Peripheral fatigue limits endurance exercise via a sensory feedback-mediatedreduction in spinal motoneuronal output

Markus Amann,1,2* Massimo Venturelli,1,3* Stephen J. Ives,2 John McDaniel,1,2 Gwenael Layec,1

Matthew J. Rossman,1 and Russell S. Richardson1,2,4

1Department of Medicine, University of Utah, Salt Lake City, Utah; 2Geriatric Research, Education, and Clinical Center,Veterans’ Affairs Medical Center, Salt Lake City, Utah; 3Department of Neuroscience and Kinesiology, University of Verona,Verona, Italy; and 4Department of Exercise and Sport Science, University of Utah, Salt Lake City, Utah

Submitted 14 January 2013; accepted in final form 23 May 2013

Amann M, Venturelli M, Ives SJ, McDaniel J, Layec G, Ross-man MJ, Richardson RS. Peripheral fatigue limits endurance exer-cise via a sensory feedback-mediated reduction in spinal motoneuro-nal output. J Appl Physiol 115: 355–364, 2013. First published May30, 2013; doi:10.1152/japplphysiol.00049.2013.—This study soughtto determine whether afferent feedback associated with peripheralmuscle fatigue inhibits central motor drive (CMD) and thereby limitsendurance exercise performance. On two separate days, eight menperformed constant-load, single-leg knee extensor exercise to exhaus-tion (85% of peak power) with each leg (Leg1 and Leg2). On anotherday, the performance test was repeated with one leg (Leg1) andconsecutively (within 10 s) with the other/contralateral leg (Leg2-post). Exercise-induced quadriceps fatigue was assessed by reductionsin potentiated quadriceps twitch-force from pre- to postexercise(�Qtw,pot) in response to supramaximal magnetic femoral nerve stim-ulation. The output from spinal motoneurons, estimated from quadri-ceps electromyography (iEMG), was used to reflect changes in CMD.Rating of perceived exertion (RPE) was recorded during exercise.Time to exhaustion (�9.3 min) and exercise-induced �Qtw,pot

(�51%) were similar in Leg1 and Leg2 (P � 0.5). In the consecutiveleg trial, endurance performance of the first leg was similar to thatobserved during the initial trial (�9.3 min; P � 0.8); however, timeto exhaustion of the consecutively exercising contralateral leg (Leg2-post) was shorter than the initial Leg2 trial (4.7 � 0.6 vs. 9.2 � 0.4min; P � 0.01). Additionally, �Qtw,pot following Leg2-post was lessthan Leg2 (33 � 3 vs 52 � 3%; P � 0.01). Although the slope ofiEMG was similar during Leg2 and Leg2-post, end-exercise iEMGfollowing Leg2-post was 26% lower compared with Leg2 (P � 0.05).Despite a similar rate of rise, RPE was consistently �28% higherthroughout Leg2-post vs. Leg2 (P � 0.05). In conclusion, this studyprovides evidence that peripheral fatigue and associated afferentfeedback limits the development of peripheral fatigue and compro-mises endurance exercise performance by inhibiting CMD.

central motor drive; neural feedback; group III and IV muscle affer-ents; central fatigue

NUMEROUS STUDIES HAVE REVEALED that the inability to continuehigh-intensity, constant-load endurance exercise (i.e., exhaus-tion) coincides with a specific level of peripheral locomotormuscle fatigue (3, 4, 21, 22, 44–46). Based on the evidencethat voluntarily exercising humans never exceed this specificand individually different degree of peripheral fatigue, theexistence of a “critical threshold” of muscle fatigue was pre-viously proposed (3, 4). Muscle afferent fibers, which relayfatigue-related metabolic perturbations within the working

limb muscles to the central nervous system (CNS) (27, 30, 57),have been suggested to play an important role in determiningthis critical threshold of fatigue (5, 23), which likely coincideswith an individual’s “sensory tolerance limit” (23). Specifi-cally, during constant-load endurance exercise, mechano- andmetabo-sensitive group III/IV muscle afferents provide inhib-itory input to the CNS. This feedback limits voluntary descend-ing drive to the primary motor cortex [i.e., central motor drive(CMD)] (52) and exercise performance, restricting the devel-opment of locomotor muscle fatigue to a critical threshold thatis associated with a certain level of intramuscular metabolicperturbation (4). It should be acknowledged that this paradigmincludes only one of several potential mechanisms that mayaccount for the inability to continue high-intensity, constant-load endurance exercise and requires further study. Psycholog-ical factors (18), extreme environmental influences (6, 39, 54),and exercise-induced alterations in CNS neurotransmitter sys-tems (36) are examples of other potential mechanisms limitingCMD and/or the output of spinal motoneurons and exerciseperformance.

In recent experiments designed to examine the effect oflocomotor muscle afferents on the development of peripheralfatigue, pharmacological blockade was used to reduce sensoryfeedback during high-intensity leg cycling (2). With greatlyreduced inhibitory feedback from group III/IV leg muscleafferents to the CNS, output/drive from the spinal motoneuronsto locomotor muscles (as estimated from surface EMG) was,compared with placebo conditions, substantially increased dur-ing exercise. The exercising humans (i.e., the CNS) in theseexperiments “ignored” the sensory tolerance limit and “toler-ated” the development of peripheral muscle fatigue substan-tially beyond their critical threshold, which was determined inplacebo conditions (i.e., with intact afferent feedback) (2).Although providing strong evidence in favor of an inhibitoryinfluence of fatigue-related sensory feedback on the outputfrom spinal motoneurons, a caveat of this approach is thatblocking group III/IV muscle afferents also impairs the cardio-vascular and ventilatory responses during exercise (1, 7),which, per se, limits exercise performance (2).

In addition to reducing the inhibitory neural feedback duringexercise via spinal blockade, an alternative approach to discernthe role of group III/IV muscle afferents in regulating theoutput of spinal motoneurons and limiting endurance perfor-mance has been to elevate the inhibitory feedback mediated bythese sensory neurons. In previous investigations, peripherallocomotor muscle fatigue and associated metabolic distur-bances were either voluntarily (3) or electrically (22) inducedimmediately before a cycling performance test to increase

* M. Amann and M. Venturelli contributed equally to this work.Address for reprint requests and other correspondence: M. Amann, VA

Medical Center, GRECC 182, 500 Foothill Dr., Salt Lake City, UT 84148(e-mail: markus.amann@hsc.utah.edu).

J Appl Physiol 115: 355–364, 2013.First published May 30, 2013; doi:10.1152/japplphysiol.00049.2013.

8750-7587/13 Copyright © 2013 the American Physiological Societyhttp://www.jappl.org 355

fatigue-related inhibitory neural feedback to the CNS duringthe subsequent performance trial. The outcome of theseexperiments indicates that the higher the level of preexistingmuscle fatigue and associated inhibitory feedback, the lowerthe output of spinal motoneurons and cycling performanceduring a subsequent performance trial (3, 22). Again, al-though providing evidence for an inhibitory effect of pe-ripheral muscle fatigue and associated neural feedback onthe output of spinal motoneurons, the observed performancelimitations might, at least in part, have been due to acompromised muscle response to a given neural input (i.e.,peripheral fatigue).

To circumvent previous experimental shortcomings, we in-duced quadriceps fatigue in one leg using voluntary dynamicsingle-leg knee-extensor exercise to exhaustion with the goal toraise the ensemble muscle afferent feedback during a subse-quent endurance performance test with the other leg. Wehypothesized that 1) fatigue-related intramuscular metabolicdisturbances and associated inhibitory feedback from one legwould compromise performance of the consecutively exercisedcontralateral leg and 2) peripheral quadriceps fatigue, at vol-untary exhaustion, of the consecutively exercised leg would besubstantially below the level of fatigue observed during controltrials.

METHODS

Subjects

Eight recreationally active, healthy male volunteers participated inthis study (age 24 � 1 yr, body mass 83 � 6 kg, height 178 � 4 cm).Seven of the participants were determined to be right-leg dominant,whereas one participant was left-leg dominant (41). Quadriceps mus-cle mass (26) was similar in both limbs (2.4 � 0.1 kg; P � 0.6). Thestudy was approved by the University of Utah and the Salt Lake CityVA Medical Center Institutional Review Boards, and written, in-formed consent was obtained from each subject before participation.

Experimental Protocol

During four 1-h practice sessions, all participants were thoroughlyfamiliarized with various experimental procedures, including single-leg knee-extensor exercise (KE) (8, 43). On 2 additional days, allsubjects performed incremental single-leg KE until they were unableto continue the prescribed work rate (15 W � 5 W/min) to determinepeak power output (Wpeak) of each leg.

On 2 separate days following these initial sessions, each subjectperformed, in random order, constant-load, single-leg KE (60 RPM,85% of Wpeak) to task failure (cadence below 50 RPM for �10 s) withboth legs (days 1 and 2; Fig. 1). This RPM was chosen based on ourprevious work with this model, indicating that a failure to maintain 50RPM for longer than 10 s leads to voluntary termination of exercisewithin 30 s. Neuromuscular function of the exercising leg was

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Fig. 1. Experimental design. Days 1 and 2 and days 3 and 4 were carried out in random order and separated by at least 48 h. Leg order and dominance werebalanced.

356 Muscle Afferents and Endurance Exercise • Amann M et al.

J Appl Physiol • doi:10.1152/japplphysiol.00049.2013 • www.jappl.org

assessed before and 2 min after exercise (Fig. 1). To determinewhether exercise-induced quadriceps fatigue in one leg affected neu-romuscular function in the other leg, all subjects performed a thirdtrial (day 3; Fig. 1). Here, neuromuscular function of one leg wasassessed before and again 2 min after constant-load exercise to taskfailure with the other leg. On a fourth day, all participants carried outconstant-load, single-leg KE to task failure with one leg (Leg1) andconsecutively (�10 s) performed constant-load, single-leg KE, againto task failure, with the other leg (Leg2-post) (day 4; Fig. 1). In thistrial, at task failure following exercise with the first leg (Leg1), a cuffaround the upper part of the thigh of Leg1 was inflated to 250 mmHguntil the Leg2-post exercise trial was started (day 4; Fig. 1). Neuro-muscular function of Leg2-post was assessed before and 2 min afterexercise (Fig. 1). Sessions (day) 3 and 4 were in random order. Thewarm-up performed on each of the test days consisted of 10 min oftwo-leg KE at 15 W. To avoid initial peak force outputs at thebeginning of each performance trial, the ergometer was initiallyaccelerated by one of the investigators (�2 s). Subjects were in-structed to strictly maintain 60 RPM throughout KE. All performancetrials were separated by 48–72 h and balanced with respect to legdominance.

Exercise Responses

At rest and throughout exercise, pulmonary gas exchange andventilation were measured continuously using an open-circuit calo-rimetry system (Parvo Medics, True Max 2400, Salt Lake City, UT).Femoral blood flow (FBF) was measured at rest and during exerciseusing ultrasound Doppler (Logic 7, General Electric Medical Sys-tems). Simultaneous measurements of common femoral arterial bloodvelocity (Vmean) and vessel diameter were performed distal to theinguinal ligament and proximal to the bifurcation of the deep andsuperficial femoral arteries. Using arterial diameter and Vmean, FBFwas calculated as: FBF � Vmean�(vessel diameter/2)2 60.

Cardiac output (CO) and mean arterial pressure (MAP) weredetermined using a Finometer (Finapres Medical Systems, Amster-dam, The Netherlands) and the Modelflow algorithm (Beatscopeversion 1.1a; Finapres Medical Systems) (50). Heart rate (HR) wasmeasured from the R-R interval of an electrocardiogram (ECG) usinga three-lead arrangement. Rating of perceived exertion (RPE) wasobtained at rest and every minute during exercise using Borg’smodified CR10 scale (14) following the recommended instructions/verbiage for using the scale (38). Venous blood samples from anantecubital catheter were collected in trial 4, as illustrated in Fig. 1.To evaluate the effects of severe quadriceps fatigue on remote restedmuscles, we measured maximal handgrip forces of the dominant armbefore the performance of Leg1 and the consecutive performance testin Leg2-post on day 4 (Fig. 1).

Neuromuscular Function

Electromyography. As previously described (3), quadriceps EMGwas recorded from the vastus lateralis using electrodes with full-surface solid adhesive hydrogel (H59P, Tyco Healthcare Group,Mansfield, MA). The position of the EMG electrodes was markedwith indelible ink to ensure placement in the same location onsubsequent visits. The vastus lateralis electrodes were used to record1) magnetically evoked muscle action potentials (M-waves, peak-to-peak amplitude) to evaluate changes in membrane excitability and 2)EMG throughout exercise to estimate the output of spinal motoneu-rons and the development of peripheral quadriceps fatigue. Membraneexcitability was maintained from pre- to postexercise in all trials asindicated by unchanged peak-to-peak M-wave amplitudes. Thissuggests that the observed changes in potentiated twitch force(Qtw,pot; see below) were predominantly due to changes within thequadriceps and that electrical transmission failure or reducedsarcolemma excitability can be excluded. During KE performancetrials, EMG signal corresponding to vastus lateralis muscle con-

tractions were recorded for later analysis. The raw EMG signal wasdigitized and recorded at 1.5 kHz using adhesive silver electrodesplaced over the muscle belly �4 cm apart. The raw EMG signalwas filtered with a band-pass filter (low-pass cut-off frequency of15 Hz, high-pass cut-off frequency of 650 Hz), and muscle activitywas automatically located (AcqKnowledge, Biopac Systems, Go-leta, CA). For this, the analysis program calculated the standarddeviation (SD) of the baseline noise (i.e., electrical signal betweenthe bursts). The onset of a burst was identified as the point at whichthe EMG signal rose to a value �2.5 SD above baseline. The sameapproach was utilized to identify the offset of a burst. Accurateidentification of EMG activity was verified by visual inspection.Integrated EMG (iEMG) for each contraction throughout the pro-tocol was calculated using the Acknoweldge software.

Magnetic nerve stimulation. A detailed description of the assess-ment of muscle function with magnetic nerve stimulation can befound in prior publications by our group utilizing this technique (4).Briefly, subjects rested on an adjustable chair with the right or leftthigh lying in a preformed holder, with knee joint angle set at 90° offlexion and arms folded across the chest. A magnetic stimulator(Magstim 200; The Magstim, Wales, UK) connected to a double70-mm branding iron coil was used to stimulate the femoral nerve.The position of the coil was marked with indelible ink to ensureplacement in the same location during all visits. The evoked quadri-ceps twitch force was obtained from a calibrated load cell (modelMLP-300; Transducer Techniques, Temecula, CA) connected to anoncompliant strap, which was placed around the subject’s right orleft leg just superior to the ankle malleoli. Unpotentiated quadricepssingle twitch forces (Qtw) were obtained every 30 s at 50, 60, 70, 80,85, 90, 95, and 100% of maximal stimulator output. The increment inQtw and M-wave amplitude from 90 to 95% of the stimulator outputwas 0.6 � 0.4% (P � 0.14) and 1.4 � 0.5% (P � 0.13), respectively;the increment in Qtw and M-wave amplitude from 95 to 100% of thestimulator output was 0.4 � 0.2% (P � 0.36) and 0.1 � 0.6% (P �0.96), respectively. A plateau in baseline Qtw and M-wave amplitudeswith increasing stimulus intensities was observed in every subject.The stimulator output that produced the first maximal response was90%. The stimulator output was set to 100% in every subject and inall trials. Qtw,pot has been documented to be more sensitive fordetecting fatigue than the nonpotentiated twitch (28). Accordingly, wemeasured Qtw,pot 5 s after a 5-s isometric maximal voluntary contrac-tion (MVC) of the quadriceps and repeated this procedure six times.The interval between the MVCs was 35 s. As reported in a previousstudy (28), the degree of potentiation was slightly smaller after thefirst and, to a lesser extent, after the second MVC; therefore, the firsttwo Qtw,pot measurements were discarded. This assessment procedurewas performed 20 min before exercise and 2 min after exercise. Peakforce, maximal rate of force development (MRFD), and maximalrelaxation rate (MRR) were analyzed for all Qtw,pot (47). Voluntaryactivation of the quadriceps during the MVCs was assessed using asuperimposed twitch technique (37). Briefly, the force producedduring a single twitch superimposed on the MVC was compared withthe force produced by the potentiated single twitch delivered 5 safterward.

Blood Analysis

Venous blood samples from an antecubital catheter were drawninto glass tubes containing EDTA during trial 4 (Fig. 1). Theconcentration of branched-chain amino acids (BCAA; valine, iso-leucine, and leucine) was determined utilizing an amino acid assaykit (ab83374, Abcam Cambridge, MA). The concentration of freetryptophan (TRP) was measured using a modification of the spec-trofluorometric method (9).

357Muscle Afferents and Endurance Exercise • Amann M et al.

J Appl Physiol • doi:10.1152/japplphysiol.00049.2013 • www.jappl.org

Statistical Analysis

To determine the effects of increased afferent feedback (condition:two levels, with and without fatigue in the contralateral limb) onexercise-induced changes in various physiological parameters overtime (time: five levels, five time points), we employed a two-way (2 5) repeated-measures ANOVA. To determine the effects of increasedafferent feedback (condition: two levels, with and without fatigue inthe contralateral limb) on exercise-induced changes in quadricepsmuscle function (time: four time points, pre- and postexercise in eachcondition), we employed a two-way (2 4) repeated-measuresANOVA. Post hoc analysis was performed using Tukey’s post hoctest of honestly significant difference. Mauchly’s test of sphericitywas run to determine whether the assumption for homogeneity ofvariance was met for each variable. If there was a significant differ-ence (P � 0.05) in the variance of the differences across time in eachcondition for any measured variable and therefore the assumption ofnormal distribution was violated, the Greenhouse-Geisser Epsiloncorrection was applied to the degrees of freedom. Statistical signifi-cance was set at P � 0.05. Data are presented as means � SE.

RESULTS

Dominant vs. Non-Dominant Leg: Endurance Capacity andQuadriceps Fatigability (Days 1 and 2)

Both whole body peak oxygen uptake and Wpeak weresimilar for the dominant and the nondominant leg [1.7 � 0.2vs. 1.6 � 0.2 l/min (P � 0.82) and 61 � 6 vs. 58 � 4 W (P �0.23), respectively] (Fig. 1; days 1 and 2). Time to task failureat 85% of Wpeak was not different between the two legs (P �0.79; Table 1). Immediately after exercise with either leg,quadriceps muscle function was markedly decreased frompreexercise baseline (P � 0.001). The degree of exercise-induced peripheral fatigue was similar in the dominant and thenondominant leg (P � 0.48; Table 1).

Effect of Quadriceps Fatigue in One Leg on MuscleFunction of the Rested Contralateral Leg (Day 3)

Despite the development of severe exercise-induced quadri-ceps fatigue in one leg (Fig. 1, day 3), quadriceps musclefunction in the contralateral leg was not affected. This wasevident by similar pre- vs. postexercise values for Qtw,pot

(�170 N; P � 0.44), MVC force (�570 N; P � 0.57), andvoluntary muscle activation (�93%; P � 0.89).

Effect of Quadriceps Fatigue on Endurance ExercisePerformance and Associated Development of PeripheralFatigue in the Consecutively Exercised ContralateralLeg (Day 4)

Exercise performance. Compared with control exercise (i.e.,day 2; time to task failure: 9.2 � 0.4 min), endurance time totask failure was 49 � 6% shorter (P � 0.001) when theidentical exercise was performed with pre-induced quadricepsfatigue in the contralateral leg (i.e., Leg2post trial). This re-duction in endurance time to task failure was consistent in allsubjects (range 33 to 75%; Fig. 2).

Contractile function. Immediately after both Leg2 (day 2),and Leg2-post (day 4) exercise trials, group mean Qtw,pot wassignificantly reduced from preexercise baseline [F(1,16) �17.8; P � 0.01]. However, compared with control exercise(i.e., Leg2 trial), the exercise-induced reduction in Qtw,pot inLeg2-post was attenuated (Table 2; Fig. 2). All within-twitch

Table 1. Effects of constant-load, single-leg knee-extensorexercise to exhaustion on quadriceps muscle function of thedominant and nondominant leg

Dominant Leg Nondominant Leg

Time to task failure, min 9.2 � 0.4 9.4 � 0.9Workload, W 52 � 5 49 � 3Percent change from preexercise to 2 min

postexerciseMVC 30 � 3 29 � 2Qtw,pot 52 � 2 50 � 6MRFD 55 � 4 50 � 7MRR 51 � 4 53 � 3Muscle activation 1 � 2* 1 � 2*

Values are means � SD (n � 8). Seven subjects were right leg dominant;one subject was left leg dominant. MVC, maximal voluntary contraction;Qtw,pot, potentiated single twitch; MRFD, maximal rate of force development;MRR, maximal rate of relaxation. Preexercise, resting mean values for MVC,Qtw,pot, MRFD, MRR, and voluntary muscle activation in the dominant legwere 573 � 52 N, 170 � 20 N, 1.8 � 0.3 N/ms, 0.7 � 0.1 N/ms, and 94 �3%, respectively. Preexercise resting values were similar in the nondominantleg. *Not significantly altered from preexercise.

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Fig. 2. Individual and group mean data illustrating endurance time to taskfailure and peripheral quadriceps fatigue under control conditions (Leg2, i.e.,exercise performed with rested contralateral leg) and under experimentalconditions (Leg2post, i.e., exercise performed with severe quadriceps fatigue inthe contralateral leg).

358 Muscle Afferents and Endurance Exercise • Amann M et al.

J Appl Physiol • doi:10.1152/japplphysiol.00049.2013 • www.jappl.org

measurements (MRFD, MRR) were also significantly alteredfrom baseline immediately postexercise (Table 2). Each ofthese exercise-induced reductions was significantly greaterduring the Leg2 compared with the Leg2-post trial (Table 2).Peak force during the 5-s MVC maneuvers was significantlydecreased from baseline after all trials [F(1,16) � 8.8; P �0.01]. Again, consistent with the other fatigue-related re-sults, reductions in MVC force were significantly greaterfollowing the Leg2 trial (day 2) compared with the Leg2-post trial (day 4) (Table 2; Fig. 2). Muscle activationremained unchanged from pre- to postexercise in both trials[�94%; F(1,14) � 0.2; P � 0.3].

Cardiorespiratory and Hemodynamic Responses

Cardiorespiratory and hemodynamic responses to constant-load KE exercise trials with and without quadriceps fatigue inthe contralateral leg are illustrated in Fig. 3. Quadriceps fatiguein the contralateral leg had a significant effect on oxygenuptake [V̇O2; F(1,14) � 56.5; P � 0.01], CO2 uptake [V̇CO2;F(1,14) � 56.5; P � 0.01], minute ventilation [V̇E; F(1,14) �57.2; P � 0.01], V̇E/V̇CO2 [F(1,14) � 57.5; P � 0.01], HR[F(1,14) � 43.1; P � 0.01], and cardiac output [CO; F(1,14) �57.0; P � 0.01] during the first 3 min of exercise. However,during the final minute of exercise, these variables were similarbetween the Leg2 (day 2) and Leg2-post (day 4) trials (all P �0.1; Fig. 3). Although MAP [F(1,14) � 57.5; P � 0.01] was,compared with Leg2, significantly higher during the first 2 minof the Leg2-post trial, there was no significant differencebetween the trials throughout the remainder of the exercise(Fig. 3F). Femoral blood flow was similar at the onset ofexercise in both trials (P � 0.47). However, at minute 1,femoral blood flow was significantly lower during Leg2-postcompared with Leg2 exercise, but this difference progressivelydiminished, and blood flow was similar throughout the rest ofexercise (Fig. 3E).

Ratings of Perceived Exertion

The rate-of-rise of RPE was similar during the Leg2 trial(day 2) compared with the Leg2-post trial (day 4) (P � 0.6).However, the RPE score was, compared with Leg2, signifi-cantly higher at the onset of the Leg2-post trial. Indeed, the

prior development of quadriceps fatigue in the contralateral leghad a significant effect on RPE during the first 3 min ofexercise, with a �28% elevation in RPE evident throughout[F(1,14) � 44.6; P � 0.01] (Fig. 4). End-exercise RPE wassimilar in both trials.

Plasma Branched-Chain Amino Acids and Tryptophan

The concentration of plasma free tryptophan (Trp) signifi-cantly increased from rest to the transition between Leg1 andLeg2-post [Fig. 1, day 4; F(2,14) � 9.7; P � 0.02]; post-exercise Trp concentration ([Trp]) was similar to the [Trp]observed during the transition between Leg1 and Leg2-post(P � 0.25). Branched-chain amino acids (BCAA) were similarat the three time points [F(2,14) � 0.6; P � 0.25]. Thereforethe [Trp]-to-[BCAA] ratio significantly increased from rest tothe transition between Leg1 and Leg2-post [F(2,14) � 6.3; P �0.04]; postexercise [Trp]-to-[BCAA] ratio was not differentfrom the ratio observed during the transition between Leg1 andLeg2-post [F(2,14) � 6.3; P � 0.84].

iEMG

iEMG rose significantly from the first minute of exercise totask failure in each of the two conditions [Fig. 5; F(1,14) of�4.3; P � 0.05]. Given the similar rate of rise during Leg2

(day 2) and Leg2-post (day 4) (P � 0.13), the increase in iEMGduring the first 3 min of exercise was very similar in bothconditions (P � 0.17). However, at end-exercise, iEMG inLeg2 had increased to a significant extent (347 � 39%; range198–395%) compared with Leg2-post (Fig. 5).

Handgrip Force

Handgrip MVC was unchanged from before the Leg1 per-formance trial to immediately after the Leg2-post performancetrial (�2 s) on day 4 (31 � 3 and 32 � 2 kg, respectively; P �0.22) (Fig. 1, day 4).

DISCUSSION

This study sought to determine whether afferent feedbackassociated with peripheral muscle fatigue and the affiliatedintramuscular metabolic disturbance inhibits spinal motoneu-ronal output and thereby limits endurance exercise perfor-mance. Pre-induced quadriceps fatigue in one leg reducedendurance time to exhaustion of the consecutively exercisedcontralateral leg by �49%. Since the circulatory and ventila-tory responses during such small muscle mass exercise are wellwithin the respective maximal capacities, the impact of muscleafferents on endurance performance was likely independent oftheir well known role in regulating, and potentially limiting,peripheral hemodynamic responses during exercise. Therefore,the present data document the limiting effect of peripheralmuscle fatigue and associated afferent feedback on enduranceexercise performance, apparently achieved by restricting theoutput of spinal motoneurons to the working skeletal muscle.

Evidence of Increased Muscle Afferent Feedback in theConsecutive Leg Exercise Trial (Leg2-Post)

An important premise of the present study was that thedevelopment of quadriceps fatigue in one leg would increasethe ensemble input of fatigue-sensitive group III/IV muscle

Table 2. Effect of constant-load, single-leg knee-extensorexercise to exhaustion on quadriceps muscle function of thecontrol trial (Leg2, day 2) vs. the consecutively exercised legtrial (Leg2-post, day 4)

Leg2 Leg2-post

Time to task failure, min 9.2 � 0.4 4.7 � 0.6 *Workload, W 51 � 4 51 � 4Percent change from pre- to 2 min

postexerciseMVC 30 � 3 23 � 3 *Qtw,pot 52 � 3 33 � 3 *MRFD 55 � 4 19 � 9 *MRR 52 � 4 36 � 4 *Muscle activation 1 � 1† 2 � 1†

Values are means � SD (n � 8). Preexercise, resting mean values for MVC,Qtw,pot, MRFD, MRR, and voluntary muscle activation were 559 � 55 N;165 � 22 N; 3.2 � 0.4 N/ms; 0.5 � 0.1 N/ms, and 94 � 3%, respectively.*Significant difference vs. Leg2 (P � 0.05). †Not significantly altered frompreexercise.

359Muscle Afferents and Endurance Exercise • Amann M et al.

J Appl Physiol • doi:10.1152/japplphysiol.00049.2013 • www.jappl.org

afferents to the CNS during the consecutive endurance test ofthe contralateral leg. This experimental design allowed theevaluation of exercise performance of a single leg, whereasafferent feedback to the CNS arose from two legs. Althoughthe direct assessment of afferent feedback in humans is cur-rently not possible, several lines of indirect evidence suggestthat this was, in fact, likely achieved. First, direct nerverecordings from group IV muscle afferents following electri-cally induced muscle fatigue in anesthetized animals indicatethat the sensory discharge remained elevated above baselinefor up to 15 min after fatiguing muscle contractions hadstopped (19, 20, 25). Second, it has previously been docu-mented that experimentally augmenting lower limb muscleafferent activity during one-leg KE, achieved by postexercisecuff occlusion of the contralateral leg, causes a greater exercise

pressor reflex compared with control conditions (no priorexercise and no cuff occlusion in other leg) (16, 49). Thepresent findings, characterized by an elevated exercise pressorand ventilatory response during Leg2-post (Fig. 3), conform tothese earlier observations. Finally, RPE is modulated by affer-ent feedback from fatiguing muscles (1, 2). In the presentstudy, RPE scores were consistently higher during the first 3min of the Leg2-post trial despite very similar levels of iEMGcompared with those recorded in the Leg2 trial (Figs. 4 and 5).Taken together, these prior studies and current observationssupport the premise that, due to the pre-induced fatigue inLeg1, the ensemble lower limb muscle afferent feedback wasgreater during the Leg2-post compared with the Leg2 trial, eventhough the exercise challenge (work rate) was similar. Theachievement of this somewhat unique experimental paradigm

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Fig. 3. Physiological responses to constant-load single leg knee-extensor exercise with-out (Leg2) and with preexisting quadricepsfatigue in the contralateral leg (Leg2-post).V̇O2, oxygen consumption; V̇CO2, carbon di-oxide production; V̇E, minute ventilation;MAP, mean arterial pressure; HR, heart rate;CO, cardiac output. *Significant differencevs. Leg2 (P � 0.05).

360 Muscle Afferents and Endurance Exercise • Amann M et al.

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is an important foundation from which to interpret the resultsof the present study.

Muscle Afferent Feedback, Central Motor Drive, and Rate ofPerceived Exertion

Although many recent studies have attempted to assess theinhibitory effect of muscle afferents on CMD/the output ofspinal motoneurons (2, 24, 48, 51, 55), each is confounded, tosome degree, by issues such as an attenuated cardiopulmonaryresponse to exercise (afferent blocking studies) and changes inperipheral muscle function (prefatigue studies). In contrast, dueto the somewhat innovative experimental design utilized here,the present study was not burdened by these caveats. Specifi-cally, this study provides evidence of the inhibitory effect ofmuscle afferents on the output of spinal motoneurons, whichresulted in an �49% reduction in endurance performance whenconsecutive leg exercise in the contralateral leg was superim-posed upon the already fatigued leg.

This study is not the first to document a “cross-over” effectfrom an exhausted muscle on one side of the body to a restedhomologous contralateral muscle. Indeed, utilizing short-durationmaximal isometric muscle contractions, several studies (32, 42,55, 58) have documented a significant reduction in CMD/theoutput of spinal motoneurons to the contralateral rested muscle.With the exception of one study (32), these changes were, incontrast to our findings, insufficient to impair exercise perfor-mance. This discrepancy between prior observations and thepresent results might be explained, at least in part, by genderdifferences, differences in the exercise modality, differences in themuscle mass utilized and thus the total amount of group III/IVafferent feedback, and/or the use of flexor vs. extensor musclesbetween which responsiveness has been documented to be differ-entially affected by muscle afferents (33).

The exact mechanism by which group III/IV muscle afferentfeedback impairs the output of spinal motoneurons and exer-cise performance is unclear; however, at least two potentialmechanisms have previously been suggested: first, a groupIII/IV-mediated inhibition of the motor pathway from themotor cortex to the contracting muscles; and second, a groupIII/IV-mediated impairment of voluntary descending drive oc-curring upstream from the motor cortex (53). Regarding theformer, based on studies of ischemia, utilizing maximal iso-metric single-arm muscle exercise, group III/IV-mediated af-ferent feedback (evoked by postexercise muscle occlusion) hasbeen documented to depress the responsiveness of the mo-

toneuron pool innervating extensor muscles, which might, atleast in part, account for impaired output of spinal motoneu-rons and performance (33). However, this hypothesis is some-what contradicted by experiments from the same group when itwas revealed that group III/IV afferent feedback evoked byhypertonic saline infusion facilitates the responsiveness offlexor and extensor motoneurons while inhibiting motor corti-cal cells. The net effect was unchanged excitability of themotor pathway from the motor cortex to the contracting mus-cles (34). Further conflict in this area is provided by thefindings from postexercise muscle occlusion studies, whichdocument a clear dissociation of exercise-induced alterations inthe responsiveness of motoneurons and motor cortical cellsfrom group III/IV muscle afferent firing and voluntary muscleactivation, at least in flexor muscles (24, 52). Based on theseopposing reports, it remains unclear whether group III/IVmuscle afferent feedback depressed the pathway from themotor cortex to the knee extensors in the present study andthereby potentially contributed to the compromised output ofspinal motoneurons and exercise performance in Leg2-post.These uncertainties leave us with the previously proposedmechanism that the group III/IV-related impairment in theoutput of spinal motoneurons and performance was mediatedupstream from the motor cortex (53).

It has been theorized, in a recent viewpoint article, that RPEduring exercise is independent of muscle afferent feedback and isexclusively determined by the corollary discharge associated withCMD (31). Of note, the present data collected across the Leg1 andLeg2-post trials fail to support this controversial idea as RPEvalues were consistently higher when the same exercise wasperformed with indistinguishable levels of iEMG (Fig. 4). Byexperimental design, what was different between these trials wasthe cardiorespiratory response and the augmented afferent feed-back from the lower limbs in the Leg2-post trial, which likelyresulted in the greater RPE. Therefore, the present findings pro-vide further evidence in support of the concept that RPE isactually modulated, in part, by muscle afferent feedback.

A Potential Link Between Afferent Feedback, PeripheralLocomotor Muscle Fatigue, CMD, and EndurancePerformance

Growing evidence suggests that humans voluntarily termi-nate high-intensity, constant-load endurance exercise once

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Fig. 4. Ratings of perceived exertion (RPE) during constant-load, single-legknee extensor exercise performed without (Leg2) and with (Leg2-post) apreexisting level of quadriceps fatigue in the contralateral leg.

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Fig. 5. Integrated EMG (iEMG) of vastus lateralis during constant-load,single-leg knee extensor exercise performed with the same leg without (Leg2)and with a severe degree of preexisting quadriceps fatigue in the contralateralleg (Leg2-post). Values are normalized to the first minute of exercise. Meanvalues for iEMG during each muscle contraction (knee extension) werecalculated and averaged over each 60-s period. Data are from five subjects.*Significant difference vs. end-exercise Leg2 (P � 0.05).

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J Appl Physiol • doi:10.1152/japplphysiol.00049.2013 • www.jappl.org

their individual sensory tolerance limit, a hypothetical con-struct that might coincide with a certain level of peripheralfatigue and associated intramuscular metabolic milieu, isreached (23). Group III/IV muscle afferents, which relateintramuscular metabolic changes to the CNS, have been sug-gested to play a critical role in determining the sensory toler-ance limit (4, 23). The findings from the present study nowsuggest that the processes determining the sensory tolerancelimit, and thus the termination of exercise, might include themagnitude of both muscle afferent feedback and CMD. Aconceptual framework for the interactions between afferentfeedback, peripheral fatigue, CMD, and endurance exerciseperformance during the events of the present study is illustratedin Fig. 6. Specifically, with the initial development of periph-eral fatigue during exercise of Leg1 (point A in Fig. 6), bothmuscle afferent feedback and CMD increased progressivelyuntil the sensory tolerance limit was reached and the subjectswere no longer able to continue the task (point B in Fig. 6). Atthis point (cessation of exercise with Leg1), CMD to Leg1

ceased entirely while, due to cuff occlusion of this leg (frompoint B to C in Fig. 6), afferent firing remained high. Within 10s of the cessation of the Leg1 trial, the cuff was released and theelevated afferent feedback from Leg1 began to recover (19, 20,25). However, now, with the start of the consecutive leg trial,concomitantly the afferent feedback and CMD related to Leg2-post started to increase (point D in Fig. 6). At this point,subjects presumably exercised below their sensory tolerancelimit and were thus willing and able to attempt the requestedtask (Leg2-post). However, during the subsequent minutes ofLeg2-post, afferent feedback from Leg1 (although recovering)likely remained fairly high, adding to the continuously increas-

ing afferent feedback and CMD associated with Leg2-post(points D and E in Fig. 6). Consequently, the sensory tolerancelimit was reached during Leg2-post more rapidly (points D andE in Fig. 6) than during the same exercise performed withoutpreexisting peripheral fatigue in the contralateral leg [i.e., Leg1

(points A and B in Fig. 6) or Leg2 trial (not shown)]. Once thesensory tolerance limit was reached in Leg2-post (point E inFig. 6), subjects were no longer able to continue the single-legKE, and the outcome was a greatly attenuated exercise perfor-mance and a significantly lower level of end-exercise periph-eral fatigue in Leg2-post (Fig. 2).

Experimental Considerations

Although this study circumvented several common caveatsof previous research in this area, there is a need to considerother factors that may have influenced this experiment. Spe-cifically, other determinants of central fatigue, apart frommuscle afferent feedback, could potentially have contributed tothe reduction in spinal motoneuronal output and exercise per-formance observed during the Leg2-post trial. For example,humoral factors associated with the severe quadriceps fatiguein Leg1 might have resulted in peripheral fatigue in the con-tralateral quadriceps (Leg2-post) or facilitated CMD inhibitionby directly affecting the CNS. To evaluate the influence ofsuch humoral factors in the periphery, we measured handgripMVC before and immediately after the consecutive exhaustiveexercise tests of both legs (Fig. 1, day 4), recorded iEMGduring leg exercise, and evaluated quadriceps muscle functionin one leg before and again after exhaustive exercise of thecontralateral leg (Fig. 1, day 3). The conclusion from theseassessments was that a humoral cross-over effect of exercise-induced peripheral quadriceps fatigue into other skeletal mus-cle can be excluded since neither handgrip MVC nor quadri-ceps muscle function of the rested contralateral leg werealtered by exhaustive single-leg KE. Furthermore, peripheralfatigue in one leg did not affect the rate of development ofquadriceps fatigue in the contralateral leg, as evidenced by thesimilar rate of rise in iEMG during Leg2 and Leg2-post (Fig. 5).

It has also been proposed that CMD might be compromisedby increases in brain serotonin levels during exercise (12,36). Brain serotonin synthesis depends, among others, onthe plasma level of TRP and its transport across the blood-brain barrier (17). An increase in the plasma ratio of TRP/BCAA is indicative of an elevated transport of TRP into thebrain, which may facilitate the development of central fatigueand associated attenuation in CMD (11). We, indeed, observeda small but significant increase in the plasma ratio of TRP/BCAA from rest to the transition phase from Leg1 to Leg2-post; however, this ratio remained unchanged throughout theremainder of the trial. The magnitude of the �20% increase inTRP/BCAA in the present study, utilizing a small muscle massexercise paradigm, was minimal compared with the over 200%increase observed after exhaustive whole body exercise (12,40). Additionally, given that handgrip MVC was unchangedfrom preexercise baseline after exhaustive exercise of bothlegs, it might be concluded that the small change in TRP/BCAA, or any other exercise- or fatigue-induced alterations inbrain neurotransmitters and their interaction with specific re-ceptors, had no significant influence on the magnitude of CMD.

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B E C

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Fig. 6. Schematic illustration reflecting potential sensory alterations during theconsecutive single-leg knee extensor performance tests. With the onset ofexercise of the first leg (Leg1), both muscle afferent feedback and central motordrive (CMD) started to progressively rise (points A and B) until the sensorytolerance limit (dashed line) was reached at exhaustion (point B). With the endof Leg1 exercise, CMD to this leg ceased entirely (thin dotted line), whereasgroup III/IV afferent firing continued due to the cuff inflation at a high level.Within 10 s, the cuff was released (point C), afferent firing from Leg1 beganto decline (dotted line), and afferent feedback and CMD related to the nowexercising second leg (Leg2-post) started to increase. In addition, afferentfeedback from Leg1 (although recovering) likely remained fairly high, addingto the continuously increasing afferent feedback and CMD associated with theexercise of the second leg (Leg2-post) (points D and E). Consequently, thetolerance limit for this Leg2-post trial was reached relatively quickly, asindicated by the short time to exhaustion (point E).

362 Muscle Afferents and Endurance Exercise • Amann M et al.

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Furthermore, a link, presumably mediated by transcallosalconnections (15), exists between right and left motor corticesin humans, and various cross-over effects have been identified.One example of these interhemispheric interactions followingunilateral fatiguing exercise is the reduction of intracorticalfacilitation in the motor cortex supplying the contralateralhomologous resting muscle (10). Furthermore, unilateral fa-tiguing exercise can decrease the postexercise excitability ofthe motor pathway from the contralateral motor cortex to thehomologous resting muscle (13). Such interhemispheric mod-ulation of motor pathway excitability could theoretically di-minish the output of the spinal motorneurons such that, tomaintain a given workload, the CNS would need to increasevoluntary drive to the motor cortex. This higher motor drivewould, of course, not be reflected in an increased iEMG at themuscle, since the higher drive would simply compensate forthe reduced motor pathway excitability with a net effect of anunchanged iEMG. However, this phenomenon could explainthe higher cardioventilatory responses during the consecutivesingle-leg KE in the present study (Fig. 4), which are wellknown to be affected by CMD (56). Additionally, the highermotor drive necessary to work against a given load wouldrequire a greater effort, which the subjects might not be able togenerate for long, and this could explain the reduced exerciseperformance in Leg2-post. The strongest argument against asignificant role for reduced intracortical facilitation or a de-creased excitability of the motor pathway supplying contralat-eral homologous resting muscle is temporal in nature. Specif-ically, neither of these processes occur immediately after afatiguing task and have actually only been observed �5 minafter unilateral exercise ceased (10, 13, 35). Additionally,during intense unilateral muscle contractions, there is someevidence that corticospinal excitability of the target muscle aswell as the homologous contralateral resting muscle may ac-tually be increased, not decreased (29). Finally, in combina-tion, these observations suggest that interhemispheric inhibi-tion at the motor cortical level, or “downstream,” likely did notcontribute to the decreased exercise performance in Leg2-post.

Finally, cognitive demand as well as afferent feedback fromthe heart and pulmonary system were presumably higher dur-ing the Leg2-post performance test (i.e., second performancetest on that day) compared with that during the Leg2 perfor-mance test (i.e., the only performance test on that day). There-fore, we cannot exclude these differences as potential contrib-utors to the shorter endurance time in Leg2-post.

In conclusion, this study provides evidence that peripheralfatigue and the associated intramuscular metabolic distur-bances compromise high-intensity endurance performance in-dependent of the well known fatigue-related changes distal tothe neuromuscular junction that attenuate the response ofmuscle to neural activation. We conclude that group III/IVmuscle afferent feedback associated with intramuscular meta-bolic perturbation has an inhibitory effect on the CNS, whichlimits the output of spinal motoneurons and therefore endur-ance exercise performance.

GRANTS

Research reported in this publication was supported by the National Heart,Lung, and Blood Institute (HL-103786 and HL-116579 to M. Amann; HL-09183 to R. S. Richardson) and a VA Merit Grant (E6910R).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).

AUTHOR CONTRIBUTIONS

Author contributions: M.A. and M.V. conception and design of research;M.A., M.V., S.J.I., J.M., G.L., and M.J.R. performed experiments; M.A. andM.V. analyzed data; M.A. and M.V. interpreted results of experiments; M.A.and M.V. prepared figures; M.A. and M.V. drafted manuscript; M.A., M.V.,S.J.I., J.M., G.L., M.J.R., and R.S.R. edited and revised manuscript; M.A.,M.V., and R.S.R. approved final version of manuscript.

REFERENCES

1. Amann M, Blain GM, Proctor LT, Sebranek JJ, Pegelow DF, Demp-sey JA. Group III and IV muscle afferents contribute to ventilatory andcardiovascular response to rhythmic exercise in humans. J Appl Physiol109: 966–976, 2010.

2. Amann M, Blain GM, Proctor LT, Sebranek JJ, Pegelow DF, Demp-sey JA. Implications of group III and IV muscle afferents for highintensity endurance exercise performance in humans. J Physiol 589:5299–5309, 2011.

3. Amann M, Dempsey JA. Locomotor muscle fatigue modifies centralmotor drive in healthy humans and imposes a limitation to exerciseperformance. J Physiol 586: 161–173, 2008.

4. Amann M, Eldridge MW, Lovering AT, Stickland MK, Pegelow DF,Dempsey JA. Arterial oxygenation influences central motor output andexercise performance via effects on peripheral locomotor muscle fatigue inhumans. J Physiol 575: 937–952, 2006.

5. Amann M, Proctor LT, Sebranek JJ, Pegelow DF, Dempsey JA.Opioid-mediated muscle afferents inhibit central motor drive and limitperipheral muscle fatigue development in humans. J Physiol 587: 271–283, 2009.

6. Amann M, Romer LM, Subudhi AW, Pegelow DF, Dempsey JA.Severity of arterial hypoxaemia affects the relative contributions of pe-ripheral muscle fatigue to exercise performance in healthy humans. JPhysiol 581: 389–403, 2007.

7. Amann M, Runnels S, Morgan DE, Trinity JD, Fjeldstad AS, WrayDW, Reese VR, Richardson RS. On the contribution of group III and IVmuscle afferents to the circulatory response to rhythmic exercise inhumans. J Physiol 589: 3855–3866, 2011.

8. Andersen P, Saltin B. Maximal perfusion of skeletal muscle in man. JPhysiol 366: 233–249, 1985.

9. Badawy AA, Evans M. The role of free serum tryptophan in the biphasiceffect of acute ethanol administration on the concentrations of rat braintryptophan, 5-hydroxytryptamine and 5-hydroxyindol-3-ylacetic acid.Biochem J 160: 315–324, 1976.

10. Baumer T, Munchau A, Weiller C, Liepert J. Fatigue suppressesipsilateral intracortical facilitation. Exp Brain Res 146: 467–473, 2002.

11. Blomstrand E. A role for branched-chain amino acids in reducing centralfatigue. J Nutr 136: 544–547, 2006.

12. Blomstrand E, Celsing F, Newsholme EA. Changes in plasma concen-trations of aromatic and branched-chain amino acids during sustainedexercise in man and their possible role in fatigue. Acta Physiol Scand 133:115–121, 1988.

13. Bonato C, Zanette G, Manganotti P, Tinazzi M, Bongiovanni G, PoloA, Fiaschi A. ‘Direct’ and ‘crossed’ modulation of human motor cortexexcitability following exercise. Neurosci Lett 216: 97–100, 1996.

14. Borg G. Borg’s Perceived Exertion and Pain Scales. Champaign, IL:Human Kinetics, 1998.

15. Boroojerdi B, Hungs M, Mull M, Topper R, Noth J. Interhemisphericinhibition in patients with multiple sclerosis. Electroencephalogr ClinNeurophysiol 109: 230–237, 1998.

16. Boushel R. Muscle metaboreflex control of the circulation during exer-cise. Acta Physiol (Oxf) 199: 367–383, 2010.

17. Chaouloff F. Physical exercise and brain monoamines: a review. ActaPhysiol Scand 137: 1–13, 1989.

18. Clark VR, Hopkins WG, Hawley JA, Burke LM. Placebo effect ofcarbohydrate feedings during a 40-km cycling time trial. Med Sci SportsExerc 32: 1642–1647, 2000.

19. Darques JL, Decherchi P, Jammes Y. Mechanisms of fatigue-inducedactivation of group IV muscle afferents: the roles played by lactic acid andinflammatory mediators. Neurosci Lett 257: 109–112, 1998.

363Muscle Afferents and Endurance Exercise • Amann M et al.

J Appl Physiol • doi:10.1152/japplphysiol.00049.2013 • www.jappl.org

20. Darques JL, Jammes Y. Fatigue-induced changes in group IV muscleafferent activity: differences between high- and low-frequency electricallyinduced fatigues. Brain Res 750: 147–154, 1997.

21. Duffield R, Green R, Castle P, Maxwell N. Precooling can prevent thereduction of self-paced exercise intensity in the heat. Med Sci Sports Exerc42: 577–584, 2010.

22. Gagnon P, Saey D, Vivodtzev I, Laviolette L, Mainguy V, Milot J,Provencher S, Maltais F. Impact of pre-induced quadriceps fatigue onexercise response in chronic obstructive pulmonary disease and healthysubjects. J Appl Physiol 107: 832–840, 2009.

23. Gandevia SC. Spinal and supraspinal factors in human muscle fatigue.Physiol Rev 81: 1725–1789, 2001.

24. Gandevia SC, Allen GM, Butler JE, Taylor JL. Supraspinal factors inhuman muscle fatigue: evidence for suboptimal output from the motorcortex. J Physiol 490: 529–536, 1996.

25. Jammes Y, Balzamo E. Changes in afferent and efferent phrenic activi-ties with electrically induced diaphragmatic fatigue. J Appl Physiol 73:894–902, 1992.

26. Jones PR, Pearson J. Anthropometric determination of leg fat and muscleplus bone volumes in young male and female adults. J Physiol 204: 63–66,1969.

27. Kaufman MP, Hayes SG, Adreani CM, Pickar JG. Discharge proper-ties of group III and IV muscle afferents. Adv Exp Med Biol 508: 25–32,2002.

28. Kufel TJ, Pineda LA, Mador MJ. Comparison of potentiated andunpotentiated twitches as an index of muscle fatigue. Muscle Nerve 25:438–444, 2002.

29. Liepert J, Dettmers C, Terborg C, Weiller C. Inhibition of ipsilateralmotor cortex during phasic generation of low force. Clin Neurophysiol112: 114–121, 2001.

30. Light AR, Hughen RW, Zhang J, Rainier J, Liu Z, Lee J. Dorsal rootganglion neurons innervating skeletal muscle respond to physiologicalcombinations of protons, ATP, and lactate mediated by ASIC, P2X, andTRPV1. J Neurophysiol 100: 1184–1201, 2008.

31. Marcora S. Perception of effort during exercise is independent of afferentfeedback from skeletal muscles, heart, and lungs. J Appl Physiol 106:2060–2062, 2009.

32. Martin PG, Rattey J. Central fatigue explains sex differences in musclefatigue and contralateral cross-over effects of maximal contractions.Pflügers Arch 454: 957–969, 2007.

33. Martin PG, Smith JL, Butler JE, Gandevia SC, Taylor JL. Fatigue-sensitive afferents inhibit extensor but not flexor motoneurons in humans.J Neurosci 26: 4796–4802, 2006.

34. Martin PG, Weerakkody N, Gandevia SC, Taylor JL. Group III and IVmuscle afferents differentially affect the motor cortex and motoneuronesin humans. J Physiol 586: 1277–1289, 2008.

35. McKay WB, Tuel SM, Sherwood AM, Stokic DS, Dimitrijevic MR.Focal depression of cortical excitability induced by fatiguing musclecontraction: a transcranial magnetic stimulation study. Exp Brain Res 105:276–282, 1995.

36. Meeusen R, Watson P, Hasegawa H, Roelands B, Piacentini MF.Central fatigue: the serotonin hypothesis and beyond. Sports Med 36:881–909, 2006.

37. Merton PA. Voluntary strength and fatigue. J Physiol 123: 553–564,1954.

38. Morgan W, Borg G. Perception of effort in the perscription of physicalactivity. In: Mental Health and Emotional Aspects of Sports, edited byNelson T. Chicago, IL: American Medical Association, 1976, p. 126–129.

39. Nybo L, Nielsen B. Hyperthermia and central fatigue during prolongedexercise in humans. J Appl Physiol 91: 1055–1060, 2001.

40. Nybo L, Secher NH. Cerebral perturbations provoked by prolongedexercise. Prog Neurobiol 72: 223–261, 2004.

41. Oldfield RC. The assessment and analysis of handedness: the Edinburghinventory. Neuropsychologia 9: 97–113, 1971.

42. Rattey J, Martin PG, Kay D, Cannon J, Marino FE. Contralateralmuscle fatigue in human quadriceps muscle: evidence for a centrallymediated fatigue response and cross-over effect. Pflügers Arch 452:199–207, 2006.

43. Richardson RS, Knight DR, Poole DC, Kurdak SS, Hogan MC, GrassiB, Wagner PD. Determinants of maximal exercise V̇O2 during single legknee extensor exercise in humans. Am J Physiol Heart Circ Physiol 268:H1453–H1461, 1995.

44. Romer LM, Haverkamp HC, Amann M, Lovering AT, Pegelow DF,Dempsey JA. Effect of acute severe hypoxia on peripheral fatigue andendurance capacity in healthy humans. Am J Physiol Regul Integr CompPhysiol 292: R598–R606, 2007.

45. 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.

46. Saey D, Michaud A, Couillard A, Cote CH, Mador MJ, LeBlanc P,Jobin J, Maltais F. Contractile fatigue, muscle morphometry, and bloodlactate in chronic obstructive pulmonary disease. Am J Respir Crit CareMed 171: 1109–1115, 2005.

47. Sandiford SD, Green HJ, Duhamel TA, Schertzer JD, Perco JD,Ouyang J. Muscle Na-K-pump and fatigue responses to progressiveexercise in normoxia and hypoxia. Am J Physiol Regul Integr CompPhysiol 289: R441–R449, 2005.

48. Sidhu SK, Bentley DJ, Carroll TJ. Locomotor exercise induces long-lasting impairments in the capacity of the human motor cortex to volun-tarily activate knee extensor muscles. J Appl Physiol 106: 556–565, 2009.

49. Strange S. Cardiovascular control during concomitant dynamic leg exer-cise and static arm exercise in humans. J Physiol 514: 283–291, 1999.

50. Tam E, Azabji Kenfack M, Cautero M, Lador F, Antonutto G, diPrampero PE, Ferretti G, Capelli C. Correction of cardiac outputobtained by Modelflow from finger pulse pressure profiles with a respi-ratory method in humans. Clin Sci (Lond) 106: 371–376, 2004.

51. Taylor JL, Butler JE, Allen GM, Gandevia SC. Changes in motorcortical excitability during human muscle fatigue. J Physiol 490: 519–528, 1996.

52. Taylor JL, Petersen N, Butler JE, Gandevia SC. Ischaemia afterexercise does not reduce responses of human motoneurones to cortical orcorticospinal tract stimulation. J Physiol 525: 793–801, 2000.

53. Taylor JL, Todd G, Gandevia SC. Evidence for a supraspinal contribu-tion to human muscle fatigue. Clin Exp Pharmacol Physiol 33: 400–405,2006.

54. Todd G, Butler JE, Taylor JL, Gandevia SC. Hyperthermia: a failure ofthe motor cortex and the muscle. J Physiol 563: 621–631, 2005.

55. Todd G, Petersen NT, Taylor JL, Gandevia SC. The effect of acontralateral contraction on maximal voluntary activation and centralfatigue in elbow flexor muscles. Exp Brain Res 150: 308–313, 2003.

56. Waldrop TG, Eldridge FL, Iwamoto GA, Mitchell JH. Central neuralcontrol of respiration and circulation during exercise. In: Handbook ofPhysiology. Exercise: Regulation and Integration of Multiple Systems.Bethesda, MD: Am. Physiol. Soc., 1996, sect. 12, chapt. 9, p. 333–380.

57. Wilson LB, Andrew D, Craig AD. Activation of spinobulbar lamina Ineurons by static muscle contraction. J Neurophysiol 87: 1641–1645,2002.

58. Zijdewind I, Zwarts MJ, Kernell D. Influence of a voluntary fatigue teston the contralateral homologous muscle in humans? Neurosci Lett 253:41–44, 1998.

364 Muscle Afferents and Endurance Exercise • Amann M et al.

J Appl Physiol • doi:10.1152/japplphysiol.00049.2013 • www.jappl.org