± 0.1 7.8 ± 0.1 † 7.5 ± 0.1†,‡
r.p.m. 105 ± 3 105 ± 2 105 ± 2 104 ± 2 107 ± 2
Sp,O2 (%) 92.8 ± 0.8 97.4 ± 0.4∗ 92.1 ± 0.8 94.3 ± 0.8 † 95.1 ± 0.5†
HR (beats min−1 ) 194 ± 2 175 ± 3∗ 197 ± 3 192 ± 3† 192 ± 3†
RPE (dyspnea) 8.8 ± 0.4 5.4 ± 0.5∗ 8.5 ± 0.4 8.7 ± 0.4 8.7 ± 0.2
RPE (limb discomfort) 8.7 ± 0.4 5.3 ± 0.6∗ 8.6 ± 0.3 8.8 ± 0.4 8.6 ± 0.2
f R( breaths min−1 ) 61 ± 2 43 ± 2∗ 62 ± 3 63 ± 3 63 ± 3
V T (l) 2.7 ± 0.1 2.5 ± 0.1 2.8 ± 0.2 2.5 ± 0.1 † 2.6 ± 0.2 †
V̇E (l min−1 ) 165 ± 8 104 ± 3∗ 174 ± 8 154 ± 8† 160 ± 9†
V̇O2 (l min−1 ) 4.4 ± 0.2 3.4 ± 0.1∗ 4.4 ± 0.2 3.8 ± 0.2 † 4.0 ± 0.2†,‡
V̇O2 (% of V̇O2 ,max ) 98 ± 1 75 ± 2∗ 98 ± 1 86 ± 4 † 93 ± 2†,‡
V̇CO2 (l min−1 ) 4.3 ± 0.2 3.4 ± 0.1∗ 4.6 ± 0.3 3.7 ± 0.2† 4.1 ± 0.3†,‡
V̇E / V̇O2 42 ± 1 31 ± 1∗ 41 ± 2 42 ± 1 41 ± 1
V̇E / V̇CO2 41 ± 1 31 ± 2∗ 38 ± 1 42 ± 2 40 ± 1
PET,O2 (mmHg) 112 ± 1 103 ± 1∗ 110 ± 2 113 ± 2 112 ± 2
PET,CO2 (mmHg) 31 ± 2 38 ± 1∗ 30 ± 1 32 ± 1 32 ± 2
Capillary [La− ]B (mmol l−1 ) 13.5 ± 1.5 4.7 ± 1.0∗ 12.2 ± 0.5 7.6 ± 0.9† 7.5 ± 0.6 †
Values are expressed as means ± S.E.M. a Mean power output over entire time trial. Note that all given mean values
for the time trials and prefatigue trials (except power output and exercise time) were taken over the final 30 s of
exercise.∗ P < 0.05 versus PFT83 %, †P < 0.05 versus Ctrl, ‡P < 0.05 versus PFT83 %-TT; N = 8

protocol at rest on separate visits to the laboratory. There
was no systematic bias in the baseline measurements
between days. Mean between-day, within-subject
coefficients of variation for Qtw,pot were 4.3 ± 0.8
(range 1.0–6.8), 2.1 ± 1.3 (range 0.6–5.9) for MVC and
1.2 ± 0.5 (range 0.0–3.4) for voluntary muscle activation.
Additional reliability measures regarding magnetic nerve
stimulation as well as technical considerations addressing
Pre-Fatigue Trials

Pre-fatigue trial Assessment of 20 min PFT83% 4 min Assessment of

Warm-up
“PFT83%” Muscle Functions 346 ± 13 W, 10 ± 1 min Muscle Functions

Pre-fatigue trial Assessment of 20 min PFT67% 4 min Assessment of

Warm-up
“PFT67%” Muscle Functions 276 ± 10 W, 10 ± 1 min Muscle Functions

Performance Trials

Performance trial Assessment of 20 min Time trial 4 min Assessment of

Warm-up
“Ctrl” Muscle Functions 5 km Muscle Functions

Performance trial Assessment of 20 min PFT83% 4 min Time trial 4 min Assessment of
Warm-up
“PFT83-TT” Muscle Functions 346 ± 13 W, 10 ± 1 min 5 km Muscle Functions

Performance trial Assessment of 20 min PFT67% 4 min Time trial 4 min Assessment of
Warm-up
“PFT67-TT” Muscle Functions 276 ± 10 W, 10 ± 1 min 5 km Muscle Functions

Figure 1. Schematic illustration of the experimental design

As the first step, the prefatigue trials were carried out in the indicated order and separated by at least 48 h. For
the second step various performance trials were conducted in random order and separated by at least 48 h.


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J Physiol 586.1 Locomotor muscle fatigue and exercise performance 165

the limitations of surface EMG and magnetic femoral muscle fatigue. However, the decrease in force output
nerve stimulation can be found in published reports following PFT83% (59 ± 5 N) was substantially greater
(Enoka & Stuart, 1992; Keenan et al. 2005; Amann et al. compared with PFT67% (35 ± 4 N) 4 min post exercise
2006a,b, 2007b; Romer et al. 2006). (P < 0.01) (Table 2, Fig. 3). Various within-twitch
Exercise trials. Following the practice trials, all eight measurements, namely MRFD, MRR and RT0.5 , as well
subjects repeated Ctrl (TT) and PFT83% (constant as MVC force measures, complemented the findings
workload trial to exhaustion) twice on different days reported for Qtw,pot . Significant differences for various
for reproducibility measures. No systemic changes within-twitch variables and MVC force were found
occurred in group mean values for performance time between the two PFTs (Table 2).
(Ctrl and PFT83% ) and mean power output (Ctrl).
Between-day coefficients of variation for performance EMG activity. Integrated EMG of vastus lateralis rose
time were 0.7 ± 0.1% (range 0.2–1.1) and 5.2 ± 1.3% significantly from the first minute of exercise to the
(range 0.8–12.6) for Ctrl and PFT83% , respectively; and point of exhaustion in all eight subjects at both PFTs
1.3 ± 0.1% (range 1.0–1.8) for mean power output during (P < 0.01). The exercise-induced increase in iEMG was
Ctrl. significantly greater in PFT83% versus PFT67% (15.8 ± 1.8
and 8.0 ± 1.9%, respectively) (Fig. 4). The continuous
increase in iEMG was associated with a significant decrease
Statistical analyses
in MPF from the first minute to the termination of
Repeated measures ANOVA was used to test for exercise at both trials. At termination of exercise, MPF
within-group effects across time. Following significant had fallen significantly more during PFT83% versus PFT67%
main effects, planned pairwise comparisons were made (11.6 ± 1.1 and 6.7 ± 0.9%, respectively) (Fig. 4).
using the Holm’s sequential Bonferroni procedure. Results
are expressed as means ± s.e.m. Statistical significance was
set at P < 0.05. The effects of pre-existing fatigue on subsequent TT
performance, iEMG and locomotor muscle fatigue
Results TT performance. Exercise performance was significantly
affected by the level of pre-existing locomotor muscle
The effects of PFTs on locomotor muscle fatigue
fatigue. Time to complete the 5 km performance task
Contractile function. Qtw,pot following exercise was increased from Ctrl (no pre-existing level of fatigue)
markedly decreased (P < 0.01) from pre-exercise baseline to PFT67% -TT (moderate level of pre-existing fatigue,
in both PFTs indicating substantial levels of locomotor Table 2) by 2.0 ± 0.8% (range 1–8%; P < 0.05) and from

Pre-fatigue: PFT83% (346 W)

14 Pre-fatigue: PFT67% (276 W)
Capillary blood lactate (mmol l–1)

12
‡
10
*
8 *
* * *
6
*
4
Ctrl (7.3 min; 347 W)
2 PFT83%-TT (7.8 min; 298 W)
PFT67%-TT (7.5 min; 332 W)
0
0 2 4 6 8 10 0 1 2 3 4 5
Time [min] Distance [km]

Figure 2. Capillary blood lactate during the two constant-workload prefatiguing trials (PFT83% ,
347 ± 14 W; PFT67% , 276 ± 10 W; 10.1 ± 0.5 min each) followed by the two experimental time trials
(PFT83% -TT and PFT67% -TT)
The control time trial (Ctrl) was performed without pre-existing locomotor muscle fatigue. The two experimental
time trials were started after a 4 min resting phase following the prefatiguing exercises which resulted in a reduction
in potentiated twitch force (Qtw,pot ) of about 36 and 20% for PFT83% and PFT67% , respectively. ∗ P < 0.05, ‡P < 0.05
versus Ctrl.


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166 M. Amann and J. A. Dempsey J Physiol 586.1

Table 2. Effects of constant work rate (prefatigue trials) and 5 km time trial exercise on quadriceps muscle functions

Prefatigue trial Time trials

PFT83% PFT67% Ctrl PFT83% -TT PFT67% -TT

Power output (W) 347 ± 14 276 ± 10 347 ± 14 298 ± 14† 332 ± 18†,‡
Exercise time (s) 10.1 ± 0.5 10.1 ± 0.5 7.3 ± 0.1 7.8 ± 0.1† 7.5 ± 0.2†,‡
Percentage change from pre to 4 min postexercise
Potentiated single twitch (N) −35.8 ± 2.3 −20.1 ± 0.9∗ −35.5 ± 2.3 −36.7 ± 2.8 −35.1 ± 2.2
MRFD (N s−1 ) −33.2 ± 3.1 −15.5 ± 1.1∗ −32.4 ± 2.5 −34.5 ± 3.3 −32.4 ± 3.0
MRR (N s−1 ) −34.0 ± 2.7 −18.0 ± 1.0∗ −33.2 ± 2.5 −35.6 ± 1.9 −33.2 ± 2.5
CT (s) −6.5 ± 0.7 − 5.2 ± 0.4∗ − 6.4 ± 0.7 −6.3 ± 0.6 −6.1 ± 0.6
RT0.5 (s) 6.8 ± 1.1 2.2 ± 0.7∗ 7.2 ± 1.5 7.2 ± 1.5 6.6 ± 0.9
MVC peak force (N) −10.3 ± 1.6 0.7 ± 1.3 #∗ −9.6 ± 0.8 −10.4 ± 1.9 −9.3 ± 1.0
% Muscle activation 0.4 ± 0.8 # −0.2 ± 0.4 # −0.5 ± 0.3 # 0.0 ± 0.5 # 0.3 ± 0.4 #
Peripheral fatigue was assessed via supramaximal magnetic stimulation of the femoral nerve before and 4 min after exercise. Changes
in fatigue variables are expressed as a percent change from pre-exercise baseline to 4 min after the termination of exercise Values
are expressed as means ± S.E.M. MRFD, maximal rate of force development; MRR, maximal rate of relaxation; CT, contraction time;
RT0.5 , one-half relaxation time; MVC, maximal voluntary contraction. Percent muscle activation is based on superimposed twitch
technique. Majority of variables changed significantly compared with baseline 4 min after exercise (P < 0.01). #Not significantly
different from pre-exercise baseline. Pre-exercise, resting mean values for potentiated single twitch, MRFD, MRR, CT, RT0.5 , MVC, and
percentage muscle activation were 170 ± 2 N, 1553 ± 21 N s−1 , 1060 ± 13 N s−1 , 0.26 ± 0.00 s, 0.12 ± 0.00 s, 548 ± 7 N, and 95.6 ± 0.5%,
respectively. N = 8;∗ P < 0.05 versus PFT83% , †P < 0.05 versus Ctrl, ‡P < 0.05 versus PFT83% -TT

Ctrl to PFT83% -TT (severe level of pre-existing fatigue,
Table 2) by 6.1 ± 0.7% (range 3–9%; P < 0.01) in all eight
subjects (Table 1). These changes in time to completion
are reflected in mean power output during the TTs which
was 4.4 ± 1.8% (range 1–16%) lower in PFT67% -TT and
14.1 ± 1.6% (range 6–21%) lower in PFT83% -TT versus
Ctrl (P < 0.05 and 0.01, respectively) (Table 1). The profile
of power output during various performance trials are
shown in Fig. 5.
Central neural drive. Figure 5 illustrates changes in iEMG
during the three performance trials; each point represents
a 500 m segment of the TT. For all TTs, mean iEMG of
the vastus lateralis was normalized to the iEMG obtained

–40
(percentage reduction in Qtw,pot from
Locomotor muscle fatigue

pre- to post-exercise)

–30

*
–20
PFT83%-TT

PFT67%-TT

–10
PFT83%

PFT67%

Ctrl

0
Pre-fatigue trials Performance trials

Figure 3. Peripheral quadriceps fatigue expressed as a percent change in Qtw,pot from pre- to 4 min
post-exercise
The two constant-workload trials (PFT83% , 347 ± 14 W; and PFT67% , 276 ± 10 W; 10.1 ± 0.5 min each) were
performed to induce a pre-existing level of peripheral fatigue. The control performance trial (Ctrl) was conducted
without pre-existing locomotor muscle fatigue. The two experimental performance trials (PFT83% -TT and
PFT67% -TT) were conducted with a pre-existing level of peripheral quadriceps fatigue. The time trials started
after a 4 min resting phase following either PFT83% or PFT67% . Note that despite significantly different levels
of pre-existing locomotor muscle fatigue, resulting in substantially different exercise performances, end-exercise
locomotor muscle fatigue was almost identical between the three performance trials and the PFT83% prefatiguing
trial (dashed line) supporting the hypothesis of an existing critical threshold of fatigue. n = 8; ∗ P < 0.01.


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J Physiol 586.1 Locomotor muscle fatigue and exercise performance 167

A
115

iEMG (%change from 1st min)

*
110 *
*

105

100

100 B

MPF (%change from 1st min)

98

96
Figure 4. Myoelectrical activity 94
A, integrated EMG (iEMG), and B, mean power
frequency (MPF), of vastus lateralis used to illustrate the 92 *
*
development of peripheral locomotor muscle fatigue *
90
during the two constant-workload prefatigue trials
PFT83%
(PFT83%, 347 ± 14 W; and PFT67%, 276 ± 10 W). 88
PFT67%
Values are normalized to the first minute of exercise.
Mean values for iEMG and MPF during each muscle 86
contraction (cycle revolution) were calculated and 0 1 2 3 4 5 6 7 8 9 10
averaged over each 60 s period. ∗ P < 0.01. Time (min)

from pre-exercise MVC manoeuvres (performed without muscle fatigue, i.e. from Ctrl to PFT67% -TT (6.9 ± 0.7%)
pre-existing fatigue) on each day. The average iEMG ratio and PFT67% -TT to PFT83% -TT (17.5 ± 1.4%) (Fig. 6).
over the entire TT was reduced (P < 0.05) with each A reduction in average iEMG from Ctrl to PFT83% -TT
increment in pre-existing level of peripheral locomotor occurred in seven of the eight subjects (range 8–36%).

A
iEMG (% of pre-exercise MVC)

50

45

40
Figure 5. Effect of pre-existing locomotor muscle
fatigue on neural drive and power output during 35
a 5 km time trial
The control time trial was performed without
30
pre-existing locomotor muscle fatigue. The two
experimental time trials (PFT83% -TT and PFT67% -TT) B
were performed with different levels of pre-existing PFT83%-TT (7.8 ± 0.1 min)
quadriceps fatigue (Qtw of about −36 and −20% for 390 PFT67%-TT (7.5 ± 0.1 min)
PFT83% -TT and PFT67% -TT, respectively). A, effects of Ctrl (7.3 ± 0.1 min)
Power output (W)

pre-existing locomotor muscle fatigue on group mean 360

iEMG of vastus lateralis normalized to the iEMG
obtained during pre-exercise (unfatigued) maximal
voluntary contractions (MVC) of the quadriceps. Each 330
point represents the mean iEMG of the preceding
0.5 km section. Mean iEMG during the time trial was 300
significantly reduced from Ctrl to PFT83% -TT. B, group
mean variations in power output during the 5 km time 270
trial with three different levels of pre-existing fatigue.
Group mean power output was 347 ± 14 W,
298 ± 14 W and 332 ± 18 W (P < 0.05) for Ctrl, 0 1 2 3 4 5
PFT83% -TT and PFT67% -TT, respectively; n = 8. Distance (km)


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168 M. Amann and J. A. Dempsey J Physiol 586.1

(percentage reduction in Qtw,pot from pre-exercise)

Neural drive
Mean power output
Post-5 km time trial fatigue
400

Mean power output (Watts)

45
–40
Neural drive (iEMG, % of
Peripheral fatigue

40
pre-exercise MVC)

360
–30
35 Figure 6. Summary of effects of pre-existing level
–20 320 of locomotor muscle fatigue on group mean
30 neural drive and mean power output during a
5 km time trial, and end-exercise locomotor
–10 25 280 muscle fatigue (percentage reduction in Qtw,pot )
The control 5 km time trial was started without
0 20 pre-existing locomotor muscle fatigue. The remaining
Ctrl PFT67%-TT PFT83%-TT time trials were started with significant levels of
(No pre-fatigue) (Moderate level of (Severe level of locomotor muscle fatigue (Qtw,pot −20 and −36%
pre-fatigue) pre-fatigue) for PFT67% -TT and PFT83% -TT, respectively, P < 0.05).

Contractile function. Immediately after each TT, group exercise-induced reduction in Qtw,pot existing prior to the
mean Qtw,pot was reduced between 57 and 62 N from start of a 5 km TT causes a significant reduction in average
pre-exercise baseline (P < 0.01). These reductions in iEMG during the TT and the greater the peripheral fatigue
Qtw,pot 4 min following the TTs were not significantly the greater the reduction in iEMG during subsequent
different between conditions of varying pre-existing levels exercise.
of locomotor muscle fatigue (−35 to −37%; P = 0.35)
(Table 2, Fig. 6). All within-twitch measurements (MRFD,
MRR, CT and RT0.5 ) were significantly altered from Contractile functions: PFT83% versus performance trials.
baseline immediately post-exercise (Table 2). No The reductions in Qtw,pot 4 min after exercise was nearly
differences in these variables were observed 4 min identical between PFT83% and the three performance trials
post-exercise between the three performance trials (P = 0.44; Table 2, Fig. 3). Furthermore, no significant
(P = 0.18–0.91). Peak force during the 5 s MVC differences were observed among various within twitch
manoeuvres was significantly decreased from baseline after measurements (P = 0.37–0.92) and reductions in peak
all trials (P < 0.01). These reductions in MVC force did not forces during the MVC manoeuvres were similar following
differ among the three TTs (P = 0.78) (Table 2). exercise (P = 0.78) (Table 2).

Relationship between Qtw,pot and TT iEMG. Figure 7

illustrates the relationship between pre-TT quadriceps Discussion
strength (Qtw,pot ) and average neural drive (iEMG) during
We asked if central motor drive – and therefore exercise
subsequent TTs. In general, the results suggest that any
performance – is regulated to avoid the development
of peripheral locomotor muscle fatigue beyond an
individual, highly task-specific, critical threshold. Using
(percentage of pre-exercise MVC)

constant-workload trials we induced two significantly

Mean iEMG during time trial

55 different levels of locomotor muscle fatigue immediately

prior to the start of a 5 km cycling TT performance test
50 during which the subjects were able to voluntarily choose
their power output in order to finish the task as fast
45
as possible. Pre-existing locomotor muscle fatigue had
Ctrl a substantial dose-dependent inverse effect on central
40 PFT67%
PFT85% motor output and power output during the 5 km TTs
100 120 140 160 180 and a direct effect on performance time. However, despite
Qtw,pot (N) the significant differences in quadriceps fatigue at the
initiation of the TT, the magnitude of peripheral muscle
Figure 7. Group mean data (n = 8) showing the relationship fatigue developed at end-exercise was identical (Fig. 6).
between Qtw,pot as measured prior to the start of a 5 km time
trial, and mean iEMG of vastus lateralis during subsequent time
These data emphasize the crucial role of locomotor muscle
trials fatigue on exercise performance via its inhibitory influence
Pre-existing levels of fatigue (i.e. reductions in pre-time trial Qtw,pot on central motor drive and, furthermore, confirm the
from Ctrl) was induced via constant-workload exercise. status of peripheral fatigue as a carefully regulated variable.


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J Physiol 586.1 Locomotor muscle fatigue and exercise performance
Indices of reductions in central motor drive
with locomotor muscle fatigue
Changes in central motor drive during various TTs
generally followed those in power output, both with
increasing distance covered and with alterations in the level
of prefatigued locomotor muscle (Fig. 5). Accordingly, we
believe that the observed changes in EMG of the vastus
lateralis associated with alterations in the pre-existing
level of locomotor muscle fatigue permit the qualitative
conclusion that changes in locomotor muscle power
output were in a similar direction to those in central
neural locomotor output. However, we cannot quantify
the proportion of the observed changes in power output
attributable to changes in central neural drive. Instead, it is
also plausible that the observed level of peripheral fatigue
(i.e. biochemical changes within the muscle) prevented the
muscle from responding to the same extent to an identical
level of motor command (also see below).
The estimation of central motor drive will be affected by
the accuracy of EMG measurements via surface electrodes
(Keenan et al. 2005; Amann et al. 2006a,b) and potential
changes could be masked by noise. Therefore, since we
postulate that the limitation to exercise performance is due
primarily to a consciously and/or subconsciously reduced
central motor command rather than due to the inability
of the locomotor musculature to respond to increases
in neural drive, an additional and crucial observation
indicating reduced central command during the TT tests
needs to be emphasized. Namely, power output was
identical, at least for brief time periods, at the beginning
of each TT – despite different levels of pre-existing fatigue
– and rose to almost identical levels in the final 200 m
(Fig. 5). These findings indicate that the locomotor
musculature maintained responsive to central motor
drive throughout exercise even in conditions of
severe peripheral fatigue. This maintained capability
of the locomotor muscles to increase power output
in response to increases in central neural drive
emphasizes the fact that the subjects chose – again,
consciously and/or subconsciously – to keep central
motor output at a certain submaximal level presumably
to avoid further accumulation of peripheral fatigue
(i.e. further accumulation of nociceptor stimulating
metabolic byproducts; see below) and consequently
intolerable levels of sensory input. Accordingly, we suggest
that the stimulation of intramuscular pain receptors
via metabolic byproducts of muscular contractions and
associated feedback to the CNS could be viewed as a
dose-dependent trigger of central fatigue, i.e. the stronger
the stimulus and the greater the rate of development of
peripheral fatigue, the greater the inhibitory afferent feed-
back to the CNS which in turn affects the determination
of central motor drive.

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169
Effect of prior fatigue on exercise performance
and the development of locomotor muscle fatigue
Central neural drive – and consequently power output
– during various 5 km TTs was inversely related to the
level of pre-existing locomotor muscle fatigue. In other
words, the higher the level of pre-existing locomotor
muscle fatigue (i.e. the lower the pre-existing Qtw,pot ),
the lower the average neural drive during the subsequent
TT (Fig. 7). The striking finding was that at end-exercise
the level of peripheral fatigue was identical between the
three TTs – independent of the level of pre-existing fatigue
and/or the marked differences in exercise performance
(see summary in Fig. 6). For instance, one of the TTs
was started with a severe level of pre-existing fatigue
as induced via high-intensity constant-workload exercise
to voluntary exhaustion (PFT83% ). Hence, the individual
critical threshold of peripheral fatigue, as proposed pre-
viously (Amann et al. 2006a), – or sensory tolerance
limit (Gandevia, 2001) – had already been achieved
when the TT started (see Fig. 3). Astonishingly, since
the level of locomotor muscle fatigue at the end of
the TT (PFT83% -TT) was identical compared with the
pre-existing level at the start of the TT (i.e. at the
critical threshold of fatigue) (see Fig. 3), the subjects,
who were instructed to finish the TT as fast as possible,
must have voluntarily chosen a power output throughout
the race low enough to result in no further accumulation
of peripheral fatigue. On the other hand, when the
TT was started with no pre-existing fatigue (control)
or a lower level of pre-existing locomotor muscle
fatigue (PFT67% -TT, see Fig. 3), peripheral fatigue further
accumulated throughout the subsequent TT to reach
the critical threshold at end-exercise. Combined, these
findings suggest that central neural drive during various
TTs is modulated to result in a rate of development of
peripheral fatigue that prohibits one from exceeding the
critical threshold or sensory tolerance limit associated
with a certain level of peripheral fatigue. Our present
use of prior exercise as a means of varying the degree of
peripheral fatigue has produced very similar effects on
central motor output, performance, and end-exercise peri-
pheral fatigue as we previously reported using varying FI,O2
values to change arterial O2 content across the range of
hyperoxia to moderate hypoxaemia (Amann et al. 2006a,
2007b).
We emphasize that the percentage reduction in Qtw,pot
associated with the critical threshold of peripheral fatigue
as observed in these and previous experiments is likely to be
highly task specific (Enoka & Stuart, 1992) and conditions
specific. For example, we have recently reported a much
lower level of peripheral fatigue to develop following
exhaustive exercise in very severe hypoxia (Sa,O2 <70%)
(Amann et al. 2007b) and others have suggested that brief
all-out Wingate-type tests or small muscle group tests also
170 M. Amann and J. A. Dempsey
do not provide large amounts of peripheral muscle fatigue
(Calbet et al. 2003, 2006).
Prior exercise – varying in duration, intensity and
muscle group utilized – has previously been used to
induce different levels of metabolites in order to investigate
their influence on subsequent metabolic and perception
responses and exercise performance (Karlsson et al. 1975;
Hogan & Welch, 1984; Bangsbo et al. 1996; Hargreaves
et al. 1998; Burnley et al. 2002; Wilkerson et al. 2004;
Eston et al. 2007; Raymer et al. 2007). Although no
previous study has prefatigued the locomotor muscle,
quantified the degree of peripheral fatigue and evaluated
these effects on subsequent central motor drive and
exercise performance, the approach by Hogan & Welch
(1984) is relevant to our work. While working at the
same absolute workload and for the same duration
but breathing different FI,O2 values (0.16 or 0.60)
during exercise, the authors induced different levels of
systemic [H+ ] and [La− ] and investigated these effects on
subsequent (4 min break) performance trials in normoxia
utilizing the same muscle group (cycling). Blood [H+ ]
and [La− ] at the beginning of these constant-workload
performance trials were significantly higher following the
hypoxic versus hyperoxic ‘pre-treatment’ and resulted in a
significantly shorter time to exhaustion for the subsequent
constant-load exercise trial. Nevertheless, [H+ ] and [La− ]
at exhaustion were not significantly different between trials
despite the marked differences in exercise performance
time. Their postulate of muscle intracellular [H+ ] as a
regulated variable may be consistent with our present
findings since [H+ ] accumulation might be considered an
indicator of peripheral fatigue (Hogan & Welch, 1984).
However, the view on intracellular [H+ ] is controversial
inasmuch that some believe in its role as only a marker of
muscle fatigue (Miller et al. 1988; Cady et al. 1989; Weiner
et al. 1990; Kent-Braun, 1999; Kristensen et al. 2005;
Messonnier et al. 2007), while more recent investigations
cast doubt on the influence of in vivo muscle pH on
fatigability (Pate et al. 1995; Bangsbo et al. 1996; Bruton
et al. 1998; Dibold & Fitts, 2000; Pedersen et al. 2004).
Our current findings do not support a role for blood
[La− ] as a regulated variable at least during TT cycling
performances. First, the level of blood [La− ] at the end of
various TTs was different in the current investigation (see
Fig. 2) despite nearly identical levels of locomotor muscle
fatigue. Furthermore, in one of our earlier studies different
exercise performances also yielded significantly different
levels of blood [La− ] whereas end-exercise locomotor
muscle fatigue was identical (Amann et al. 2006a).
Intermediate role of the somatosensory system
in the regulation of central motor drive
How does the central nervous system know when and
to what extent voluntary motor neuron activation (i.e.
J Physiol 586.1
central motor drive) needs to be adjusted in order
to avoid excessive development of peripheral fatigue
beyond a sensory tolerance limit associated with potential
locomotor muscle tissue damage and pain? Aδ and
C-polymodal nociceptors are distributed throughout
muscles and connected via myelinated and unmyelinated
peripheral nerve fibres (group III and IV afferents,
respectively) to the dorsal horn in the spinal cord
from which the impulse ascends to the brain. Noxious
stimuli of these free nerve endings include substances
released and triggered by damaged cells (e.g. bradykinin,
prostaglandins, histamine, etc.) as well as metabolic
products of muscular contraction (e.g. H+ ) (Rotto &
Kaufman, 1988; Mense, 1996) and fatigue (Darques
et al. 1998). The afferent supraspinal projection of these
nociceptive stimuli involves multiple ascending pathways
feeding into subcortical and cortical structures including
thalamus, limbic system and prefrontal cortex (Almeida
et al. 2004). Therefore, by projecting into these areas of
the brain, nociceptive afferent feedback is likely to be
involved in the determination of goal-directed behaviour
(limbic processing, i.e. motivation; Schultz et al. 1998) and
motor processing (Chaudhuri & Behan, 2000), both of
which are significant determinants of central motor drive.
It has recently been suggested that the inhibitory effects
of group III and IV afferents on voluntary motoneuron
activation during local isometric exercise act ‘upstream’ of
the motor cortex (Gandevia et al. 1996; Taylor et al. 1996,
2000).
Limitations: other potential mediators of central
motor drive
The reduced central motor drive observed during the
TTs subsequent to the PFTs is a distinct indication
of central fatigue whose mechanisms are complex,
interactive and not mutually exclusive (Gandevia,
2001). While we present simple interventional evidence
supporting a significant contribution of peripheral
locomotor muscle fatigue to central fatigue, other
determinants have been suggested and might additionally
and/or equally augment the reduction in central drive
during the TTs with prior exercise versus the control trial
without prior exercise. First, prior exercise in the current
study might have caused a disturbance in brain neuro-
transmitter levels or turnover known to result in central
fatigue (Newsholme et al. 1987; Blomstrand et al. 1988;
Davis & Bailey, 1997; Meeusen et al. 2006; Newsholme &
Blomstrand, 2006) and potential carry-over effects could
have contributed to the reduced motor drive during sub-
sequent TTs. Especially relevant in this context is the
increase in brain serotonin (5-hydroxytryptamine), which
is a result of exercise-induced increases in the plasma
level of its precursor tryptophan (Chaouloff et al. 1985;

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J Physiol 586.1 Locomotor muscle fatigue and exercise performance
Blomstrand, 2006), since the level of circulating plasma
tryptophan might still have been significantly increased
at the start of the TTs following the PFTs. Second, it has
been shown that central command during high intensity
exercise can lead to a local depletion of brain glycogen
(Dalsgaard et al. 2002) causing central fatigue. Therefore,
depletion or even only a partial reduction of brain glycogen
during the PFTs might have affected central motor drive
during subsequent TTs since the glycogen stores could
most probably not have been replenished during the
4 min break between exercises. Third, increases in core
and especially brain temperature of over 40◦ C have been
shown to impair voluntary central motor drive and the
ability to sustain maximal muscle activation (Nybo &
Secher, 2004). Although oesophageal temperature during
a laboratory 5 km TT (21◦ C ambient temperature) rises
only to about 39◦ C (Amann et al. 2006a), a higher core
temperature with prior exercise can not be excluded and
might have contributed to the reduction in central motor
drive. Finally, while our correlative findings support the
concept that neural feedback from fatiguing locomotor
muscle exerts an inhibitory effect on central motor drive,
it has been suggested that inhibitory reflexes might also
originate in fatiguing respiratory muscles (Bigland-Ritchie
& Vollestad, 1988; Kayser, 2003).
Our correlative findings to date are fairly consistent in
support of a significant role for peripheral muscle fatigue
as a major determinant of central motor drive (Amann
et al. 2006a, 2007b; Romer et al. 2007) and our pre-
sent findings using an interventional approach are also
consistent with this postulate. Nonetheless, this complex
question now needs to be addressed using a more specific
intervention capable of clearly differentiating the effects of
peripheral muscle fatigue, per se, on central motor output
in the exercising human. The use of spinal blockade of
sensory input from fatiguing locomotor muscles (Rotto &
Kaufman, 1988) should accomplish this goal.
Summary and future direction
By inducing various degrees of locomotor muscle
fatigue prior to a performance task, we have shown a
dose-dependent effect of peripheral fatigue on central
neural drive during exercise. Central motor command,
and consequently power output and exercise performance,
was highest during the TT performed without pre-existing
peripheral fatigue and lowest when the TT was started
with a severe degree of locomotor muscle fatigue.
Furthermore, exercise-induced locomotor muscle fatigue
at the termination of the TTs was nearly identical
despite significant differences in exercise performance and
pre-existing levels of quadriceps fatigue confirming the
status of locomotor muscle fatigue as a carefully regulated
variable. Nonetheless, a limitation is imposed on our
interpretation of our findings because the prefatiguing

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171
exercise might also bring into play other non-peripheral
effectors of central fatigue. We now need further more
specific intervention studies which block sensory neural
feedback from fatiguing locomotor muscles to evaluate its
specific effects on central motor command.
References
Almeida TF, Roizenblatt S & Tufik S (2004). Afferent pain
pathways: a neuroanatomical review. Brain Res 1000, 40–56.
Amann M, Eldridge MW, Lovering AT, Stickland MK, Pegelow
DF & Dempsey JA (2006a). Arterial oxygenation influences
central motor output and exercise performance via effects on
peripheral locomotor muscle fatigue. J Physiol 575, 937–952.
Amann M, Pegelow DF, Jacques AJ & Dempsey JA (2007a).
Inspiratory muscle work in acute hypoxia influences
locomotor muscle fatigue and exercise performance of
healthy humans. Am J Physiol Regul Integr Comp Physiol 293,
R2036–R2045.
Amann M, Romer LM, Pegelow DF, Jacques AJ, Hess CJ &
Dempsey JA (2006b). Effects of arterial oxygen content on
peripheral locomotor muscle fatigue. J Appl Physiol 101,
119–127.
Amann M, Romer LM, Subudhi AW, Pegelow DF & Dempsey
JA (2007b). Severity of arterial hypoxaemia affects the
relative contributions of peripheral muscle fatigue to exercise
performance in healthy humans. J Physiol 581, 389–403.
Amann M, Subudhi A & Foster C (2004). Influence of testing
protocol on ventilatory thresholds and cycling performance.
Med Sci Sports Exerc 36, 613–622.
Bangsbo J, Madsen K, Kiens B & Richter EA (1996). Effect of
muscle acidity on muscle metabolism and fatigue during
intense exercise in man. J Physiol 495, 587–596.
Bigland-Ritchie B & Vollestad N (1988). Hypoxia and Fatigue:
How are they related? Benchmark, Indianapolis, IL.
Blomstrand E (2006). A role for branched-chain amino acids in
reducing central fatigue. J Nutr 136, 544S–547S.
Blomstrand E, Celsing F & Newsholme EA (1988). Changes in
plasma concentrations of aromatic and branched-chain
amino acids during sustained exercise in man and their
possible role in fatigue. Acta Physiol Scand 133, 115–121.
Borg G (1998). Borg’s Perceived Exertion and Pain Scales.
Human Kinetics, Champaign, IL.
Bruton JD, Lannergren J & Westerblad H (1998). Effects of
CO2 -induced acidification on the fatigue resistance of single
mouse muscle fibers at 28◦ C. J Appl Physiol 85, 478–483.
Burnley M, Doust JH, Ball D & Jones AM (2002). Effects of
prior heavy exercise on V̇O2 kinetics during heavy exercise are
related to changes in muscle activity. J Appl Physiol 93,
167–174.
Cady EB, Jones DA, Lynn J & Newham DJ (1989). Changes in
force and intracellular metabolites during fatigue of human
skeletal muscle. J Physiol 418, 311–325.
Calbet JAL (2006). The rate of fatigue accumulation as a sensed
variable. J Physiol 575, 688–689.
Calbet JA, De Paz JA, Garatachea N, Cabeza De Vaca S &
Chavarren J (2003). Anaerobic energy provision does not
limit Wingate exercise performance in endurance-trained
cyclists. J Appl Physiol 94, 668–676.
172 M. Amann and J. A. Dempsey
Caquelard F, Burnet H, Tagliarini F, Cauchy E, Richalet JP &
Jammes Y (2000). Effects of prolonged hypobaric hypoxia on
human skeletal muscle function and electromyographic
events. Clin Sci (Lond) 98, 329–337.
Chaouloff F, Elghozi JL, Guezennec Y & Laude D (1985).
Effects of conditioned running on plasma, liver and brain
tryptophan and on brain 5-hydroxytryptamine metabolism
of the rat. Br J Pharmacol 86, 33–41.
Chaudhuri A & Behan PO (2000). Fatigue and basal ganglia.
J Neurol Sci 179, 34–42.
Dalsgaard MK, Ide K, Cai Y, Quistorff B & Secher NH (2002).
The intent to exercise influences the cerebral
O2 /carbohydrate uptake ratio in humans. J Physiol 540,
681–689.
Darques JL, Decherchi P & Jammes Y (1998). Mechanisms of
fatigue-induced activation of group IV muscle afferents: the
roles played by lactic acid and inflammatory mediators.
Neurosci Lett 257, 109–112.
Davis JM & Bailey SP (1997). Possible mechanisms of central
nervous system fatigue during exercise. Med Sci Sports Exerc
29, 45–57.
Dibold E & Fitts RH (2000). The effects of temperature and Pi
on single muscle fiber contractile properties. Biophys J 78,
119a.
Enoka RM & Stuart DG (1992). Neurobiology of muscle
fatigue. J Appl Physiol 72, 1631–1648.
Eston R, Faulkner J, St Clair Gibson A, Noakes T & Parfitt G
(2007). The effect of antecedent fatiguing activity on the
relationship between perceived exertion and physiological
activity during a constant load exercise task. Psychophysiology
44, 779–786.
Gandevia SC (2001). Spinal and supraspinal factors in human
muscle fatigue. Physiol Rev 81, 1725–1789.
Gandevia SC, Allen GM, Butler JE & Taylor JL (1996).
Supraspinal factors in human muscle fatigue: evidence for
suboptimal output from the motor cortex. J Physiol 490,
529–536.
Hargreaves M, McKenna MJ, Jenkins DG, Warmington SA, Li
JL, Snow RJ & Febbraio MA (1998). Muscle metabolites and
performance during high-intensity, intermittent exercise.
J Appl Physiol 84, 1687–1691.
Harms CA, McClaran SR, Nickele GA, Pegelow DF, Nelson WB
& Dempsey JA (1998). Exercise-induced arterial hypoxaemia
in healthy young women. J Physiol 507, 619–628.
Hogan MC & Welch HG (1984). Effect of varied lactate levels
on bicycle ergometer performance. J Appl Physiol 57,
507–513.
Karlsson J, Bonde-Petersen F, Henriksson J & Knuttgen HG
(1975). Effects of previous exercise with arms or legs on
metabolism and performance in exhaustive exercise. J Appl
Physiol 38, 763–767.
Katayama K, Amann M, Pegelow DF, Jacques AJ & Dempsey JA
(2007). Effect of arterial oxygenation on quadriceps
fatigability during isolated muscle exercise. Am J Physiol
Regul Integr Comp Physiol 292, R1279–R1286.
Kayser B (2003). Exercise starts and ends in the brain.
Eur J Appl Physiol 90, 411–419.
Keenan KG, Farina D, Maluf KS, Merletti R & Enoka RM
(2005). Influence of amplitude cancellation on the simulated
surface electromyogram. J Appl Physiol 98, 120–131.
J Physiol 586.1
Kent-Braun JA (1999). Central and peripheral contributions to
muscle fatigue in humans during sustained maximal effort.
Eur J Appl Physiol 80, 57–63.
Kristensen M, Albertsen J, Rentsch M & Juel C (2005). Lactate
and force production in skeletal muscle. J Physiol 562,
521–526.
Kufel TJ, Pineda LA & Mador MJ (2002). Comparison of
potentiated and unpotentiated twitches as an index of
muscle fatigue. Muscle Nerve 25, 438–444.
Lepers R, Maffiuletti NA, Rochette L, Brugniaux J & Millet GY
(2002). Neuromuscular fatigue during a long-duration
cycling exercise. J Appl Physiol 92, 1487–1493.
Meeusen R, Watson P, Hasegawa H, Roelands B & Piacentini
MF (2006). Central fatigue: the serotonin hypothesis and
beyond. Sports Med 36, 881–909.
Mense S (1996). Group III and IV receptors in skeletal muscle:
are they specific or polymodal? Prog Brain Res 113,
83–100.
Merton PA (1954). Voluntary strength and fatigue. J Physiol
123, 553–564.
Messonnier L, Kristensen M, Juel C & Denis C (2007).
Importance of pH regulation and lactate/H+ transport
capacity for work production during supramaximal exercise
in humans. J Appl Physiol 102, 1936–1944.
Miller RG, Boska MD, Moussavi RS, Carson PJ & Weiner MW
(1988). 31 P nuclear magnetic resonance studies of high
energy phosphates and pH in human muscle fatigue.
Comparison of aerobic and anaerobic exercise. J Clin Invest
81, 1190–1196.
Newsholme EA, Acworth I & Blomstrand E (1987). Amino
Acids, Brain Neurotransmitters and a Functional Link between
Muscle and Brain that is Important in Sustained Exercise. John
Libby Eurotext, London.
Newsholme EA & Blomstrand E (2006). Branched-chain amino
acids and central fatigue. J Nutr 136, 274S–276S.
Nybo L & Secher NH (2004). Cerebral perturbations provoked
by prolonged exercise. Prog Neurobiol 72, 223–261.
Pate E, Bhimani M, Franks-Skiba K & Cooke R (1995).
Reduced effect of pH on skinned rabbit psoas muscle
mechanics at high temperatures: implications for fatigue.
J Physiol 486, 689–694.
Pedersen TH, Nielsen OB, Lamb GD & Stephenson DG (2004).
Intracellular acidosis enhances the excitability of working
muscle. Science 305, 1144–1147.
Rassier DE & Macintosh BR (2000). Coexistence of
potentiation and fatigue in skeletal muscle. Braz J Med Biol
Res 33, 499–508.
Raymer GH, Forbes SC, Kowalchuk JM, Thompson RT &
Marsh GD (2007). Prior exercise delays the onset of acidosis
during incremental exercise. J Appl Physiol 102,
1799–1805.
Romer LM, Haverkamp HC, Amann M, Lovering AT, Pegelow
DF & Dempsey JA (2007). Effect of acute severe hypoxia on
peripheral fatigue and endurance capacity in healthy
humans. Am J Physiol Regul Integr Comp Physiol 292,
R598–R606.
Romer LM, Haverkamp HC, Lovering AT, Pegelow DF &
Dempsey JA (2006). Effect of exercise-induced arterial
hypoxemia on quadriceps muscle fatigue in healthy humans.
Am J Physiol Regul Integr Comp Physiol 290, R365–R375.

C 2008 The Authors. Journal compilation 
C 2008 The Physiological Society
J Physiol 586.1 Locomotor muscle fatigue and exercise performance
Rotto DM & Kaufman MP (1988). Effect of metabolic products
of muscular contraction on discharge of group III and IV
afferents. J Appl Physiol 64, 2306–2313.
Sandiford SD, Green HJ, Duhamel TA, Schertzer JD, Perco JD
& Ouyang J (2005). Muscle Na+ –K+ -pump and fatigue
responses to progressive exercise in normoxia and hypoxia.
Am J Physiol Regul Integr Comp Physiol 289, R441–R449.
Schultz W, Tremblay L & Hollerman JR (1998). Reward
prediction in primate basal ganglia and frontal cortex.
Neuropharmacology 37, 421–429.
Strojnik V & Komi PV (1998). Neuromuscular fatigue after
maximal stretch-shortening cycle exercise. J Appl Physiol 84,
344–350.
Taylor JL, Butler JE, Allen GM & Gandevia SC (1996). Changes
in motor cortical excitability during human muscle fatigue.
J Physiol 490, 519–528.
Taylor JL, Petersen N, Butler JE & Gandevia SC (2000).
Ischaemia after exercise does not reduce responses of human
motoneurones to cortical or corticospinal tract stimulation.
J Physiol 525, 793–801.

C 2008 The Authors. Journal compilation 
C 2008 The Physiological Society
173
Weiner MW, Moussavi RS, Baker AJ, Boska MD & Miller RG
(1990). Constant relationships between force, phosphate
concentration, and pH in muscles with differential
fatigability. Neurology 40, 1888–1893.
Wilkerson DP, Koppo K, Barstow TJ & Jones AM (2004). Effect
of prior multiple-sprint exercise on pulmonary O2 uptake
kinetics following the onset of perimaximal exercise. J Appl
Physiol 97, 1227–1236.
Acknowledgements
This research was supported by a National Heart, Lung and
Blood Institute (NHLBI) RO1 grant (HL-15469). We thank Mrs
Cynthia E. Bird and Mrs Rose E. Voelker for valuable assistance
with lactate assessment and EMG data analyses, respectively. Mr
David Pegelow’s technical assistance with data collection was
important to the conduct of these studies.