Am J Physiol Regul Integr Comp Physiol 306: R934–R940, 2014.
First published April 16, 2014; doi:10.1152/ajpregu.00043.2014.
The role of active muscle mass in determining the magnitude of peripheral
fatigue during dynamic exercise
Matthew J. Rossman,1,2 Ryan S. Garten,1,3 Massimo Venturelli,3,4 Markus Amann,1,2,3
and Russell S. Richardson1,2,3
1
Geriatric Research, Education, and Clinical Center, George E. Whalen VA Medical Center, Salt Lake City, Utah;
Department of Exercise and Sport Science, University of Utah, Salt Lake City, Utah; 3Department of Internal Medicine,
Division of Geriatrics, University of Utah, Salt Lake City, Utah; and 4Department of Biomedical Sciences for Health,
University of Milan, Milan, Italy
2
Submitted 30 January 2014; accepted in final form 12 March 2014
dynamic exercise; locomotor muscle; knee-extensor exercise; central
motor drive
groups III and IV skeletal muscle
afferent fibers, responsive to mechanical deformation and the
intramuscular metabolic disturbance (2), has been implicated
as a determinant of exercise performance, exerting inhibitory
feedback on central motor drive to active muscles during
dynamic exercise (3, 4). It has been hypothesized that the
voluntarily termination of high-intensity, constant workload
exercise occurs once a sensory tolerance limit (17) is reached,
which is directly affected by the ensemble group III/IV afferent
THE CENTRAL PROJECTION OF
Address for reprint requests and other correspondence: R. S. Richardson,
VA Medical Center Bldg 2, Rm 1D25, 500 Foothill Dr., Salt Lake City, UT
84148 (e-mail: [email protected]).
R934
input from the active muscles (3). Thus, group III/IV afferents,
among other factors (17, 29, 30), facilitate central fatigue,
defined as a failure or unwillingness of the central nervous
system (CNS) to drive the motor neurons, and, thereby, limit
the development of peripheral fatigue, defined as a reduction in
muscle force output in response to a given neural input. Indeed,
consistent with this paradigm, despite differing levels of oxygen availability and differing exercise intensities, both of
which alter endurance time, similar end-exercise levels of
intramuscular metabolites linked to peripheral fatigue have
been documented following exhaustive exercise (12, 18, 39).
However, how the magnitude of end-exercise peripheral fatigue is influenced by active muscle mass and, therefore,
possibly by the volume of group III/IV afferent feedback is still
not well understood.
Recently, our group examined the magnitude of peripheral
quadriceps fatigue following exhaustive, dynamic, single-leg
knee-extensor exercise (KE) and whole body cycling (38). This
approach was used to achieve large differences in active
muscle mass [⬃2.5 kg for KE compared with ⬃15 kg for cycle
exercise (33)] and, therefore, locally vary the magnitude of
afferent feedback (15, 20). Specifically, this study was designed and interpreted on the premise that during single-leg
KE, the source of afferent feedback would be limited to one
quadriceps muscle group, and so the sensory tolerance limit
associated with task failure with this model would be reached
by a strong, local afferent signal mainly from a smaller muscle
mass. This would contrast starkly to cycle exercise during
which the equal ensemble afferent feedback associated with the
sensory tolerance limit, would consist of the sum of weaker
and more diffuse signals from a much larger muscle mass (38).
As hypothesized, peripheral fatigue assessed in the quadriceps
following KE was far greater than during cycle exercise,
suggesting that confining group III and IV skeletal muscle
afferent feedback to a small muscle mass enables the CNS to
tolerate greater peripheral fatigue (38). However, it is important to acknowledge that although the use of cycle exercise and
KE resulted in substantial differences in active muscle mass
and a similar muscular action (knee extension), such an approach may have been somewhat confounded by other considerable differences associated with the two distinct exercise
modalities. For example, the loss of hip extension power (14)
and central cardiopulmonary limitations (34) during bicycle
exercise, but not during KE were unaccounted for in this prior
study. Additional neural factors, such as differences in coordination and the bilateral deficit (19, 21), may also contribute
http://www.ajpregu.org
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.1 on June 15, 2017
Rossman MJ, Garten RS, Venturelli M, Amann M, Richardson
RS. The role of active muscle mass in determining the magnitude of
peripheral fatigue during dynamic exercise. Am J Physiol Regul Integr
Comp Physiol 306: R934 –R940, 2014. First published April 16, 2014;
doi:10.1152/ajpregu.00043.2014.—Greater peripheral quadriceps fatigue at the voluntary termination of single-leg knee-extensor exercise
(KE), compared with whole-body cycling, has been attributed to
confining group III and IV skeletal muscle afferent feedback to a
small muscle mass, enabling the central nervous system (CNS) to
tolerate greater peripheral fatigue. However, as task specificity and
vastly differing systemic challenges may have complicated this interpretation, eight males were studied during constant workload trials to
exhaustion at 85% of peak workload during single-leg and double-leg
KE. It was hypothesized that because of the smaller muscle mass
engaged during single-leg KE, a greater magnitude of peripheral
quadriceps fatigue would be present at exhaustion. Vastus lateralis
integrated electromyogram (iEMG) signal relative to the first minute
of exercise, preexercise to postexercise maximal voluntary contractions (MVCs) of the quadriceps, and twitch-force evoked by supramaximal magnetic femoral nerve stimulation (Qtw,pot) quantified peripheral quadriceps fatigue. Trials performed with single-leg KE
(8.1 ⫾ 1.2 min; 45 ⫾ 4 W) resulted in significantly greater peripheral
quadriceps fatigue than double-leg KE (10 ⫾ 1.3 min; 83 ⫾ 7 W), as
documented by changes in the iEMG signal (147 ⫾ 24 vs. 85 ⫾ 13%),
MVC (⫺25 ⫾ 3 vs. ⫺12 ⫾ 3%), and Qtw,pot (⫺44 ⫾ 6 vs. ⫺33 ⫾
7%), for single-leg and double-leg KE, respectively. Therefore, avoiding concerns over task specificity and cardiorespiratory limitations,
this study reveals that a reduction in muscle mass permits the development of greater peripheral muscle fatigue and supports the concept
that the CNS tolerates a greater magnitude of peripheral fatigue when
the source of group III/IV afferent feedback is limited to a small
muscle mass.
ACTIVE MUSCLE MASS AND PERIPHERAL FATIGUE
METHODS
Subjects. Eight recreationally active healthy males (27 ⫾ 1 yr,
84 ⫾ 3 kg, 178 ⫾ 2 cm; Table 1) volunteered to participate in this
study. Written, informed consent was obtained from participants prior
to their inclusion, and the Institutional Review Boards of the University of Utah and the Salt Lake City Veteran’s Administration Medical
Center approved the study. Testing was performed in a thermoneutral
environment.
Protocol. During two to four initial preliminary visits to the
laboratory, subjects were familiarized with both single- and doubleleg KE. Subjects then performed maximal incremental exercise tests
with both modalities to determine peak workload and practice constant workload trials to the limit of tolerance (TLim). On subsequent
visits, separated by 48 –96 h and in a counter-balanced order, constant
workload TLim trials at 85% of peak workload (60 rpm) for both
single- and double-leg KE were performed. This 85% of peak workload led to task failure (defined as a fall below 50 rpm for ⬎10 s) in
5–15 min during preliminary testing. Prior to the TLim trials, 2 min of
resting data were collected, and subjects were allowed a 3-min
warm-up period (5 W for single-leg KE and 10 W for double-leg KE).
Throughout each trial, minute ventilation (VE), gas exchange (V̇O2
and V̇CO2), heart rate (HR), mean arterial pressure (MAP), stroke
volume (SV), cardiac output (CO), the electromyogram from the
vastus lateralis (EMG), as well as rating of perceived exertion (RPE)
(11), were assessed. To quantify peripheral fatigue, neuromuscular
function tests were performed before exercise and again 2 min
following task failure. The fatigue assessment procedure in both trials
was performed on the same leg used for both exercise trials, which
was balanced between dominant and nondominant limbs (31).
Knee-extensor exercise. Dynamic KE was performed utilizing a
cycle erogmeter (Monark, Sweden) modified to allow the performance
Table 1. Subject characteristics
Characteristic
Value
Age, yr
Height, cm
Weight, kg
Body mass index, kg/m2
Quadriceps muscle mass, kg
Peak knee extensor work rate, W
V̇O2max, ml·kg⫺1·min⫺1
Hemoglobin, g/dl
Triglycerides, ␮g/dl
Cholesterol, mg/dl
HDL, mg/dl
LDL, mg/dl
26 ⫾ 1
178 ⫾ 2
73 ⫾ 3
23 ⫾ 0.4
2.4 ⫾ 0.1
53 ⫾ 4
47.4 ⫾ 2
16.3 ⫾ 0.4
92 ⫾ 12
166 ⫾ 8
50 ⫾ 3
103 ⫾ 7
Values are expressed as means ⫾ SE; n ⫽ 8. HDL, high-density lipoprotein;
LDL, low-density lipoprotein.
of KE (33). Briefly, for single-leg KE exercise, this exercise modality
recruits the quadriceps muscle group for active leg extension from 90°
to ⬃170° before a lever arm attached to a flywheel passively returns
the leg to 90°. For double-leg knee-extensor exercise, a second lever
arm was attached to the contralateral crank-arm of the ergometer, such
that subjects recruited the quadriceps muscle groups of both legs
simultaneously to perform KE. Subjects were instructed to maintain a
rate of 60 rpm during all KE exercise trials. For the determination of
peak workload, subjects performed 1-min stage, incremental exercise
tests to exhaustion (10 W ⫹ 5 W/min for single-leg KE and 20 W ⫹
10 W/min for double-leg KE).
Pulmonary and cardiovascular responses. VE and pulmonary gas
exchange were measured at rest and during exercise using an open
circuit system (ParvoMedics, Sandy, UT). HR was determined from
the R-R interval of a three-lead electrocardiogram (AcqKnowledge;
Biopac Systems, Goleta, CA). SV, CO, and MAP were determined
with a finometer (Finapres Medical Systems, Amsterdam, The Netherlands) placed at the heart level. SV was calculated from beat-by-beat
pressure waveforms assessed by photoplethysmography using the
Modelflow method (Beatscope version 1.1; Finapres Medical Systems), and CO was calculated as the product of SV and HR.
Neuromuscular function. The magnitude of peripheral quadriceps
fatigue was quantified using supramaximal magnetic stimulation of
the femoral nerve (6, 24, 32): the exercise-induced reduction in
potentiated quadriceps twitch force (Qtw,pot) assessed before exercise
and again 2 min after both TLim trials. This time delay was necessary
to transfer the subjects from the KE ergometer to the neuromuscular
function assessment apparatus and was, thus, standardized for both
exercise modalities. For the neuromuscular function test procedure,
subjects lay semirecumbent, with a knee joint angle of 90°, a magnetic
stimulator (Magstim 200; Magstim, Carmarthenshire, Wales) connected to a double 70-mm coil was used to stimulate the femoral
nerve. The evoked twitch force was obtained from a calibrated load
cell (Transducer Techniques, Temecula, CA) connected to a noncompliant strap placed around the subject’s ankle. A series of six maximum voluntary contractions (MVCs), each followed by a Qtw,pot,
were performed with 30 s between each MVC, such that the entire
procedure lasted 2.5 min. In addition, to determine the percent
voluntary muscle activation (VA), a superimposed twitch technique
was employed (6, 28). Peak force, maximal rate of force development
(MRFD), and maximal relaxation rate (MRR) were analyzed for all
Qtw,pot values (25). To ensure supramaximality of stimulation during
magnetic stimulation of the femoral nerve, the plateau in evokedtwitch forces, obtained every 30 s, at 70, 80, 85, 90, 95, and 100% of
maximal stimulator output, was also evaluated.
Quadriceps EMG was recorded from the vastus lateralis muscle (6)
during exercise, as well as the neuromuscular function assessment
procedure. The electrodes were placed in a bipolar configuration over
the middle of the muscle belly, with the active electrodes placed over
the motor point of the muscle and the reference electrode in an
electrically neutral site. These electrodes were used to record magnetically evoked compound action potentials (M-waves) to evaluate
changes in membrane excitability, as well as the EMG from the vastus
lateralis throughout exercise to provide an index of central motor
drive. Raw EMG signals were filtered with a bandpass filter (with a
low-pass cut-off frequency of 15 Hz and a high-pass cut-off frequency
of 650 Hz) and after visual inspection of the filtered signal, a threshold
voltage was set to identify the onset of EMG activity (AcqKnowledge;
Biopac Systems). For data analysis, the integral of each EMG burst
(integrated EMG, iEMG) was calculated to determine a percent
increase in iEMG from the first minute of exercise (6).
Statistical analysis. Two-way repeated-measures ANOVA were
used to compare the effect of exercise modality on physiological
parameters during exercise, with the Tukey’s honestly significant
difference test used for post hoc analysis if a significant main effect or
interaction effect was found. Student’s paired t-tests were used to
compare the effect of exercise modality on end-exercise physiological
AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00043.2014 • www.ajpregu.org
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.1 on June 15, 2017
to the task-specific complexities and difference in fatigue
accompanying alterations in active muscle mass.
The aim of this study was to better elucidate the role of
active muscle mass and associated ensemble afferent input to
the CNS in determining the magnitude of peripheral fatigue
following dynamic quadriceps exercise. Specifically, we used
exhaustive single- and double-leg KE to vary active muscle
mass and associated neural feedback, while minimizing concerns about task specificity and cardiopulmonary limitations.
We tested the hypothesis that the afferent signal constrained to
one quadriceps muscle group during single-leg KE would
result in a greater magnitude of end-exercise peripheral fatigue
at the attainment of the sensory tolerance and task failure than
double-leg KE. Thus, quadriceps fatigue would be greater
following single-leg KE compared with double-leg KE.
R935
R936
ACTIVE MUSCLE MASS AND PERIPHERAL FATIGUE
VO2 (L/min)
VE (L/min)
*
2.0
Double Leg KE
60
40
20
1.5
1.0
0.5
*
45
VE/VCO2
2.0
1.5
1.0
40
35
30
25
0.5
20
0
2
4
6
8
10
12
0
2
Time (min)
RESULTS
*
8
10
12
140
120
100
Single Leg KE
80
140
Stroke volume
(ml/beat)
160
*
120
100
80
Double Leg KE
60
20
60
150
*
MAP (mmHg)
Heart rate (beats/min)
Peak exercise responses. Double-leg KE engaged a significantly greater quadriceps muscle mass compared with singleleg KE (4.8 ⫾ 0.2 kg vs. 2.4 ⫾ 0.1 kg, respectively). The
maximal workload attained during the incremental exercise
tests was significantly greater for double-leg compared with
single-leg KE (98 ⫾ 7 W vs. 53 ⫾ 4 W, respectively), eliciting
a higher peak pulmonary oxygen uptake (1.96 ⫾ 0.1 vs. 1.52 ⫾
0.1 l/min). Of note, the peak oxygen consumption value obtained during the double-leg KE test was significantly less than
that obtained by the same subjects during maximal incremental
cycling in a separate study (1.96 ⫾ 0.1 vs. 3.46 ⫾ 0.2 l/min,
respectively), suggesting the absence of cardiorespiratory limitations during both single-leg and double-leg cycling.
TLim trials. The TLim trials, performed at 85% of peak
workload, equated to 45 ⫾ 4 W for the single-leg KE trial and
Cardiac Output (L/min)
6
Time (min)
83 ⫾ 7 W for the double-leg KE trial. TLim time at these
workloads was not significantly different between conditions
(single-leg KE: 8.1 ⫾ 1.2 min, double-leg KE: 10.0 ⫾ 1.3
min). Pulmonary gas exchange and ventilatory responses to the
TLim trials are documented in Fig. 1, and the cardiovascular
responses are documented in Fig. 2. These assessments, apart
from MAP and VE/V̇CO2, were augmented during double-leg
compared with single-leg KE; the maximal values obtained,
however, remained below the previously documented limits of
the cardiorespiratory system in all subjects. RPE was higher for
single-leg compared with double-leg KE during the fifth minute of the TLim trials (data not presented), but was not different
between conditions at task failure (double-leg KE: 9.8 ⫾ 0.2,
single-leg KE: 9.8 ⫾ 0.3).
Neuromuscular function. Supramaximality of stimulation
was demonstrated in all subjects by a plateau in twitch force
and M-wave amplitudes with increasing stimulus intensity,
representing maximal depolarization of the femoral nerve.
Membrane excitability was maintained from preexercise to
parameters and the magnitude of peripheral fatigue. Statistical significance was set at ␣ ⫽ 0.05. Results are expressed as means ⫾ SE.
Fig. 2. Cardiovascular responses to constant
load, single-leg, and double-leg KE to exhaustion. Data are expressed as means ⫾ SE.
Group mean data are represented for time
points 0 –5, and the final point represents
values reached at task failure, n ⫽ 5. *Significant difference between single-leg and double-leg KE.
4
15
10
5
140
130
120
110
100
90
0
80
0
2
4
6
8
10
12
0
2
Time (min)
AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00043.2014 • www.ajpregu.org
4
6
Time (min)
8
10
12
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.1 on June 15, 2017
VCO2 (L/min)
Fig. 1. Gas exchange and ventilatory response to constant load, single-leg and double-leg knee-extensor exercise (KE) to exhaustion. Data are represented as means ⫾
SE. Group mean data are represented for time
points 0 –5, and the final point represents
values reached at task failure. *Significant
difference (P ⬍ 0.05) between single-leg and
double-leg KE.
*
Single Leg KE
80
ACTIVE MUSCLE MASS AND PERIPHERAL FATIGUE
exercise to postexercise in both trials and also revealed greater
peripheral fatigue following single-leg KE (Fig. 3).
DISCUSSION
Presumably, as a component of homeostasis, group III/IV
muscle afferents appear to play an important role in determining exercise cessation by inhibiting central motor drive to
active skeletal muscle and ultimately restricting the development of peripheral fatigue. On the basis of this paradigm, the
current study tested the hypothesis that when the source of
group III/IV afferent feedback is limited to a small muscle
mass, the central nervous system will tolerate a greater degree
of peripheral fatigue. Utilizing single- and double-leg KE to
vary group III/IV muscle afferent input to the CNS, while
minimizing the potential influence of task specificity and cardiopulmonary limitations, we observed a greater degree of
end-exercise peripheral quadriceps fatigue when exercise was
confined to one compared with both quadriceps muscle groups.
This finding suggests that during small muscle mass exercise
(single-leg KE), the sensory tolerance limit, which is greatly
affected by afferent feedback (17), was likely evoked by a
severe metabolic disturbance in the single quadriceps. This is
in contrast to the equal sum, but more diffuse, signals from the
Fig. 3. Change in quadriceps muscle function as a
consequence of constant load and double-leg and single-leg KE to exhaustion. Data are expressed as means
⫾ SE, and values represent the percent change from
preexercise to postexercise, except for the integrated
electromyogram signal (iEMG) from the vastus lateralis, which is a comparison between the first and last
minute of exercise. MVC, maximal voluntary contraction; Qtw,pot, potentiated twitch force; MRFD, maximal
rate of force development; MRR, maximal rate of relaxation. *Significant difference (P ⬍ 0.05) between
single-leg and double-leg KE.
AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00043.2014 • www.ajpregu.org
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.1 on June 15, 2017
postexercise with both exercise modalities, as indicated by
unchanged M-wave characteristics. MVC and Qtw,pot, measured prior to single-leg and double-leg KE was not different
between conditions (MVC: 553 ⫾ 31 vs. 530 ⫾ 41 N; Qtw,pot:
219 ⫾ 18 vs. 210 ⫾ 19, for single-leg and double-leg KE,
respectively).
Quadriceps fatigue. The vastus lateralis iEMG signal normalized to the first minute of exercise, an index of the development of peripheral fatigue during exercise, was increased
during exercise to a greater extent during single-leg KE compared with double-leg KE (Fig. 3). Qtw,pot, measured after
exercise, was significantly reduced from preexercise values,
with a fall of 44 ⫾ 6% for single-leg KE and 33 ⫾ 7% for
double-leg KE. This fall in Qtw,pot was significantly greater for
single-leg compared with double-leg KE (Fig. 3), suggesting
greater peripheral quadriceps fatigue after single-leg KE. MVC
force was also reduced from preexercise values to a greater
extent following single-leg KE (Fig. 3). As VA was reduced
from preexercise to postexercise to a similar extent following
both exercise modalities (Fig. 3), the greater reduction in MVC
following single-leg KE supports greater peripheral quadriceps
fatigue in this trial. The other intratwitch indices of fatigue
(MRFD and MRR) were also significantly reduced from pre-
R937
R938
ACTIVE MUSCLE MASS AND PERIPHERAL FATIGUE
muscle mass across modalities. Although somewhat speculative, these data imply that during cycle exercise, which substantially engages the quadriceps muscles of both legs, the
afferent signal arising from these muscle groups may be the
dominant source of inhibitory afferent feedback.
As the quadriceps muscles are predominantly muscle groups
employed during cycle exercise (33), inference about their role
in fatigue determination appears reasonable. However, it is
important to acknowledge that the decrease in Qtw,pot exhibited
by the subjects in the current study following single-leg KE
was less (43%) than that previously observed by our group
with this modality (53%) (38). Therefore, if the current subjects, as a whole, simply tolerated less peripheral fatigue in all
conditions, the recognized similarity between the level of
peripheral fatigue during double-leg KE (which might be
expected to result in more fatigue than cycle exercise, due to
the smaller muscle mass) and the previously published values
for cycle exercise could just be coincidental. Further investigations are required to determine whether this hypothesis about
the dominant role of the quadriceps in determining cycle
exercise-induced fatigue is correct.
Muscle mass and the potential for exercise-induced
adaptation. Single-leg KE has previously been utilized as a
dynamic exercise model that avoids cardiopulmonary limitations (35, 36). Impressive improvements in peripheral skeletal
muscle function, such as increased oxidative enzyme capacity,
in both health (1, 37) and disease (13, 26), have been achieved
with this approach. In the current study, single-leg KE, utilizing ⬃2.5 kg of muscle in contrast to the ⬃5 kg of muscle mass
during double-leg KE, attenuated the cardiovascular (Fig. 1)
and respiratory (Fig. 2) responses to the TLim trials, but,
interestingly, resulted in a greater degree of peripheral fatigue
(Fig. 3). As the metabolic disturbance in the muscle during
exercise substantially influences the magnitude of peripheral
fatigue measured immediately after task failure, the attainment
of greater peripheral quadriceps fatigue following single-leg
KE suggests a greater intramuscular metabolic disturbance.
Thus, in addition to the typically recognized reduction in the
cardiopulmonary demand associated with small-muscle mass
exercise, these data reveal that reducing active muscle mass
facilitates the attainment of greater peripheral fatigue. As
exercise training induces an adaptive response to a homeostatic
disturbance, a greater magnitude of peripheral fatigue has the
potential to be translated into greater skeletal muscle adaptation following small-muscle mass exercise. Thus, the use of
small muscle mass exercise, with a reduced cardiopulmonary
challenge, which in and of itself likely promotes better exercise
adherence, and the now recognized greater level of tolerable
peripheral fatigue has important implications for the use of
small-muscle mass exercise in rehabilitative medicine.
Central motor drive and the sensory tolerance limit. Previous work from our group, as well as the current study, has
predominantly emphasized the role of inhibitory skeletal muscle afferent feedback in determining the sensory tolerance limit
and the voluntary termination of exercise. Importantly, other
neural mechanisms may have contributed to the observed
differences in fatigue. For example, a slight bilateral deficit in
peak workload, such that the maximal workload for double-leg
KE was slightly less than two times the single-leg peak
workload, was observed, which has previously been attributed
to the integration of neural factors from both peripheral and
AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00043.2014 • www.ajpregu.org
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.1 on June 15, 2017
two quadriceps muscle groups (double-leg KE) that were each
likely less challenged metabolically. As exercise-induced adaptation is a response to the degree of homeostatic disturbance,
these findings have important implications for optimizing exercise training and rehabilitative medicine.
Muscle mass and peripheral fatigue. Previous research from
our group has documented greater peripheral quadriceps fatigue following single-leg KE compared with whole body
cycling, which was attributed to muscle mass-induced alterations in afferent feedback (38). Indeed, Freund et al. (15)
utilized the postexercise circulatory occlusion technique with
one or two legs following whole body cycle exercise to isolate
the contribution of the metabolite-sensitive afferents to elevations in MAP during exercise and documented higher blood
pressure when two legs were occluded, revealing that the
magnitude of ensemble-afferent feedback is proportional to
active muscle mass. Thus, to reach an equal magnitude of
ensemble afferent feedback as a consequence of exercise with
one quadriceps compared with two at task failure, attaining the
same sensory tolerance limit, a strong, local afferent signal
from the small muscle mass would be required. This translates
to a greater magnitude of peripheral fatigue and likely intramuscular metabolic disturbance as a consequence of smallmuscle mass exercise. In line with this paradigm, Matkowski et
al. (27) observed a greater degree of contractile dysfunction
following unilateral, submaximal isometric knee extension to
task failure in contrast to a bilateral contraction.
The current study utilized single-leg and double-leg KE to
mitigate concerns about task specificity of fatigue and cardiopulmonary limitations arising from the comparison of cycling
with KE in our previous work (38). The current comparison
enabled the desired variation in active muscle mass and isolated the contribution of the lower limbs. Greater peripheral
quadriceps fatigue following single-leg KE was evidenced by
an almost 50% greater decline in quadriceps MVC and an
increase in iEMG, as well as a greater decrease in Qtw,pot and
in all measured indices of peripheral fatigue (Fig. 3). Thus, in
parallel with our previous study revealing greater peripheral
fatigue following single-leg KE compared with whole body
cycling (38), these data suggest that the CNS tolerates a greater
magnitude of peripheral fatigue when the source of the afferent
signal is confined to a small muscle mass. Collectively, these
studies support the important link between active muscle mass
and afferent feedback and document that a greater degree of
peripheral fatigue can be achieved utilizing small-muscle mass
exercise.
Cycle exercise and the magnitude of peripheral fatigue.
Following exhaustive whole body cycling, there appears to be
a consistent level of peripheral quadriceps fatigue, which is
equivalent to approximately a one-third preexercise to postexercise reduction in Qtw,pot (3). Although this level varies
somewhat between individuals, numerous studies have identified similar average decreases in Qtw,pot, suggestive of a critical
level of peripheral fatigue, which is not typically surpassed
under normal circumstances during high-intensity cycling exercise (3, 6, 7, 9, 22, 23, 38). Interestingly, in the current study,
the level of peripheral fatigue following double-leg KE was
similar (⬃33% exercise-induced decrease in Qtw,pot) to that
typically observed following whole body cycling. Thus, similar
levels of peripheral fatigue are observed following whole body
cycling and double-leg KE, despite differing amounts of active
ACTIVE MUSCLE MASS AND PERIPHERAL FATIGUE
Perspectives and Significance
Reducing the amount of active muscle mass during dynamic
KE enabled the attainment of a greater degree of peripheral
quadriceps fatigue following constant workload exercise to
exhaustion. This is likely due to the constraint of the group
III/IV afferent signal to one quadriceps during single-leg KE,
in contrast to the more diffuse signals from both quadriceps
muscle groups, and potentially elevated central motor drive,
during double-leg KE. By minimizing differences in systemic
challenge and task specificity, these data substantiate the role
of active muscle mass in determining the level of tolerable
peripheral fatigue. In addition, these findings have important
implications for the adoption of small muscle mass exercise in
rehabilitative medicine to facilitate the attainment of greater
peripheral quadriceps fatigue, and, thus, potentially promote
greater skeletal muscle adaptation.
ACKNOWLEDGMENTS
The authors would like to thank the subjects for their gracious participation.
GRANTS
We thank the National Institutes of Health for financial support through
Grants PO1 HL-09830, HL-116579, and HL-103786 and a VA Merit Grant
E6910R.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
AUTHOR CONTRIBUTIONS
Author contributions: M.J.R., M.V., M.A., and R.S.R. conception and
design of research; M.J.R., R.S.G., M.V., and M.A. performed experiments; M.J.R. analyzed data; M.J.R., M.V., M.A., and R.S.R. interpreted
results of experiments; M.J.R. and M.A. prepared figures; M.J.R. and R.S.R.
drafted manuscript; M.J.R., R.S.G., M.V., M.A., and R.S.R. edited and revised
manuscript; M.J.R., R.S.G., M.V., M.A., and R.S.R. approved final version of
manuscript.
REFERENCES
1. Abbiss CR, Karagounis LG, Laursen PB, Peiffer JJ, Martin DT,
Hawley JA, Fatehee NN, Martin JC. Single-leg cycle training is superior
to double-leg cycling in improving the oxidative potential and metabolic
profile of trained skeletal muscle. J Appl Physiol 110: 1248 –1255, 2011.
2. Adreani CM, Hill JM, Kaufman MP. Responses of group III and IV
muscle afferents to dynamic exercise. J Appl Physiol 82: 1811–1817,
1997.
3. Amann M. Central and peripheral fatigue: interaction during cycling
exercise in humans. Med Sci Sports Exerc 43: 2039 –2045, 2011.
4. Amann M, Blain GM, Proctor LT, Sebranek JJ, Pegelow DF, Dempsey JA. Implications of group III and IV muscle afferents for high
intensity endurance exercise performance in humans. J Physiol 589:
5299 –5309, 2011.
5. Amann M, Calbet JA. Convective oxygen transport and fatigue. J Appl
Physiol 104: 861–870, 2008.
6. Amann M, Dempsey JA. Locomotor muscle fatigue modifies central
motor drive in healthy humans and imposes a limitation to exercise
performance. J Physiol 586: 161–173, 2008.
7. Amann M, Eldridge MW, Lovering AT, Stickland MK, Pegelow DF,
Dempsey JA. Arterial oxygenation influences central motor output and
exercise performance via effects on peripheral locomotor muscle fatigue in
humans. J Physiol 575: 937–952, 2006.
8. Amann M, Proctor LT, Sebranek JJ, Eldridge MW, Pegelow DF,
Dempsey JA. Somatosensory feedback from the limbs exerts inhibitory
influences on central neural drive during whole body endurance exercise.
J Appl Physiol 105: 1714 –1724, 2008.
9. Amann M, Proctor LT, Sebranek JJ, Pegelow DF, Dempsey JA.
Opioid-mediated muscle afferents inhibit central motor drive and limit
peripheral muscle fatigue development in humans. J Physiol 587: 271–
283, 2009.
10. Amann M, Venturelli M, Ives SJ, McDaniel J, Layec G, Rossman MJ,
Richardson RS. Peripheral fatigue limits endurance exercise via a sensory
feedback-mediated reduction in spinal motoneuronal output. J Appl
Physiol 115: 355–364, 2013.
11. Borg G. Borg’s Perceived Exertion and Pain Scales. Champaign, IL:
Human Kinetics, 1998.
12. Burnley M, Vanhatalo A, Fulford J, Jones AM. Similar metabolic
perturbations during all-out and constant force exhaustive exercise in
humans: a 31P magnetic resonance spectroscopy study. Exp Physiol 95:
798 –807, 2010.
13. Dolmage TE, Goldstein RS. Effects of one-legged exercise training of
patients with COPD. Chest 133: 370 –376, 2008.
14. Elmer SJ, Barratt PR, Korff T, Martin JC. Joint-specific power
production during submaximal and maximal cycling. Med Sci Sports
Exerc 43: 1940 –1947, 2011.
15. Freund PR, Hobbs SF, Rowell LB. Cardiovascular responses to muscle
ischemia in man— dependency on muscle mass. J Appl Physiol 45:
762–767, 1978.
16. Gallagher KM, Fadel PJ, Stromstad M, Ide K, Smith SA, Querry RG,
Raven PB, Secher NH. Effects of partial neuromuscular blockade on
carotid baroreflex function during exercise in humans. J Physiol 533:
861–870, 2001.
17. Gandevia SC. Spinal and supraspinal factors in human muscle fatigue.
Physiol Rev 81: 1725–1789, 2001.
18. Hogan MC, Richardson RS, Haseler LJ. Human muscle performance
and PCr hydrolysis with varied inspired oxygen fractions: a 31P-MRS
study. J Appl Physiol 86: 1367–1373, 1999.
19. Howard JD, Enoka RM. Maximum bilateral contractions are modified by
neurally mediated interlimb effects. J Appl Physiol 70: 306 –316, 1991.
AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00043.2014 • www.ajpregu.org
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.1 on June 15, 2017
central sources (19). In addition, very recent data (10) suggest
that the magnitude of central motor drive (or “neural drive”),
which is likely higher when greater muscle mass is engaged
during exercise (5), may also increase the perception of effort
(16). This could contribute to the sensory tolerance limit,
which might limit the magnitude of peripheral fatigue tolerated
by the CNS. Recently, our group demonstrated significantly
less peripheral fatigue following exhaustive, single-leg KE
when the exercise bout was preceded by an exhaustive singleleg KE bout of the contralateral limb (10). These observations
were hypothesized to be the result of both inhibitory afferent
feedback from the previously exercised leg curtailing the
exercise performance of the second leg, as well as elevated
central motor drive.
In the current study, indirect evidence for a higher central
motor drive during double-leg KE, which engaged twice the
active muscle mass, is provided by the greater EMG signal
from one leg, multiplied by two to estimate central motor drive
during double-leg KE, compared with the EMG signal from the
same leg during single-leg KE at exhaustion (⬃0.2 mVs vs.
⬃0.1 mVs). Further indirect indices of a higher central motor
drive are provided by the greater central cardiovascular and
respiratory responses during double-leg KE (Figs. 1 and 2),
both of which are determined by feedback and feedforward
mechanisms (8). In the presence of greater central motor drive,
less overall afferent feedback from the exercising limbs would
be required to reach the sensory tolerance limit during doubleleg KE. Accordingly, the reduced magnitude of peripheral
fatigue following double-leg KE (Fig. 3) was likely due to both
a more diffuse afferent signal arising from the greater active
muscle mass involved during exercise and greater central
motor drive. Thus, when muscle mass and central motor drive
are elevated, less peripheral fatigue is tolerated to avoid severe
exercise-induced damage, which might threaten whole body
homeostasis.
R939
R940
ACTIVE MUSCLE MASS AND PERIPHERAL FATIGUE
31. Oldfield RC. The assessment and analysis of handedness: the Edinburgh
inventory. Neuropsychologia 9: 97–113, 1971.
32. Polkey MI, Kyroussis D, Hamnegard CH, Mills GH, Green M, Moxham J. Quadriceps strength and fatigue assessed by magnetic stimulation
of the femoral nerve in man. Muscle Nerve 19: 549 –555, 1996.
33. Richardson RS, Frank LR, Haseler LJ. Dynamic knee-extensor and
cycle exercise: functional MRI of muscular activity. Int J Sports Med 19:
182–187, 1998.
34. Richardson RS, Grassi B, Gavin TP, Haseler LJ, Tagore K, Roca J,
Wagner PD. Evidence of O2 supply-dependent V̇O2max in the exercisetrained human quadriceps. J Appl Physiol 86: 1048 –1053, 1999.
35. Richardson RS, Knight DR, Poole DC, Kurdak SS, Hogan MC, Grassi
B, Wagner PD. Determinants of maximal exercise V̇O2 during single leg
knee-extensor exercise in humans. Am J Physiol Heart Circ Physiol 268:
H1453–H1461, 1995.
36. Richardson RS, Leek BT, Gavin TP, Haseler LJ, Mudaliar SR, Henry
R, Mathieu-Costello O, Wagner PD. Reduced mechanical efficiency in
chronic obstructive pulmonary disease but normal peak V̇O2 with small
muscle mass exercise. Am J Respir Crit Care Med 169: 89 –96, 2004.
37. Richardson RS, Wagner H, Mudaliar SR, Saucedo E, Henry R,
Wagner PD. Exercise adaptation attenuates VEGF gene expression in
human skeletal muscle. Am J Physiol Heart Circ Physiol 279: H772–
H778, 2000.
38. Rossman MJ, Venturelli M, McDaniel J, Amann M, Richardson RS.
Muscle mass and peripheral fatigue: A potential role for afferent feedback? Acta Physiol (Oxf) 206: 242–250, 2012.
39. Vanhatalo A, Fulford J, DiMenna FJ, Jones AM. Influence of hyperoxia on muscle metabolic responses and the power-duration relationship
during severe-intensity exercise in humans: a 31P magnetic resonance
spectroscopy study. Exp Physiol 95: 528 –540, 2010.
AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00043.2014 • www.ajpregu.org
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.1 on June 15, 2017
20. Iwamoto GA, Botterman BR. Peripheral factors influencing expression
of pressor reflex evoked by muscular contraction. J Appl Physiol 58:
1676 –1682, 1985.
21. Jakobi JM, Chilibeck PD. Bilateral and unilateral contractions: possible
differences in maximal voluntary force. Can J Appl Physiol 26: 12–33,
2001.
22. Jeffery Mador M, Kufel TJ, Pineda L. Quadriceps fatigue after cycle
exercise in patients with chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 161: 447–453, 2000.
23. Jeffery Mador M, Kufel TJ, Pineda LA. Quadriceps and diaphragmatic
function after exhaustive cycle exercise in the healthy elderly. Am J Respir
Crit Care Med 162: 1760 –1766, 2000.
24. Kufel TJ, Pineda LA, Mador MJ. Comparison of potentiated and
unpotentiated twitches as an index of muscle fatigue. Muscle Nerve 25:
438 –444, 2002.
25. Lepers R, Maffiuletti NA, Rochette L, Brugniaux J, Millet GY.
Neuromuscular fatigue during a long-duration cycling exercise. J Appl
Physiol 92: 1487–1493, 2002.
26. Magnusson G, Gordon A, Kaijser L, Sylven C, Isberg B, Karpakka J,
Saltin B. High-intensity knee extensor training, in patients with chronic
heart failure. Major skeletal muscle improvement. Eur Heart J 17: 1048 –
1055, 1996.
27. Matkowski B, Place N, Martin A, Lepers R. Neuromuscular fatigue
differs following unilateral vs. bilateral sustained submaximal contractions. Scand J Med Sci Sports 21: 268 –276, 2011.
28. Merton PA. Voluntary strength and fatigue. J Physiol 123: 553–564,
1954.
29. Nybo L, Nielsen B. Hyperthermia and central fatigue during prolonged
exercise in humans. J Appl Physiol 91: 1055–1060, 2001.
30. Nybo L, Rasmussen P. Inadequate cerebral oxygen delivery and central
fatigue during strenuous exercise. Exerc Sport Sci Rev 35: 110 –118, 2007.