You are on page 1of 10

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

Peripheral fatigue limits endurance exercise via a sensory feedback-mediated reduction 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
Department 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, 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. First published May 30, 2013; doi:10.1152/japplphysiol.00049.2013.—This study sought to determine whether afferent feedback associated with peripheral muscle fatigue inhibits central motor drive (CMD) and thereby limits endurance exercise performance. On two separate days, eight men performed constant-load, single-leg knee extensor exercise to exhaustion (85% of peak power) with each leg (Leg1 and Leg2). On another day, the performance test was repeated with one leg (Leg1) and consecutively (within 10 s) with the other/contralateral leg (Leg2post). Exercise-induced quadriceps fatigue was assessed by reductions in potentiated quadriceps twitch-force from pre- to postexercise (⌬Qtw,pot) in response to supramaximal magnetic femoral nerve stimulation. The output from spinal motoneurons, estimated from quadriceps electromyography (iEMG), was used to reflect changes in CMD. Rating of perceived exertion (RPE) was recorded during exercise. Time to exhaustion (ϳ9.3 min) and exercise-induced ⌬Qtw,pot (ϳ51%) were similar in Leg1 and Leg2 (P Ͼ 0.5). In the consecutive leg trial, endurance performance of the first leg was similar to that observed during the initial trial (ϳ9.3 min; P ϭ 0.8); however, time to exhaustion of the consecutively exercising contralateral leg (Leg2post) was shorter than the initial Leg2 trial (4.7 Ϯ 0.6 vs. 9.2 Ϯ 0.4 min; P Ͻ 0.01). Additionally, ⌬Qtw,pot following Leg2-post was less than Leg2 (33 Ϯ 3 vs 52 Ϯ 3%; P Ͻ 0.01). Although the slope of iEMG was similar during Leg2 and Leg2-post, end-exercise iEMG following Leg2-post was 26% lower compared with Leg2 (P Ͻ 0.05). Despite a similar rate of rise, RPE was consistently ϳ28% higher throughout Leg2-post vs. Leg2 (P Ͻ 0.05). In conclusion, this study provides evidence that peripheral fatigue and associated afferent feedback limits the development of peripheral fatigue and compromises endurance exercise performance by inhibiting CMD. central motor drive; neural feedback; group III and IV muscle afferents; central fatigue

that the inability to continue high-intensity, constant-load endurance exercise (i.e., exhaustion) coincides with a specific level of peripheral locomotor muscle fatigue (3, 4, 21, 22, 44 – 46). Based on the evidence that voluntarily exercising humans never exceed this specific and individually different degree of peripheral fatigue, the existence of a “critical threshold” of muscle fatigue was previously proposed (3, 4). Muscle afferent fibers, which relay fatigue-related metabolic perturbations within the working

* 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:

limb muscles to the central nervous system (CNS) (27, 30, 57), have been suggested to play an important role in determining this critical threshold of fatigue (5, 23), which likely coincides with an individual’s “sensory tolerance limit” (23). Specifically, during constant-load endurance exercise, mechano- and metabo-sensitive group III/IV muscle afferents provide inhibitory input to the CNS. This feedback limits voluntary descending drive to the primary motor cortex [i.e., central motor drive (CMD)] (52) and exercise performance, restricting the development of locomotor muscle fatigue to a critical threshold that is associated with a certain level of intramuscular metabolic perturbation (4). It should be acknowledged that this paradigm includes only one of several potential mechanisms that may account for the inability to continue high-intensity, constantload endurance exercise and requires further study. Psychological factors (18), extreme environmental influences (6, 39, 54), and exercise-induced alterations in CNS neurotransmitter systems (36) are examples of other potential mechanisms limiting CMD and/or the output of spinal motoneurons and exercise performance. In recent experiments designed to examine the effect of locomotor muscle afferents on the development of peripheral fatigue, pharmacological blockade was used to reduce sensory feedback during high-intensity leg cycling (2). With greatly reduced inhibitory feedback from group III/IV leg muscle afferents to the CNS, output/drive from the spinal motoneurons to locomotor muscles (as estimated from surface EMG) was, compared with placebo conditions, substantially increased during exercise. The exercising humans (i.e., the CNS) in these experiments “ignored” the sensory tolerance limit and “tolerated” the development of peripheral muscle fatigue substantially beyond their critical threshold, which was determined in placebo conditions (i.e., with intact afferent feedback) (2). Although providing strong evidence in favor of an inhibitory influence of fatigue-related sensory feedback on the output from spinal motoneurons, a caveat of this approach is that blocking group III/IV muscle afferents also impairs the cardiovascular and ventilatory responses during exercise (1, 7), which, per se, limits exercise performance (2). In addition to reducing the inhibitory neural feedback during exercise via spinal blockade, an alternative approach to discern the role of group III/IV muscle afferents in regulating the output of spinal motoneurons and limiting endurance performance has been to elevate the inhibitory feedback mediated by these sensory neurons. In previous investigations, peripheral locomotor muscle fatigue and associated metabolic disturbances were either voluntarily (3) or electrically (22) induced immediately before a cycling performance test to increase

8750-7587/13 Copyright © 2013 the American Physiological Society

indicating that a failure to maintain 50 RPM for longer than 10 s leads to voluntary termination of exercise within 30 s. all subjects performed incremental single-leg KE until they were unable to continue the prescribed work rate (15 W ϩ 5 W/min) to determine peak power output (Wpeak) of each leg. whereas one participant was left-leg dominant (41). body mass 83 Ϯ 6 kg.00049. J Appl Physiol • doi:10. We hypothesized that 1) fatigue-related intramuscular metabolic disturbances and associated inhibitory feedback from one leg would compromise performance of the consecutively exercised contralateral leg and 2) peripheral quadriceps fatigue.. The study was approved by the University of Utah and the Salt Lake City VA Medical Center Institutional Review Boards. METHODS Subjects Eight recreationally active.356 Muscle Afferents and Endurance Exercise • Amann M et al.4 Ϯ 0. single-leg KE (60 . we induced quadriceps fatigue in one leg using voluntary dynamic single-leg knee-extensor exercise to exhaustion with the goal to raise the ensemble muscle afferent feedback during a subsequent endurance performance test with the other leg. informed consent was obtained from each subject before participation. height 178 Ϯ 4 cm). peripheral fatigue). including singleleg knee-extensor exercise (KE) (8. in random order. On 2 separate days following these initial sessions. at voluntary exhaustion. Quadriceps muscle mass (26) was similar in both limbs (2. although providing evidence for an inhibitory effect of peripheral muscle fatigue and associated neural feedback on the output of spinal motoneurons. The outcome of these experiments indicates that the higher the level of preexisting muscle fatigue and associated inhibitory feedback. and written. P ϭ 0. Again. 22). Experimental design. each subject performed. 85% of Wpeak) to task failure (cadence below 50 RPM for Ն10 s) with both legs (days 1 and 2. Days 1 and 2 and days 3 and 4 were carried out in random order and separated by at least 48 h. constant-load. all participants were thoroughly familiarized with various experimental procedures. the lower the output of spinal motoneurons and cycling performance during a subsequent performance trial (3. have been due to a compromised muscle response to a given neural input (i. Fig. fatigue-related inhibitory neural feedback to the CNS during the subsequent performance trial. Experimental Protocol During four 1-h practice sessions.1 kg. To circumvent previous experimental shortcomings. the observed performance limitations might. Seven of the participants were determined to be right-leg dominant.1152/japplphysiol. at least in part. 43). 1. of the consecutively exercised leg would be substantially below the level of fatigue observed during control trials. Neuromuscular function of the exercising leg was Day 1: Leg1 Leg1: Assessment of Muscle Function 20 min Warm-up 2 min Performance test: Leg1 Leg1: Assessment of Muscle Function Day 2: Leg2 Leg2: Assessment of Muscle Function 20 min Warm-up Performance test: Leg2 2 min Leg2: Assessment of Muscle Function Day 3: Cross-over Leg2: Assessment of Muscle Function 20 min Warm-up Performance test: Leg1 2 min Leg2: Assessment of Muscle Function Day 4: Transition Hand grip 20 min Warm-up Thigh cuff on Thigh cuff off Hand grip 2 min Leg2: Assessment of Muscle Function Performance test: Leg1 10-s transition Performance test: Leg2post Leg2post: Assessment of Muscle Function Blood sample Blood sample Blood sample Fig. Leg order and dominance were balanced. This RPM was chosen based on our previous work with this model. 1).e.jappl.6). healthy male volunteers participated in this study (age 24 Ϯ 1 yr. On 2 additional days.2013 • www.

The Magstim.2013 • www. The interval between the MVCs was 35 s.Muscle Afferents and Endurance Exercise • Amann M et al. Goleta.2% (P ϭ 0. the analysis program calculated the standard deviation (SD) of the baseline noise (i. Temecula. The warm-up performed on each of the test days consisted of 10 min of two-leg KE at 15 W. UT). Integrated EMG (iEMG) for each contraction throughout the protocol was calculated using the Acknoweldge software.5 kHz using adhesive silver electrodes placed over the muscle belly ϳ4 cm apart. at task failure following exercise with the first leg (Leg1). CA) connected to a noncompliant strap. To avoid initial peak force outputs at the beginning of each performance trial. MA). In this trial. MA). 1). General Electric Medical Systems). high-pass cut-off frequency of 650 Hz).6% (P ϭ 0. The increment in Qtw and M-wave amplitude from 90 to 95% of the stimulator output was 0. 60. neuromuscular function of one leg was assessed before and again 2 min after constant-load exercise to task failure with the other leg. Sessions (day) 3 and 4 were in random order. Biopac Systems. As reported in a previous study (28). The stimulator output was set to 100% in every subject and in all trials. all participants carried out constant-load. 95. Finapres Medical Systems) (50).pot has been documented to be more sensitive for detecting fatigue than the nonpotentiated twitch (28). A detailed description of the assessment of muscle function with magnetic nerve stimulation can be found in prior publications by our group utilizing this technique (4). Exercise Responses At rest and throughout exercise. The concentration of free tryptophan (TRP) was measured using a modification of the spectrofluorometric method (9). electrical signal between the bursts). FBF was calculated as: FBF ϭ Vmean␲(vessel diameter/2)2 ϫ 60.pot.13). During KE performance trials. we measured maximal handgrip forces of the dominant arm before the performance of Leg1 and the consecutive performance test in Leg2-post on day 4 (Fig. single-leg KE. As previously described (3). 1). Accordingly. after the second MVC. Fig.36) and Ϫ0. with knee joint angle set at 90° of flexion and arms folded across the chest. Femoral blood flow (FBF) was measured at rest and during exercise using ultrasound Doppler (Logic 7. Accurate identification of EMG activity was verified by visual inspection.pot 5 s after a 5-s isometric maximal voluntary contraction (MVC) of the quadriceps and repeated this procedure six times. Neuromuscular Function Electromyography. 1. Simultaneous measurements of common femoral arterial blood velocity (Vmean) and vessel diameter were performed distal to the inguinal ligament and proximal to the bifurcation of the deep and superficial femoral arteries. Membrane excitability was maintained from pre. Venous blood samples from an antecubital catheter were collected in trial 4.96). The same approach was utilized to identify the offset of a burst. UK) connected to a double 70-mm branding iron coil was used to stimulate the femoral nerve. all subjects performed a third trial (day 3. J Appl Physiol • doi:10. The position of the EMG electrodes was marked with indelible ink to ensure placement in the same location on subsequent visits. Abcam Cambridge. with the other leg (Leg2-post) (day 4. and 100% of maximal stimulator output. maximal rate of force development (MRFD). 1). the degree of potentiation was slightly smaller after the first and. For postexercise in all trials as indicated by unchanged peak-to-peak M-wave amplitudes. The raw EMG signal was filtered with a band-pass filter (low-pass cut-off frequency of 15 Hz. 1). valine. Voluntary activation of the quadriceps during the MVCs was assessed using a superimposed twitch technique (37). The onset of a burst was identified as the point at which the EMG signal rose to a value Ͼ2. All performance trials were separated by 48 –72 h and balanced with respect to leg dominance. True Max 2400. A plateau in baseline Qtw and M-wave amplitudes with increasing stimulus intensities was observed in every subject. as illustrated in Fig. 1). The Netherlands) and the Modelflow algorithm (Beatscope version 1. The concentration of branched-chain amino acids (BCAA.pot (47). The raw EMG signal was digitized and recorded at 1. a cuff around the upper part of the thigh of Leg1 was inflated to 250 mmHg until the Leg2-post exercise trial was started (day 4. Subjects were instructed to strictly maintain 60 RPM throughout KE. Qtw. On a fourth day. the increment in Qtw and M-wave amplitude from 95 to 100% of the stimulator output was 0. Using arterial diameter and Vmean. 85. respectively. To determine whether exercise-induced quadriceps fatigue in one leg affected neuromuscular function in the other leg. Transducer Techniques. 70. The evoked quadriceps twitch force was obtained from a calibrated load cell (model MLP-300. therefore. which was placed around the subject’s right or left leg just superior to the ankle malleoli. A magnetic stimulator (Magstim 200. Salt Lake City. Neuromuscular function of Leg2-post was assessed before and 2 min after exercise (Fig. peak-topeak amplitude) to evaluate changes in membrane excitability and 2) EMG throughout exercise to estimate the output of spinal motoneurons and the development of peripheral quadriceps fatigue. Wales. This suggests that the observed changes in potentiated twitch force (Qtw.jappl. the force produced during a single twitch superimposed on the MVC was compared with the force produced by the potentiated single twitch delivered 5 s afterward. Here. quadriceps EMG was recorded from the vastus lateralis using electrodes with fullsurface solid adhesive hydrogel (H59P. we measured Qtw. Unpotentiated quadriceps single twitch forces (Qtw) were obtained every 30 s at 50. 1).pot measurements were discarded. Magnetic nerve stimulation. Cardiac output (CO) and mean arterial pressure (MAP) were determined using a Finometer (Finapres Medical Systems. respectively. isoleucine.1152/japplphysiol.6 Ϯ 0. subjects rested on an adjustable chair with the right or left thigh lying in a preformed holder.1a. again to task failure.5% (P ϭ 0. EMG signal corresponding to vastus lateralis muscle con- tractions were recorded for later analysis. and maximal relaxation rate (MRR) were analyzed for all Qtw. Briefly. and leucine) was determined utilizing an amino acid assay kit (ab83374. Fig. and muscle activity was automatically located (AcqKnowledge. CA). single-leg KE to task failure with one leg (Leg1) and consecutively (Ͻ10 s) performed constant-load. see below) were predominantly due to changes within the quadriceps and that electrical transmission failure or reduced sarcolemma excitability can be excluded. the ergometer was initially accelerated by one of the investigators (Ͻ2 s).14) and 1. the first two Qtw. 1).4% (P ϭ 0. Peak force.4 Ϯ 0. Blood Analysis Venous blood samples from an antecubital catheter were drawn into glass tubes containing EDTA during trial 4 (Fig. 80. The position of the coil was marked with indelible ink to ensure placement in the same location during all visits.1 Ϯ 0.. The stimulator output that produced the first maximal response was 90%. 357 assessed before and 2 min after exercise (Fig. To evaluate the effects of severe quadriceps fatigue on remote rested muscles.4 Ϯ 0. Tyco Healthcare Group. 90. to a lesser extent. Briefly. Fig.00049.5 SD above baseline. Mansfield. Heart rate (HR) was measured from the R-R interval of an electrocardiogram (ECG) using a three-lead arrangement. pulmonary gas exchange and ventilation were measured continuously using an open-circuit calorimetry system (Parvo Medics. This assessment procedure was performed 20 min before exercise and 2 min after exercise.e. The vastus lateralis electrodes were used to record 1) magnetically evoked muscle action potentials (M-waves. Rating of perceived exertion (RPE) was obtained at rest and every minute during exercise using Borg’s modified CR10 scale (14) following the recommended instructions/ verbiage for using the scale (38). .

MVC force (ϳ570 N.1152/japplphysiol.4 min).vs. 1.pot. with and without fatigue in the contralateral limb) on exercise-induced changes in various physiological parameters over time (time: five levels. day 3). Statistical significance was set at P Ͻ 0. Fig.e. W Percent change from preexercise to 2 min postexercise MVC Qtw. MRR.05) in the variance of the differences across time in each condition for any measured variable and therefore the assumption of normal distribution was violated. P Ͻ 0. resting mean values for MVC. quadriceps muscle function was markedly decreased from preexercise baseline (P Ͻ 0. MRR. Time to task failure at 85% of Wpeak was not different between the two legs (P ϭ 0.57). P ϭ 0. Preexercise resting values were similar in the nondominant leg.7 Ϯ 0. If there was a significant difference (P Ͻ 0. 2. Immediately after exercise with either leg.3 N/ms. single-leg knee-extensor exercise to exhaustion on quadriceps muscle function of the dominant and nondominant leg Dominant Leg Nondominant Leg C Qtw.8 Ϯ 0.4 Ϯ 0.pot Table 1.6 Ϯ 0.pot.2 vs.and postexercise in each condition). Contractile function.2 Ϯ 0. we employed a two-way (2 ϫ 4) repeated-measures ANOVA. Fig.89). Effect of Quadriceps Fatigue in One Leg on Muscle Function of the Rested Contralateral Leg (Day 3) Despite the development of severe exercise-induced quadriceps fatigue in one leg (Fig. min Workload.jappl.pot MVC 20 40 60 Leg2 Leg2post Fig.01].8.. The degree of exerciseinduced peripheral fatigue was similar in the dominant and the nondominant leg (P ϭ 0. maximal rate of . Immediately after both Leg2 (day 2).82) and 61 Ϯ 6 vs.2 Ϯ 0.e. To determine the effects of increased afferent feedback (condition: two levels. Non-Dominant Leg: Endurance Capacity and Quadriceps Fatigability (Days 1 and 2) Both whole body peak oxygen uptake and Wpeak were similar for the dominant and the nondominant leg [1. respectively] (Fig. day 2. 1.1 N/ms. group mean Qtw. MRFD. quadriceps muscle function in the contralateral leg was not affected. However. *Not significantly altered from preexercise. Mauchly’s test of sphericity was run to determine whether the assumption for homogeneity of variance was met for each variable. Data are presented as means Ϯ SE.48. Effect of Quadriceps Fatigue on Endurance Exercise Performance and Associated Development of Peripheral Fatigue in the Consecutively Exercised Contralateral Leg (Day 4) Exercise performance. Seven subjects were right leg dominant.e. and 94 Ϯ 3%.00049. P ϭ 0. Qtw. 2). i. Preexercise.pot in Leg2-post was attenuated (Table 2.pot MRFD MRR Muscle activation 9. Table 1). and voluntary muscle activation in the dominant leg were 573 Ϯ 52 N. and voluntary muscle activation (ϳ93%. we employed a two-way (2 ϫ 5) repeated-measures ANOVA.001) when the identical exercise was performed with pre-induced quadriceps fatigue in the contralateral leg (i. RESULTS 5 B 0 10 20 30 40 Dominant vs. Table 1). and Leg2-post (day 4) exercise trials. This was evident by similar pre. with and without fatigue in the contralateral limb) on exercise-induced changes in quadriceps muscle function (time: four time points. Leg2post trial). time to task failure: 9.2013 • www.16) ϭ 17. exercise performed with rested contralateral leg) and under experimental conditions (Leg2post. compared with control exercise (i. Individual and group mean data illustrating endurance time to task failure and peripheral quadriceps fatigue under control conditions (Leg2.79. endurance time to task failure was Ϫ49 Ϯ 6% shorter (P Ͻ 0. Effects of constant-load.e. 58 Ϯ 4 W (P ϭ 0. 170 Ϯ 20 N. i. Qtw. All within-twitch Time to task failure. A Time to exhaustion 10 (min) ( % from pre-exercise baseline) ( % from pre-exercise baseline) To determine the effects of increased afferent feedback (condition: two levels. MVC. Compared with control exercise (i.358 Statistical Analysis Muscle Afferents and Endurance Exercise • Amann M et al. (ϳ170 N.4 52 Ϯ 5 Ϫ30 Ϯ 3 Ϫ52 Ϯ 2 Ϫ55 Ϯ 4 Ϫ51 Ϯ 4 1 Ϯ 2* 9.... days 1 and 2).. maximal rate of force development.44).7 Ϯ 0. 1. 0.001). P ϭ 0. the exercise-induced reduction in Qtw. 1.9 49 Ϯ 3 Ϫ29 Ϯ 2 Ϫ50 Ϯ 6 Ϫ50 Ϯ 7 Ϫ53 Ϯ 3 Ϫ1 Ϯ 2* Values are means Ϯ SD (n ϭ 8). exercise performed with severe quadriceps fatigue in the contralateral leg). Leg2 trial).pot was significantly reduced from preexercise baseline [F(1. five time points).05. This reduction in endurance time to task failure was consistent in all subjects (range Ϫ33 to Ϫ75%.23). maximal voluntary contraction. postexercise values for Qtw. J Appl Physiol • doi:10. one subject was left leg dominant. MRFD. potentiated single twitch.2 l/min (P ϭ 0. respectively. pre. 2). the Greenhouse-Geisser Epsilon correction was applied to the degrees of freedom. Post hoc analysis was performed using Tukey’s post hoc test of honestly significant difference.e.

Preexercise. MRFD.14) ϭ F(1. 1. 5. Again. 3). †Not significantly altered from preexercise. and potentially limiting.3.14) ϭ 43. postexercise [Trp]-to-[BCAA] ratio was not different from the ratio observed during the transition between Leg1 and Leg2-post [F(2. 359 Table 2. minute ventilation [V ˙ E/V ˙ CO2 [F(1. V [F(1. Plasma Branched-Chain Amino Acids and Tryptophan The concentration of plasma free tryptophan (Trp) significantly increased from rest to the transition between Leg1 and Leg2-post [Fig. P Ͻ 0. Although MAP [F(1. and voluntary muscle activation were 559 Ϯ 55 N. the increase in iEMG during the first 3 min of exercise was very similar in both conditions (P Ͼ 0. 3F). 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 ϭ 0. Fig.1. P Ͻ 0. during the final minute of exercise. F(1. Fig. 1.6). HR 57. Quadriceps fatigue in the contralateral leg had a significant effect on oxygen ˙ O2.1 N/ms.2. Given the similar rate of rise during Leg2 (day 2) and Leg2-post (day 4) (P ϭ 0. Indeed.8. 3. range 198 –395%) compared with Leg2-post (Fig. the present data document the limiting effect of peripheral muscle fatigue and associated afferent feedback on endurance exercise performance.01]. P Ͼ 0.14) ϭ 6. single-leg knee-extensor exercise to exhaustion on quadriceps muscle function of the control trial (Leg2. DISCUSSION Time to task failure.04].14) ϭ 56. Evidence of Increased Muscle Afferent Feedback in the Consecutive Leg Exercise Trial (Leg2-Post) An important premise of the present study was that the development of quadriceps fatigue in one leg would increase the ensemble input of fatigue-sensitive group III/IV muscle J Appl Physiol • doi:10.3]. However. However.14) ϭ 44. End-exercise RPE was similar in both trials. Femoral blood flow was similar at the onset of exercise in both trials (P ϭ 0.05].6 * 51 Ϯ 4 Ϫ23 Ϯ 3 * Ϫ33 Ϯ 3 * Ϫ19 Ϯ 9 * Ϫ36 Ϯ 4 * Ϫ2 Ϯ 1† Values are means Ϯ SD (n ϭ 8). P ϭ 0. P Ͻ 0.01] during the first 3 min of exercise. at end-exercise. postexercise Trp concentration ([Trp]) was similar to the [Trp] observed during the transition between Leg1 and Leg2-post (P ϭ 0. the RPE score was.02].16) ϭ 8.Muscle Afferents and Endurance Exercise • Amann M et al. P ϭ 0.pot MRFD MRR Muscle activation 9. the This study sought to determine whether afferent feedback associated with peripheral muscle fatigue and the affiliated intramuscular metabolic disturbance inhibits spinal motoneuronal output and thereby limits endurance exercise performance. MRR) were also significantly altered from baseline immediately postexercise (Table 2). 3. Branched-chain amino acids (BCAA) were similar at the three time points [F(2. 3E). iEMG iEMG rose significantly from the first minute of exercise to task failure in each of the two conditions [Fig.5 Ϯ 0. P Ͻ 0.7. resting mean values for MVC.pot. there was no significant difference between the trials throughout the remainder of the exercise (Fig. Peak force during the 5-s MVC maneuvers was significantly decreased from baseline after all trials [F(1.17).3. F(1. P Ͻ 0. compared with Leg2.14) ϭ 56. F(2. day 4).13).01]. these variables were similar between the Leg2 (day 2) and Leg2-post (day 4) trials (all P Ͼ 2 min postexercise MVC Qtw. P Ͻ 0.47).org . respectively. femoral blood flow was significantly lower during Leg2-post compared with Leg2 exercise. P Ͻ 0.14) ϭ 0. respectively. *Significant difference vs. CO2 uptake [V ˙ CO2.6. day 4) Leg2 Leg2-post prior development of quadriceps fatigue in the contralateral leg had a significant effect on RPE during the first 3 min of exercise. 0.25]. Cardiorespiratory and Hemodynamic Responses Cardiorespiratory and hemodynamic responses to constantload KE exercise trials with and without quadriceps fatigue in the contralateral leg are illustrated in Fig. significantly higher during the first 2 min of the Leg2-post trial.14) ϭ 57.5.14) ϭ 6. the impact of muscle afferents on endurance performance was likely independent of their well known role in regulating. apparently achieved by restricting the output of spinal motoneurons to the working skeletal muscle. reductions in MVC force were significantly greater following the Leg2 trial (day 2) compared with the Leg2post trial (day 4) (Table 2.14) ϭ 0.14) of Ͼ4. 2).01] (Fig.25).1. P Ͻ 0.jappl.5.22) (Fig. Muscle activation remained unchanged from pre. and cardiac output [CO.00049. with a ϳ28% elevation in RPE evident throughout [F(1. Handgrip Force Handgrip MVC was unchanged from before the Leg1 performance trial to immediately after the Leg2-post performance trial (Ͻ2 s) on day 4 (31 Ϯ 3 and 32 Ϯ 2 kg.1152/japplphysiol. consistent with the other fatigue-related results. compared with Leg2.4 N/ms. day 2) vs. 5).01]. P ϭ 0. P Ͻ 0. However.14) ϭ 57.3.84].4 51 Ϯ 4 Ϫ30 Ϯ 3 Ϫ52 Ϯ 3 Ϫ55 Ϯ 4 Ϫ52 Ϯ 4 Ϫ1 Ϯ 1† 4. Qtw. P ϭ 0. Each of these exercise-induced reductions was significantly greater during the Leg2 compared with the Leg2-post trial (Table 2).0. measurements (MRFD.01]. uptake [V ˙ postexercise in both trials [ϳ94%. W Percent change from pre.01]. Therefore the [Trp]-to-[BCAA] ratio significantly increased from rest to the transition between Leg1 and Leg2-post [F(2. Pre-induced quadriceps fatigue in one leg reduced endurance time to exhaustion of the consecutively exercised contralateral leg by ϳ49%. 165 Ϯ 22 N. min Workload.2. F(1.2 Ϯ 0. F(1.14) ϭ 9. Effect of constant-load. at minute 1. Therefore. However. P ϭ 0. and 94 Ϯ 3%. significantly higher at the onset of the Leg2-post trial. and blood flow was similar throughout the rest of exercise (Fig. iEMG in Leg2 had increased to a significant extent (347 Ϯ 39%.05). day 4. P Ͻ 0. Leg2 (P Ͻ 0.2013 • www.5. but this difference progressively diminished.01] was.7 Ϯ 0. 4). F(1.2 Ϯ 0. the consecutively exercised leg trial (Leg2-post. Since the circulatory and ventilatory responses during such small muscle mass exercise are well within the respective maximal capacities.01].14) ϭ 57. peripheral hemodynamic responses during exercise.5.6. MRR.

4 and 5).5 * * * F 140 MAP (mmHg) * 120 * 1. cardiac output. Leg2 (P Ͻ 0.2013 • www. mean arterial pressure. 100 0. achieved by postexercise cuff occlusion of the contralateral leg. 2). This experimental design allowed the evaluation of exercise performance of a single leg. oxide production. causes a greater exercise pressor reflex compared with control conditions (no prior exercise and no cuff occlusion in other leg) (16.jappl. V MAP. CO. Second. In the present study. RPE is modulated by afferent feedback from fatiguing muscles (1.5 B VCO2 (l · min-1) 2. in fact. . direct nerve recordings from group IV muscle afferents following electrically induced muscle fatigue in anesthetized animals indicate that the sensory discharge remained elevated above baseline for up to 15 min after fatiguing muscle contractions had stopped (19.0 * 1. *Significant difference vs. characterized by an elevated exercise pressor and ventilatory response during Leg2-post (Fig. 3. oxygen consumption. heart rate.5 C 100 * * G * * 180 160 140 120 100 80 * * * * 50 D VE/VCO2 0 50 * * 40 * H CO (l · min-1) * 60 15 * 10 * * * 5 30 0 2 4 6 Time (min) 8 10 0 2 4 6 Time (min) 8 10 afferents to the CNS during the consecutive endurance test of the contralateral leg. Femoral blood flow (ml · min-1) A VO2 (l · min-1) 1. carbon diV ˙ E. 25).0 * Leg2post Leg2 * * E 4000 3000 2000 1000 0 * 0. several lines of indirect evidence suggest that this was. minute ventilation. it has previously been documented that experimentally augmenting lower limb muscle afferent activity during one-leg KE.0 VE (l · min-1) HR (bpm) Fig. The present findings.05). Taken together. whereas afferent feedback to the CNS arose from two legs. even though the exercise challenge (work rate) was similar. First. The achievement of this somewhat unique experimental paradigm J Appl Physiol • doi:10. RPE scores were consistently higher during the first 3 min of the Leg2-post trial despite very similar levels of iEMG compared with those recorded in the Leg2 trial (Figs. Although the direct assessment of afferent feedback in humans is currently not possible.360 Muscle Afferents and Endurance Exercise • Amann M et al.5 * 1. these prior studies and current observations support the premise that. 49). V ˙ CO2. 20. conform to these earlier observations. 3). the ensemble lower limb muscle afferent feedback was greater during the Leg2-post compared with the Leg2 trial.1152/japplphysiol. Finally. likely achieved. due to the pre-induced fatigue in Leg1. Physiological responses to constantload single leg knee-extensor exercise without (Leg2) and with preexisting quadriceps fatigue in the contralateral leg (Leg2-post).00049. ˙ O2.

which likely resulted in the greater RPE. it remains unclear whether group III/IV muscle afferent feedback depressed the pathway from the motor cortex to the knee extensors in the present study and thereby potentially contributed to the compromised output of spinal motoneurons and exercise performance in Leg2-post. insufficient to impair exercise performance. CMD. which document a clear dissociation of exercise-induced alterations in the responsiveness of motoneurons and motor cortical cells from group III/IV muscle afferent firing and voluntary muscle activation. 55). each is confounded. and Endurance Performance Growing evidence suggests that humans voluntarily terminate high-intensity. due to the somewhat innovative experimental design utilized here. which resulted in an ϳ49% reduction in endurance performance when consecutive leg exercise in the contralateral leg was superimposed upon the already fatigued leg.05). at least two potential mechanisms have previously been suggested: first.00049. In contrast. The net effect was unchanged excitability of the motor pathway from the motor cortex to the contracting muscles (34). 51. Ratings of perceived exertion (RPE) during constant-load. is an important foundation from which to interpret the results of the present study. utilizing maximal isometric single-arm muscle exercise. 24. Specifically. Regarding the former. Integrated EMG (iEMG) of vastus lateralis during constant-load. 48. at least in part. By experimental design. this study provides evidence of the inhibitory effect of muscle afferents on the output of spinal motoneurons. Central Motor Drive. however. a group III/IV-mediated impairment of voluntary descending drive occurring upstream from the motor cortex (53). 42. based on studies of ischemia. at least in part. constant-load endurance exercise once iEMG percent increase from 1st minute (%) 350 300 250 200 150 100 1 2 3 4 5 6 7 8 9 10 Leg2 Leg2post RPE (0-10) * Time (min) Fig. J Appl Physiol • doi:10. to some degree. in a recent viewpoint article. The exact mechanism by which group III/IV muscle afferent feedback impairs the output of spinal motoneurons and exercise performance is unclear. in contrast to our findings. Indeed. This study is not the first to document a “cross-over” effect from an exhausted muscle on one side of the body to a rested homologous contralateral muscle. this hypothesis is somewhat contradicted by experiments from the same group when it was revealed that group III/IV afferent feedback evoked by hypertonic saline infusion facilitates the responsiveness of flexor and extensor motoneurons while inhibiting motor cortical cells. which might.1152/japplphysiol. differences in the exercise modality. Further conflict in this area is provided by the findings from postexercise muscle occlusion studies. end-exercise Leg2 (P Ͻ 0. the present findings provide further evidence in support of the concept that RPE is actually modulated.Muscle Afferents and Endurance Exercise 10 8 • Amann M et al. Values are normalized to the first minute of exercise. a group III/IV-mediated inhibition of the motor pathway from the motor cortex to the contracting muscles. This discrepancy between prior observations and the present results might be explained. account for impaired output of spinal motoneurons and performance (33). Based on these opposing reports. 58) have documented a significant reduction in CMD/the output of spinal motoneurons to the contralateral rested muscle. and/or the use of flexor vs. and second. single-leg knee extensor exercise performed with the same leg without (Leg2) and with a severe degree of preexisting quadriceps fatigue in the contralateral leg (Leg2-post).org . It has been theorized. group III/IV-mediated afferent feedback (evoked by postexercise muscle occlusion) has been documented to depress the responsiveness of the mo- toneuron pool innervating extensor muscles. and Rate of Perceived Exertion Although many recent studies have attempted to assess the inhibitory effect of muscle afferents on CMD/the output of spinal motoneurons (2. Peripheral Locomotor Muscle Fatigue. *Significant difference vs. what was different between these trials was the cardiorespiratory response and the augmented afferent feedback from the lower limbs in the Leg2-post trial. that RPE during exercise is independent of muscle afferent feedback and is exclusively determined by the corollary discharge associated with CMD (31). utilizing short-duration maximal isometric muscle contractions. Data are from five subjects. 5. extensor muscles between which responsiveness has been documented to be differentially affected by muscle afferents (33). in part. the present study was not burdened by these caveats. the present data collected across the Leg1 and Leg2-post trials fail to support this controversial idea as RPE values were consistently higher when the same exercise was performed with indistinguishable levels of iEMG (Fig. With the exception of one study (32). However.jappl. by gender differences. these changes were. by muscle afferent feedback. 55. Muscle Afferent Feedback. These uncertainties leave us with the previously proposed mechanism that the group III/IV-related impairment in the output of spinal motoneurons and performance was mediated upstream from the motor cortex (53). single-leg knee extensor exercise performed without (Leg2) and with (Leg2-post) a preexisting level of quadriceps fatigue in the contralateral leg. by issues such as an attenuated cardiopulmonary response to exercise (afferent blocking studies) and changes in peripheral muscle function (prefatigue studies). 52). 4.02 6 4 2 0 0 1 2 3 4 Leg2 Leg2post Time (min) 5 6 7 8 9 10 Fig. Mean values for iEMG during each muscle contraction (knee extension) were calculated and averaged over each 60-s period. at least in flexor muscles (24. Of note.2013 • www. A Potential Link Between Afferent Feedback. 4). 361 P = 0. differences in the muscle mass utilized and thus the total amount of group III/IV afferent feedback. Therefore. several studies (32.

utilizing a small muscle mass exercise paradigm. The magnitude of the ϳ20% increase in TRP/BCAA in the present study. which may facilitate the development of central fatigue and associated attenuation in CMD (11). 6. 6). CMD. The findings from the present study now suggest that the processes determining the sensory tolerance limit. At this point. during the subsequent minutes of Leg2-post. the tolerance limit for this Leg2-post trial was reached relatively quickly.362 Muscle Afferents and Endurance Exercise • Amann M et . 5). subjects were no longer able to continue the single-leg KE. adding to the continuously increasing afferent feedback and CMD associated with the exercise of the second leg (Leg2-post) (points D and E). day 3). We. 6. it might be concluded that the small change in TRP/ BCAA. At this point (cessation of exercise with Leg1). 6). 6) than during the same exercise performed without preexisting peripheral fatigue in the contralateral leg [i. due to cuff occlusion of this leg (from point B to C in Fig. indeed. However. however. with the initial development of peripheral fatigue during exercise of Leg1 (point A in Fig. CMD to this leg ceased entirely (thin dotted line). CMD to Leg1 ceased entirely while. was minimal compared with the over 200% increase observed after exhaustive whole body exercise (12. and the outcome was a greatly attenuated exercise performance and a significantly lower level of end-exercise peripheral fatigue in Leg2-post (Fig. In addition. and evaluated quadriceps muscle function in one leg before and again after exhaustive exercise of the contralateral leg (Fig. whereas group III/IV afferent firing continued due to the cuff inflation at a high level. Brain serotonin synthesis depends. or any other exercise. with the start of the consecutive leg trial. there is a need to consider other factors that may have influenced this experiment. 1. 6). Experimental Considerations Although this study circumvented several common caveats of previous research in this area. concomitantly the afferent feedback and CMD related to Leg2post started to increase (point D in Fig. Cuff on Sensory tolerance limit Sensory tolerance limit (%) B C D E Cessation of CMD to Leg1 Leg1-recovery afferents from Leg1 A Total exercise time (min) Fig. 23).e. on the plasma level of TRP and its transport across the bloodbrain barrier (17). A conceptual framework for the interactions between afferent feedback. Consequently. the sensory tolerance limit was reached during Leg2-post more rapidly (points D and E in Fig. now.00049. had no significant influence on the magnitude of CMD. other determinants of central fatigue. have been suggested to play a critical role in determining the sensory tolerance limit (4. we measured handgrip MVC before and immediately after the consecutive exhaustive exercise tests of both legs (Fig. recorded iEMG during leg exercise. apart from muscle afferent feedback. and afferent feedback and CMD related to the now exercising second leg (Leg2-post) started to increase. the cuff was released and the elevated afferent feedback from Leg1 began to recover (19.2013 • www. Leg1 (points A and B in Fig. For example. which relate intramuscular metabolic changes to the CNS. given that handgrip MVC was unchanged from preexercise baseline after exhaustive exercise of both legs. humoral factors associated with the severe quadriceps fatigue in Leg1 might have resulted in peripheral fatigue in the contralateral quadriceps (Leg2-post) or facilitated CMD inhibition by directly affecting the CNS. It has also been proposed that CMD might be compromised by increases in brain serotonin levels during exercise (12. Within 10 s of the cessation of the Leg1 trial. Schematic illustration reflecting potential sensory alterations during the consecutive single-leg knee extensor performance tests. Specifically. With the onset of exercise of the first leg (Leg1). peripheral fatigue. 6). 20. observed a small but significant increase in the plasma ratio of TRP/ BCAA from rest to the transition phase from Leg1 to Leg2post. and thus the termination of exercise. among others. With the end of Leg1 exercise. day 4). Consequently. as evidenced by the similar rate of rise in iEMG during Leg2 and Leg2-post (Fig.1152/japplphysiol. Within 10 s. 1. could potentially have contributed to the reduction in spinal motoneuronal output and exercise performance observed during the Leg2-post trial. and endurance exercise performance during the events of the present study is illustrated in Fig. Additionally. afferent firing remained high. might include the magnitude of both muscle afferent feedback and CMD. An increase in the plasma ratio of TRP/ BCAA is indicative of an elevated transport of TRP into the brain. Specifically. Once the sensory tolerance limit was reached in Leg2-post (point E in Fig. 6). this ratio remained unchanged throughout the remainder of the trial. Furthermore.or fatigue-induced alterations in brain neurotransmitters and their interaction with specific receptors. adding to the continuously increas- ing afferent feedback and CMD associated with Leg2-post (points D and E in Fig. Group III/IV muscle afferents. To evaluate the influence of such humoral factors in the periphery. both muscle afferent feedback and CMD increased progressively until the sensory tolerance limit was reached and the subjects were no longer able to continue the task (point B in Fig. 2). 6) or Leg2 trial (not shown)]. is reached (23). The conclusion from these assessments was that a humoral cross-over effect of exerciseinduced peripheral quadriceps fatigue into other skeletal muscle can be excluded since neither handgrip MVC nor quadriceps muscle function of the rested contralateral leg were altered by exhaustive single-leg KE.jappl. afferent feedback from Leg1 (although recovering) likely remained fairly high. 36). the cuff was released (point C). However. 40). afferent feedback from Leg1 (although recovering) likely remained fairly high. 6).. J Appl Physiol • doi:10. peripheral fatigue in one leg did not affect the rate of development of quadriceps fatigue in the contralateral leg. a hypothetical construct that might coincide with a certain level of peripheral fatigue and associated intramuscular metabolic milieu. afferent firing from Leg1 began to decline (dotted line). as indicated by the short time to exhaustion (point E). 25). subjects presumably exercised below their sensory tolerance limit and were thus willing and able to attempt the requested task (Leg2-post). both muscle afferent feedback and central motor drive (CMD) started to progressively rise (points A and B) until the sensory tolerance limit (dashed line) was reached at exhaustion (point B). their individual sensory tolerance limit.

Tinazzi M. Blomstrand E. 12. 15. However. Amann M. 17. Borg’s Perceived Exertion and Pain Scales. 1996. J.00049. M. presumably mediated by transcallosal connections (15). Severity of arterial hypoxaemia affects the relative contributions of peripheral muscle fatigue to exercise performance in healthy humans. 1988. Acta Physiol Scand 137: 1–13. Fjeldstad AS. 19. which the subjects might not be able to generate for long.A. Eldridge MW. M.V. this phenomenon could explain the higher cardioventilatory responses during the consecutive single-leg KE in the present study (Fig. Exp Brain Res 146: 467–473. and M. S. AUTHOR CONTRIBUTIONS Author contributions: M. edited and revised manuscript. M. Munchau A. and R. Blomstrand E.S. Jammes Y. Proctor LT. 2008. 16. Pegelow DF. M. 3. Proctor LT. Proctor LT. since the higher drive would simply compensate for the reduced motor pathway excitability with a net effect of an unchanged iEMG. 2006. Badawy AA. Arterial oxygenation influences central motor output and exercise performance via effects on peripheral locomotor muscle fatigue in humans. 8. Placebo effect of carbohydrate feedings during a 40-km cycling time trial. Stickland MK. Newsholme EA.R. Changes in plasma concentrations of aromatic and branched-chain amino acids during sustained exercise in man and their possible role in fatigue. Additionally. which are well known to be affected by CMD (56). Trinity JD.A. and M.J. Finally. 2002. drafted manuscript.R. there is some evidence that corticospinal excitability of the target muscle as well as the homologous contralateral resting muscle may actually be increased. 2007. One example of these interhemispheric interactions following unilateral fatiguing exercise is the reduction of intracortical facilitation in the motor cortex supplying the contralateral homologous resting muscle (10). this study provides evidence that peripheral fatigue and the associated intramuscular metabolic disturbances compromise high-intensity endurance performance independent of the well known fatigue-related changes distal to the neuromuscular junction that attenuate the response of muscle to neural activation. and M. Andersen P.. exists between right and left motor cortices in humans. 2. The role of free serum tryptophan in the biphasic effect of acute ethanol administration on the concentrations of rat brain tryptophan. Wray DW. Acta Physiol Scand 133: 115–121. which limits the output of spinal motoneurons and therefore endurance exercise performance. Locomotor muscle fatigue modifies central motor drive in healthy humans and imposes a limitation to exercise performance.. Dempsey JA.. not be reflected in an increased iEMG at the muscle. these observations suggest that interhemispheric inhibition at the motor cortical level.A. Dempsey . in combination. 14. Boushel R. Fiaschi A. the only performance test on that day). Clark VR. Neurosci Lett 257: 109 –112..e. conception and design of research. In conclusion. 35).. 13. G. M. Saltin B. 1998. Runnels S. This higher motor drive would. 1976. Richardson RS. Baumer T. we cannot exclude these differences as potential contributors to the shorter endurance time in Leg2-post. Pegelow DF.V. Physical exercise and brain monoamines: a review. and this could explain the reduced exercise performance in Leg2-post. 10. S.Muscle Afferents and Endurance Exercise • Amann M et al.. Subudhi AW. J. second performance test on that day) compared with that during the Leg2 performance test (i.L. of course. not decreased (29). Interhemispheric inhibition in patients with multiple sclerosis. Borg G. Furthermore. DISCLOSURES No conflicts of interest. REFERENCES 1. G. M. Sebranek JJ.” likely did not contribute to the decreased exercise performance in Leg2-post.. Boroojerdi B. 4. during intense unilateral muscle contractions. Specifically. Amann M.A.A. Sebranek JJ. the higher motor drive necessary to work against a given load would require a greater effort.M.. the CNS would need to increase voluntary drive to the motor cortex. Darques JL. and M.V. Burke LM. Amann M. Sebranek JJ. HL09183 to R. ‘Direct’ and ‘crossed’ modulation of human motor cortex excitability following exercise. M.L. IL: Human Kinetics. Champaign. Maximal perfusion of skeletal muscle in man. J Nutr 136: 544 –547. Bonato C. neither of these processes occur immediately after a fatiguing task and have actually only been observed Ͼ5 min after unilateral exercise ceased (10. analyzed data. Group III and IV muscle afferents contribute to ventilatory and cardiovascular response to rhythmic exercise in humans. 2000. Liepert J. A role for branched-chain amino acids in reducing central fatigue. 11.V.A.. Therefore. 2011. 2006.J. 5-hydroxytryptamine and 5-hydroxyindol-3-ylacetic acid. We conclude that group III/IV muscle afferent feedback associated with intramuscular metabolic perturbation has an inhibitory effect on the CNS. Amann. Amann M. cognitive demand as well as afferent feedback from the heart and pulmonary system were presumably higher during the Leg2-post performance test (i. Amann M. Reese VR.jappl. 1989. are declared by the author(s). 2011. J Appl Physiol 109: 966 –976. Mull M.J. and various cross-over effects have been identified. Celsing F. Manganotti P. J Physiol 589: 5299 –5309. 18. Romer LM. Pegelow DF. M. Pegelow DF. J Physiol 366: 233–249. interpreted results of experiments. 363 Furthermore.1152/japplphysiol.S. Bongiovanni G. Chaouloff F. Opioid-mediated muscle afferents inhibit central motor drive and limit peripheral muscle fatigue development in humans.R. 2009. Amann M.V. Biochem J 160: 315–324. Zanette G.V. 1998. 2010. Noth J. J Appl Physiol • doi:10. Richardson) and a VA Merit Grant (E6910R). Blain GM. The strongest argument against a significant role for reduced intracortical facilitation or a decreased excitability of the motor pathway supplying contralateral homologous resting muscle is temporal in nature. Decherchi P.A. Dempsey JA. Lung. and M. 13. financial or otherwise. Hungs M. Electroencephalogr Clin Neurophysiol 109: 230 –237.I.2013 • www. Acta Physiol (Oxf) 199: 367–383. a link. M. Additionally. 2010. Lovering AT... Such interhemispheric modulation of motor pathway excitability could theoretically diminish the output of the spinal motorneurons such that. Hopkins WG. and R. Evans M. 1985. or “downstream. prepared figures. Topper R..V. J Physiol 587: 271– 283.V. to maintain a given workload. J Physiol 581: 389 –403. Med Sci Sports Exerc 32: 1642–1647. approved final version of manuscript. Implications of group III and IV muscle afferents for high intensity endurance exercise performance in humans. Hawley JA.. J Physiol 586: 161–173. Pegelow DF.M. S.I. Amann M. J Physiol 589: 3855–3866. and M.J. M. unilateral fatiguing exercise can decrease the postexercise excitability of the motor pathway from the contralateral motor cortex to the homologous resting muscle (13).A. 6. 4). GRANTS Research reported in this publication was supported by the National Heart. Blain GM.e.. Muscle metaboreflex control of the circulation during exercise. Dempsey JA. performed experiments. Mechanisms of fatigue-induced activation of group IV muscle afferents: the roles played by lactic acid and inflammatory mediators. Dempsey JA. M. Morgan DE. Finally. J Physiol 575: 937–952.R. Polo A. 9. On the contribution of group III and IV muscle afferents to the circulatory response to rhythmic exercise in humans. Neurosci Lett 216: 97–100.. and Blood Institute (HL-103786 and HL-116579 to M. 1998. 7. Fatigue suppresses ipsilateral intracortical facilitation. Dempsey JA. 5. Weiller C.

and low-frequency electrically induced fatigues. Butler JE. chapt. Comparison of potentiated and unpotentiated twitches as an index of muscle fatigue. Gandevia SC. Balzamo E. Exp Brain Res 150: 308 –313. LeBlanc P. Green R. Pflügers Arch 452: 199 –207. Focal depression of cortical excitability induced by fatiguing muscle contraction: a transcranial magnetic stimulation study. Butler JE. Mainguy V. 1997. 48. Taylor JL. Martin PG. Provencher S. Nielsen B. Gagnon P. Poole DC. 42. Dorsal root ganglion neurons innervating skeletal muscle respond to physiological combinations of protons. Azabji Kenfack M. Darques JL. Clin Exp Pharmacol Physiol 33: 400 –405. Ferretti . Taylor JL. Allen GM. Pineda LA. Muscle Nerve 25: 438 –444. Hyperthermia and central fatigue during prolonged exercise in humans. Butler JE. Taylor JL. Pickar JG. Voluntary strength and fatigue. 23. Brain Res 750: 147–154. Grassi ˙ O2 during single leg B. Martin PG. 21.364 Muscle Afferents and Endurance Exercise • Amann M et al. Cannon J. 2009. Cardiovascular control during concomitant dynamic leg exercise and static arm exercise in humans. Gandevia SC. Couillard A. Kay D. Stokic DS. Changes in afferent and efferent phrenic activities with electrically induced diaphragmatic fatigue. Wagner PD. Hasegawa H. Changes in motor cortical excitability during human muscle fatigue. Hyperthermia: a failure of the motor cortex and the muscle. 49. Pegelow DF. Piacentini MF. Mador MJ. 39. Sports Med 36: 881–909. Schertzer JD. Nybo L. Knight DR. and blood lactate in chronic obstructive pulmonary disease. Richardson RS. Smith JL. Antonutto G. di Prampero PE. 2006. 47. Central fatigue: the serotonin hypothesis and beyond. Jobin J. 24. Taylor JL. 45. Secher NH. Chicago. In: Handbook of Physiology. 46. Tam E. 30. Hayes SG. Zwarts MJ. 2001. Pearson J. 57. Central fatigue explains sex differences in muscle fatigue and contralateral cross-over effects of maximal contractions. Weiller C. 2001. and lactate mediated by ASIC. Liu Z. Rattey J. J Appl Physiol 106: 556 –565. 2001. Perception of effort during exercise is independent of afferent feedback from skeletal muscles. J Appl Physiol 73: 894 –902. Craig AD. J Neurophysiol 87: 1641–1645. Rossman MJ. Marcora S. 36. 126 –129. Eldridge FL. 58. Saey D. Sandiford SD. J Physiol 204: 63–66. 2002. IL: American Medical Association. Haverkamp HC. Am J Physiol Regul Integr Comp Physiol 292: R598 –R606. Amann M. p. Jones PR. Gandevia SC. Inhibition of ipsilateral motor cortex during phasic generation of low force. Milot J. Waldrop TG. Butler JE. 2000. Neuropsychologia 9: 97–113. Perco JD. Venturelli M. Hogan MC. McDaniel J. Merton PA.00049. Correction of cardiac output obtained by Modelflow from finger pulse pressure profiles with a respiratory method in humans. 2007. Watson P. 2008. edited by Nelson T. Liepert J. 2007. Strange S. Group III and IV muscle afferents differentially affect the motor cortex and motoneurones in humans. Kufel TJ. J Neurophysiol 100: 1184 –1201. 1969. 12. Marino FE. Roelands B. Central neural control of respiration and circulation during exercise.1152/japplphysiol. Dimitrijevic MR. Pflügers Arch 454: 957–969. J Physiol 525: 793–801. 38. and lungs. Carroll TJ. 32. Impact of pre-induced quadriceps fatigue on exercise response in chronic obstructive pulmonary disease and healthy subjects. Influence of a voluntary fatigue test on the contralateral homologous muscle in humans? Neurosci Lett 253: 41–44. 2002. 34. and TRPV1. Gandevia SC. Allen GM. 2005. J Physiol 490: 529 –536. 56. 2004. Cautero M. J Appl Physiol • doi:10. muscle morphometry. Lovering AT. 333–380. 1992. Locomotor exercise induces longlasting impairments in the capacity of the human motor cortex to voluntarily activate knee extensor muscles. 2006.2013 • www. 28. Discharge properties of group III and IV muscle afferents. 40. 37. 2009. Todd G. Physiol. Castle P. Dempsey JA. Dettmers C. Determinants of maximal exercise V knee extensor exercise in humans. 41. Michaud A. Hughen RW. 54. Jammes Y. 1998. Taylor JL. Fatiguesensitive afferents inhibit extensor but not flexor motoneurons in humans. Weerakkody N. 43. Ouyang J. J Physiol 490: 519 – 528. 1996. Zhang J. Gandevia SC. 1976. Borg G. Soc. 35. 25. Exercise: Regulation and Integration of Multiple Systems. 44. Am J Physiol Regul Integr Comp Physiol 289: R441–R449. Activation of spinobulbar lamina I neurons by static muscle contraction. Lador F. Am J Respir Crit Care Med 171: 1109 –1115. Bentley DJ. 1996. In: Mental Health and Emotional Aspects of Sports. Rainier J. Prog Neurobiol 72: 223–261. Maxwell N. Petersen NT. 52. Sidhu SK. The assessment and analysis of handedness: the Edinburgh inventory. Gandevia SC. Lee J. 2008. 1996. J Appl Physiol 106: 2060 –2062. 51. Ischaemia after exercise does not reduce responses of human motoneurones to cortical or corticospinal tract stimulation. Romer LM. Amann M. 22. MD: Am. Vivodtzev I. 2010. Gandevia SC. Jammes Y. 2006. Richardson RS. 2002. Mador MJ. 27. Kaufman MP. J Physiol 123: 553–564. Meeusen R. 50. McKay WB. 2005. J Physiol 586: 1277–1289. Gandevia SC. Todd G. Med Sci Sports Exerc 42: 577–584. Mitchell JH. Spinal and supraspinal factors in human muscle fatigue. Wilson LB. Capelli C. Clin Sci (Lond) 106: 371–376. 26. p. The effect of a contralateral contraction on maximal voluntary activation and central fatigue in elbow flexor muscles. 2009. Zijdewind I. J Physiol 514: 283–291. Bethesda. Am J Physiol Heart Circ Physiol 268: H1453–H1461. 29. Maltais F. Physiol Rev 81: 1725–1789. 1995. 1999. Martin PG. Saey D.jappl. 2003. Effect of acute severe hypoxia on peripheral fatigue and endurance capacity in healthy humans. 1971. Tuel SM. Fatigue-induced changes in group IV muscle afferent activity: differences between high. J Appl Physiol 91: 1055–1060. 33. 1995. Kernell D. 1954. Muscle Na-K-pump and fatigue responses to progressive exercise in normoxia and hypoxia. 20. 2006. Oldfield RC. Adv Exp Med Biol 508: 25–32. Maltais F. J Neurosci 26: 4796 –4802. 2004. Taylor JL. Petersen N. Supraspinal factors in human muscle fatigue: evidence for suboptimal output from the motor cortex. Duffield R. sect. 2012. Terborg C. Gandevia SC. 9.. Contralateral muscle fatigue in human quadriceps muscle: evidence for a centrally mediated fatigue response and cross-over effect. Rattey J. J Physiol 563: 621–631. ATP. Laviolette L. Exp Brain Res 105: 276 –282. Sherwood AM. Andrew D. Cerebral perturbations provoked by prolonged exercise. Todd G. Adreani CM. Taylor JL. 55. Taylor JL. 31. Anthropometric determination of leg fat and muscle plus bone volumes in young male and female adults. Kurdak SS. Muscle mass and peripheral fatigue: a potential role for afferent feedback? Acta Physiol (Oxf) 206: 242–250. J Appl Physiol 107: 832–840. Contractile fatigue. Butler JE. Cote CH. 2005. Perception of effort in the perscription of physical activity. Green HJ. Morgan W. P2X. Clin Neurophysiol 112: 114 –121. 53. Iwamoto GA. heart. Nybo L. Martin PG. Duhamel TA. Evidence for a supraspinal contribution to human muscle fatigue. Precooling can prevent the reduction of self-paced exercise intensity in the heat. Light AR.