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Introduction: When an isometric contraction is sustained at a submaximal torque, activation of the motoneuron pool increases, making it difficult to interpret neural excitability alterations. Thus, more recently, isometric contractions with maintained electromyographic (EMG) activity (matched-EMG) are being used to induce fatigue; however, little is known about the neurophysiological adjustments that occur to satisfy the requirements of the task., Methods: For our study, 16 participants performed a 10-min sustained isometric elbow flexion contraction at 20% maximal voluntary contraction (MVC) torque or the level of integrated biceps brachii EMG recorded at 20% MVC torque. Surface EMG was used to assess global median frequency, and four fine-wire electrode pairs were used to obtain motor unit (MU) discharge rate from biceps brachii. Torque or EMG steadiness was also assessed throughout the fatiguing contractions., Results: MU discharge rate increased and torque steadiness decreased during the matched-torque contraction; however, MU discharge rate decreased during the matched-EMG contraction, and no changes occurred for EMG steadiness. Data pooled for the two contractions revealed a decrease in global median frequency. Lastly, a greater loss of MVC torque was observed immediately after the matched-torque compared with matched-EMG contraction., Conclusions: These findings indicate that, during a matched-torque fatiguing contraction, the nervous system increases MU discharge rates at the cost of poorer steadiness to maintain the requisite torque. In contrast, during a matched-EMG fatiguing contraction, a reduction of MU discharge rates allows for maintenance of EMG steadiness., (Copyright © 2024 by the American College of Sports Medicine.)

According to current guidelines, when measuring voluntary activation (VA) using transcranial magnetic stimulation (TMS), stimulator output (SO) should not exceed the intensity that, during a maximal voluntary contraction (MVC), elicits a motor evoked potential (MEP) from the antagonist muscle >15%-20% of its maximal M-wave amplitude. However, VA is based on agonist evoked-torque responses [i.e., superimposed twitch (SIT) and estimated resting twitch (ERT)], which means limiting SO based on electromyographic (EMG) responses will often lead to a submaximal SIT and ERT, possibly underestimating VA. Therefore, the purpose of this study was to compare elbow flexor VA calculated using the original method (i.e., intensity based on MEP size; SO MEP ) and a method based solely on eliciting the largest SIT at 50% MVC torque (SO SIT ), regardless of triceps brachii MEP size. Fifteen healthy, young participants performed 10 sets of brief contractions at 100%, 75%, and 50% MVC torque, with TMS delivered at SO MEP (73.0 ± 13.5%) or SO SIT (92.0 ± 10.8%) for five sets each. Although the mean ERT torque was greater using SO SIT (15.2 ± 4.8 Nm) compared with SO MEP (13.0 ± 3.7 Nm; P = 0.031), the SIT amplitude at 100% MVC torque was not different (SO MEP : 0.69 ± 0.49 Nm vs. SO SIT : 0.74 ± 0.52 Nm; P = 0.604). Despite the ERT disparity, VA scores were not different between SO MEP (94.6 ± 3.5%) and SO SIT (95.0 ± 3.3%; P = 0.572). Even though SO SIT did not lead to a higher VA score than the SO MEP method, it has the benefit of yielding the same result without the need to record antagonist EMG or perform MVCs when determining SO, which can induce fatigue before measuring VA. NEW & NOTEWORTHY When using transcranial magnetic stimulation (TMS) to determine voluntary activation (VA) of the elbow flexors, we hypothesized that a stimulator output designed to limit antagonist muscle activity would evoke submaximal agonist superimposed twitch amplitudes, thus underestimating VA. Contrary to our hypothesis, VA was not greater with an output based on maximal superimposed twitch amplitude. Nevertheless, our findings advance methodological practices by simplifying the equipment and minimizing the time required to determine VA using TMS.

Adult aging is associated with a myriad of changes within the neuromuscular system, leading to reductions in contractile function of old adults. One of the consequences of these age-related neuromuscular adaptations is altered performance fatigability, which can limit the ability of old adults to perform activities of daily living. Whereas age-related fatigability during isometric tasks has been well characterized, considerably less is known about fatigability of old adults during dynamic tasks involving movement about a joint, which provides a more functionally relevant task compared with static contractions. This review provides a comprehensive summary of age-related fatigability during dynamic contractions, where the importance of task specificity is highlighted with a brief discussion of the potential mechanisms responsible for differences in fatigability between young and old adults. The angular velocity of the task is critical for evaluating age-related fatigability, as tasks that constrain angular velocity (i.e., isokinetic) produce equivocal age-related differences in fatigability, whereas tasks involving unconstrained velocity (i.e., isotonic-like) consistently induce greater fatigability for old compared with young adults. These unconstrained velocity tasks, which are more closely associated with natural movements, offer an excellent model to uncover the underlying age-related mechanisms of increased fatigability. Future work evaluating the mechanisms of increased age-related fatigability during dynamic tasks should be evaluated using contraction modes that are specific to the task (i.e., dynamic), rather than isometric, particularly for the assessment of spinal and supra spinal components. Advancing our understanding of age-related fatigability is likely to yield novel insights and approaches for improving mobility limitations in old adults.

The purpose of this study was to assess how severe acute hypoxia alters the neural mechanisms of muscle activation across a wide range of torque output in a fatigued muscle. Torque and electromyography responses to transcranial and motor nerve stimulation were collected from 10 participants (27 years ± 5 years, 1 female) following repeated performance of a sustained maximal voluntary contraction that reduced torque to 60% of the pre-fatigue peak torque. Contractions were performed after 2 h of hypoxic exposure and during a sham intervention. For hypoxia, peripheral blood oxygen saturation was titrated to 80% over a 15-min period and remained at 80% for 2 h. Maximal voluntary torque, electromyography root mean square, voluntary activation and corticospinal excitability (motor evoked potential area) and inhibition (silent period duration) were then assessed at 100%, 90%, 80%, 70%, 50% and 25% of the target force corresponding to the fatigued maximal voluntary contraction. No hypoxia-related effects were identified for voluntary activation elicited during motor nerve stimulation. However, during measurements elicited at the level of the motor cortex, voluntary activation was reduced at each torque output considered (P = .002, η p 2  = .829). Hypoxia did not impact the correlative linear relationship between cortical voluntary activation and contraction intensity or the correlative curvilinear relationship between motor nerve voluntary activation and contraction intensity. No other hypoxia-related effects were identified for other neuromuscular variables. Acute severe hypoxia significantly impairs the ability of the motor cortex to voluntarily activate fatigued muscle across a wide range of torque output., (© 2022 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Electrically evoked contractions provide insight into intrinsic neuromuscular fatigability and also represent a valuable technique to maintain muscle mass in a clinical setting. To appropriately investigate intrinsic fatigability and design optimal stimulation protocols, it would seem to be crucial to stimulate the muscle at a frequency equivalent to the mean motor unit discharge rate expected at the target force level., (Copyright © 2022 by the American College of Sports Medicine.)

Quantifying prolonged low-frequency force depression (PLFFD) with the gold-standard 1-s trains presents challenges, so paired pulses have been used. Owing to greater impairment of high-frequency doublet than tetanic torque, paired pulses underestimate PLFFD. This study aimed to approximate the minimum number of high-frequency pulses needed to avoid such underestimation and assess the feasibility of modeling PLFFD from a limited number of experimental pulses. In 13 participants, a 1-s 10-Hz train and 100-Hz trains with 2, 4, 7, 12, 15, 25, 50, or 100 pulses were evoked before and after (15 min, 2, 4, and 7 days) eccentric exercise of the dorsiflexors. With ≤12 pulses, impairment of 100-Hz torque was greater than the 1-s train ( P ≤ 0.05; e.g., 12 vs. 100 pulses at 4 days: 97.8 ± 8.5% vs. 100.5 ± 8.2% baseline). Consequently, with ≤12 pulses, PLFFD was underestimated compared with the gold-standard measure ( P ≤ 0.05; e.g., 12 vs. 100 pulse 10:100-Hz torque ratio at 4 days: 86.8 ± 12.8% vs. 84.6 ± 13.5% baseline). Modeling reproduced 10:100-Hz ratios (PLFFD) with 95% limits of agreement of -13.6% to 16.7% of experimental values with ≥12 pulses. Our results indicate that a minimum of 13-25 pulses of 100 Hz are needed to accurately quantify PLFFD in the dorsiflexors. Although this may not be the minimum range for other muscles, a similar relationship with pulse number likely exists. Modeling may eventually provide an option to estimate PLFFD from experimental trains with relatively few pulses; however, further development is imperative to reduce variability. NEW & NOTEWORTHY Ideally, prolonged low-frequency force depression (PLFFD) is measured with 1-s trains of supramaximal stimuli; however, this induces considerable discomfort. We tested briefer trains to approximate the minimum number of high-frequency pulses needed to accurately determine PLFFD and the feasibility of modeling 1-s tetani with relatively few pulses. After eccentric exercise, 13-25 high-frequency pulses were needed to accurately measure PLFFD. Modeling reproduced mean experimental values but had considerable variability.

Unaccustomed eccentric (ECC) exercise induces muscle fatigue as well as damage and initiates a protective response to minimize impairments from a subsequent bout (i.e., repeated bout effect; RBE). It is uncertain if the sexes differ for neuromuscular responses to ECC exercise and the ensuing RBE. Twenty-six young adults (13 females) performed 2 bouts (4 weeks apart) of 200 ECC maximal voluntary contractions (MVCs) of the dorsiflexors. Isometric (ISO) MVC torque and the ratio of ISO torque in response to low- versus high-frequency stimulation (10:100 Hz) were compared before and after (2-10 min and 2, 4, and 7 days) exercise. The decline in ECC and ISO MVC torque and the 10:100 Hz ratio following bout 1 did not differ between sexes ( P > 0.05), with reductions from baseline of 31.5% ± 12.3%, 24.1% ± 15.4%, and 51.3% ± 12.2%, respectively. After bout 2, the 10:100 Hz ratio declined less (45.0% ± 12.4% from baseline) and ISO MVC torque recovered sooner compared with bout 1 but no differences between sexes were evident for the magnitude of the RBE ( P > 0.05). These data suggest that fatigability with ECC exercise does not differ for the sexes and adaptations that mitigate impairments to calcium handling are independent of sex. Novelty: One bout of 200 maximal eccentric dorsiflexor contractions caused equivalent muscle fatigue and damage for females and males. The repeated bout effect observed after a second bout 4 weeks later also had no sex-related differences. Prolonged low-frequency force depression is promoted as an indirect measure of muscle damage in humans.

Purpose: Transcutaneous electrical stimulation (TES) is used to activate muscles when volitional capacity is impaired but potential benefits are limited by rapid force loss (fatigue). Most TES fatigue protocols employ constant-frequency trains, with stimuli at a fixed interstimulus interval (ISI); however, a brief ISI between the first two pulses (variable-frequency train, VFT) to maximize the catchlike property of muscle can attenuate fatigue development. The purpose of this study was to investigate if a VFT that simulates intrinsic variability of voluntary motor unit discharge rates would also mitigate fatigue, owing to the sensitivity of muscle to acute activation history., Methods: On two visits, 24 healthy adults (25.3 ± 3.7 years; 12 females) received 3 min of intermittent TES to the quadriceps of the dominant leg. Trains of eight pulses at 10 Hz were delivered with a constant (100 ms) or variable ISI (80-120 ms). Contractile impulse, rate of force development (RFD), and rate of relaxation (RFR) were determined for each tetanus RESULTS: During fatigue and recovery, contractile impulse did not differ between protocols (p ≥ 0.796) and sexes (p ≥ 0.493), with values of 77 ± 17% control at task end and 125 ± 19% control 2 min later. RFD and RFR also showed no effect of the protocol (p ≥ 0.310) or participant sex (p ≥ 0.119). Both measures slowed (38 ± 23% and 33 ± 22%, respectively) but dissociated during recovery as RFD remained 16 ± 18% below control at 5 min, whereas RFR recovered to control by 30 s (101 ± 22%)., Conclusion: Contrary to expectations, the VFT protocol did not attenuate fatigue development, which suggests no benefit to mimicking the inherent variability of motor unit discharge rates.

Data are scant on sex-related differences for electrically evoked contractions, which assess intrinsic contractile properties while limiting spinal and supraspinal adaptations to mitigate fatigue. Furthermore, the few studies that exist use stimulus frequencies considerably higher than the natural motor unit discharge rate for the target force. The purpose of this study was to compare force loss to electrically evoked contractions at a physiological stimulus frequency among young females ( n = 12), young males ( n = 12), old females ( n = 11), and old males ( n = 11). The quadriceps of the dominant leg were fatigued by 3 min of intermittent transcutaneous muscle belly stimulation (15 Hz stimulus train to initially evoke 25% of maximal voluntary force). Impairment of tetanic contractile impulse (area under the curve) did not differ between sexes for young or old adults or between age groups, with a pooled value of 55.2% ± 12.4% control at the end of fatigue. These data contrast with previous findings at 30 Hz, when the quadriceps of females had greater fatigue resistance than males for young and old adults. The present results highlight the impact stimulus frequency has on intrinsic fatigability of muscle; the findings have implications for future fatigue paradigms and treatment approaches when utilizing electrical stimulation for rehabilitation. Novelty Fatigue was not different between sexes with a stimulation frequency comparable to discharge rates during voluntary contractions. These results highlight that stimulus frequency not only influences fatigue development but also between-group differences.

New Findings: What is the central question of this study? How does acute hypoxia alter central and peripheral fatigue during brief and sustained maximal voluntary muscle contractions? What is the main finding and its importance? Perception of fatigue during muscle contractions was increased progressively for 2 h after hypoxic exposure. However, an increase in motor cortex excitability and a decrease in voluntary activation of skeletal muscle were observed across the entire protocol when performing brief (3 s) maximal contractions. These adaptations were abolished if the brief contraction was held for a duration of 20 s, which was presumably attributable to a successful redistribution of blood to overcome the reduced oxygen content., Abstract: Few studies have examined the time course of changes in the motor system after acute exposure to hypoxia. Thus, the purpose of this study was to examine how acute hypoxia affects corticospinal excitability, voluntary activation (VA) and the perception of fatigue during brief (3 s) and sustained (20 s) maximal voluntary contractions (MVCs). Fourteen healthy individuals (23 ± 2.2 years of age; four female) were exposed to hypoxia and sham conditions. During hypoxia, peripheral blood oxygen saturation was titrated over a 15 min period and remained at 80% during testing. Corticospinal excitability and VA were assessed before titration (Pre), 0, 1 and 2 h after. At each time point, the brief and sustained elbow flexion MVCs were performed. Motor evoked potentials (MEPs) were obtained using transcranial magnetic stimulation. Superimposed and resting twitches were obtained from motor point stimulation of biceps brachii to calculate the level of VA, and ratings of perceived fatigue were obtained with a modified CR-10 Borg scale. A condition-by-time interaction was detected for the CR-10 Borg scale, whereby perception of fatigue increased progressively throughout the hypoxia protocol. However, main effects of MEP area and VA indicated that corticospinal excitability increased, and VA of the biceps brachii decreased, throughout the hypoxia protocol. Given that these changes in MEP area and VA were seen only when performing the brief MVCs (and not during the sustained MVCs), performing longer contractions might overcome reduced oxygen content by redirecting blood flow to active areas of the motor system., (© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society.)

Purpose: To investigate possible sex-related differences in group III/IV muscle afferent feedback with isometric fatigue, we aimed to assess the effect of a sustained submaximal elbow extensor contraction on motoneuronal excitability (cervicomedullary motor evoked potential [CMEP]) and voluntary activation (VA)., Methods: Twenty-four participants (12 females) performed a 15-min contraction at the level of EMG activity recorded at 15% of maximal torque. Each minute, CMEP were elicited by cervicomedullary stimulation with and without conditioning transcranial magnetic stimulation (TMS) delivered 100 ms earlier. Unconditioned and conditioned motor evoked potentials (MEP) in response to TMS were also recorded to assess motor cortical excitability. CMEP and MEP were normalized for changes in downstream excitability and expressed as percentage of their prefatigue (control) values. Postfatigue, VA was calculated from superimposed and resting tetani evoked by stimulation over triceps brachii., Results: Males were twice as strong as females, but the sexes did not differ for any variable during the fatigue protocol. On a 0-10 scale, RPE increased from ~2.5 to 9. The unconditioned CMEP did not change, whereas the conditioned CMEP was reduced by ~50%. By contrast, the unconditioned and conditioned MEP increased to ~200% and ~320% of the control values, respectively. At task termination, maximal torque was reduced ~40%, and VA was ~80%, down from a prefatigue value of ~96%., Conclusions: Results support the scant published data on the elbow extensors and indicate no sex-related differences for isometric fatigue of this muscle group. The motoneuronal and VA data suggest that metabolite buildup and group III/IV muscle afferent activity were similar for females and males.

Purpose: We investigated the effect of high-altitude acclimatization on peripheral fatigue compared with sea level and acute hypoxia., Methods: At sea level (350 m), acute hypoxia (environmental chamber), and chronic hypoxia (5050 m, 5-9 d) (partial pressure of inspired oxygen = 140, 74 and 76 mm Hg, respectively), 12 participants (11 in chronic hypoxia) had the quadriceps of their dominant leg fatigued by three bouts of 75 intermittent electrically evoked contractions (12 pulses at 15 Hz, 1.6 s between train onsets, and 15 s between bouts). The initial peak force was ~30% of maximal voluntary force. Recovery was assessed by single trains at 1, 2, and 3 min postprotocol. Tissue oxygenation of rectus femoris was recorded by near-infrared spectroscopy., Results: At the end of the fatigue protocol, the impairments of peak force and peak rates of force development and relaxation were greater (all P < 0.05) in acute hypoxia (~51%, 53%, and 64%, respectively) than sea level (~43%, 43%, and 52%) and chronic hypoxia (~38%, 35%, and 48%). Peak force and rate of force development recovered faster (P < 0.05) in chronic hypoxia (pooled data for 1-3 min: ~84% and 74% baseline, respectively) compared with sea level (~73% and 63% baseline) and acute hypoxia (~70% and 55% baseline). Tissue oxygenation did not differ among conditions for fatigue or recovery (P > 0.05)., Conclusions: Muscle adaptations occurring with chronic hypoxia, independent of other adaptations, positively influence muscle contractility during and after repeated contractions at high altitude.

This study compared the effects of fatigue on corticospinal responsiveness in the upper- and lower-limb muscles of the same participants. Seven healthy males performed a 2-min maximal voluntary isometric contraction of the elbow flexors or knee extensors on four separate days. Electromyographic responses were elicited by nerve stimulation (maximal M-wave) in all sessions and by transcranial magnetic stimulation (motor-evoked potential; silent period) and spinal tract stimulation (cervicomedullary or thoracic motor-evoked potentials; silent period) in one session each per limb. During sustained maximal voluntary contractions, motor-evoked potential area normalised to M-waves increased from baseline in biceps brachii (155 ± 55%) and rectus femoris (151 ± 44%) (both p ≤ 0.045). At the end of maximal voluntary contractions, spinal tract motor-evoked potential area normalised to M-waves was smaller than baseline in biceps brachii (74 ± 23%; p = 0.012) but not rectus femoris (108 ± 40%; p = 0.999). The ratio of motor-evoked potential to spinal tract-evoked potential areas increased dramatically from 90 to 115 s in biceps brachii (p = 0.001) but not in rectus femoris (p = 0.999). Silent period durations increased similarly in both muscles (p ≤ 0.008) after transcranial and spinal stimulation. Sustained maximal contractions elicit different neurophysiological adjustments in upper- and lower-limb muscles. Specifically, motoneuronal excitability was reduced in biceps brachii, but not in rectus femoris, and this reduction required greater compensatory adjustments from the motor cortex. Therefore, changes in cortical and spinal excitability during sustained maximal exercise are likely specific to the muscle performing the task., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Purpose: At high altitude, Lowlanders exhibit exacerbated fatigue and impaired performance. Conversely, Sherpa (native Highlanders) are known for their outstanding performance at altitude. Presently, there are no reports comparing neuromuscular fatigue and its etiology between Lowlanders and Sherpa at altitude., Methods: At 5050 m, nine age-matched Lowlanders and Sherpa (31 ± 10 vs 30 ± 12 yr, respectively) completed a 4-min sustained isometric elbow flexion at 25% maximal voluntary contraction (MVC) torque. Mid-minute, stimuli were applied to the motor cortex and brachial plexus to elicit a motor-evoked potential and maximal compound muscle action potential (Mmax), respectively. Supraspinal fatigue was assessed as the reduction in cortical voluntary activation (cVA) from prefatigue to postfatigue. Cerebral hemoglobin concentrations and tissue oxygenation index (TOI) were measured over the prefrontal cortex by near-infrared spectroscopy., Results: Prefatigue, MVC torque, and cVA were significantly greater for Lowlanders than Sherpa (79.5 ± 3.6 vs 50.1 ± 11.3 N·m, and 95.4% ± 2.7% vs 88.2% ± 6.6%, respectively). With fatigue, MVC torque and cVA declined similarly for both groups (~24%-26% and ~5%-7%, respectively). During the task, motor-evoked potential area increased more and sooner for Lowlanders (1.5 min) than Sherpa (3.5 min). The Mmax area was lower than baseline throughout fatigue for Lowlanders but unchanged for Sherpa. TOI increased earlier for Lowlanders (2 min) than Sherpa (4 min). Total hemoglobin increased only for Lowlanders (2 min). Mmax was lower, whereas TOI and total hemoglobin were higher for Lowlanders than Sherpa during the second half of the protocol., Conclusions: Although neither MVC torque loss nor development of supraspinal fatigue was different between groups, neural-evoked responses and cerebral oxygenation indices were less perturbed in Sherpa. This represents an advantage for maintenance of homeostasis, presumably due to bequeathed genotype and long-term altitude adaptations.

Key Points: This study investigated the influence of group III/IV muscle afferents on corticospinal excitability during cycling exercise and focused on GABA B neuron-mediated inhibition as a potential underlying mechanism. The study provides novel evidence to demonstrate that group III/IV muscle afferent feedback facilitates inhibitory intracortical neurons during whole body exercise. Firing of these interneurons probably contributes to the development of central fatigue during physical activity., Abstract: We investigated the influence of group III/IV muscle afferents in determining corticospinal excitability during cycling exercise and focused on GABA B neuron-mediated inhibition as a potential underlying mechanism. Both under control conditions (CTRL) and with lumbar intrathecal fentanyl (FENT) impairing feedback from group III/IV leg muscle afferents, subjects (n = 11) cycled at a comparable vastus-lateralis EMG signal (∼0.26 mV) before (PRE; 100 W) and immediately after (POST; 90 ± 2 W) fatiguing constant-load cycling exercise (80% Wpeak; 221 ± 10 W; ∼8 min). During, PRE and POST cycling, single and paired-pulse (100 ms interstimulus interval) transcranial magnetic stimulations (TMS) were applied to elicit unconditioned and conditioned motor-evoked potentials (MEPs), respectively. To distinguish between cortical and spinal contributions to the MEPs, cervicomedullary stimulations (CMS) were used to elicit unconditioned (CMS only) and conditioned (TMS+CMS, 100 ms interval) cervicomedullary motor-evoked potentials (CMEPs). While unconditioned MEPs were unchanged from PRE to POST in CTRL, unconditioned CMEPs increased significantly, resulting in a decrease in unconditioned MEP/CMEP (P < 0.05). This paralleled a reduction in conditioned MEP (P < 0.05) and no change in conditioned CMEP. During FENT, unconditioned and conditioned MEPs and CMEPs were similar and comparable during PRE and POST (P > 0.2). These findings reveal that feedback from group III/IV muscle afferents innervating locomotor muscle decreases the excitability of the motor cortex during fatiguing cycling exercise. This impairment is, at least in part, determined by the facilitating effect of these sensory neurons on inhibitory GABA B intracortical interneurons., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

To examine the impact of aging on neuromuscular fatigue following cycling (CYC; large active muscle mass) and single-leg knee-extension (KE; small active muscle mass) exercise, 8 young (25 ± 4 years) and older (72 ± 6 years) participants performed CYC and KE to task failure at a given relative intensity (80% of peak power output). The young also matched CYC and KE workload and duration of the old (iso-work comparison). Peripheral and central fatigue were quantified via pre-/postexercise decreases in quadriceps twitch torque (∆Q tw , electrical femoral nerve stimulation) and voluntary activation (∆VA). Although young performed 77% and 33% more work during CYC and KE, respectively, time to task failure in both modalities was similar to the old (~9.5 min; P > 0.2). The resulting ΔQ tw was also similar between groups (CYC ~40%, KE ~55%; P > 0.3); however, ∆VA was, in both modalities, approximately double in the young (CYC ~6%, KE ~9%; P < 0.05). While causing substantial peripheral and central fatigue in both exercise modalities in the old, ∆Q tw in the iso-work comparison was not significant (CYC; P = 0.2), or ~50% lower (KE; P < 0.05) in the young, with no central fatigue in either modality ( P > 0.4). Based on iso-work comparisons, healthy aging impairs fatigue resistance during aerobic exercise. Furthermore, comparisons of fatigue following exercise at a given relative intensity mask the age-related difference observed following exercise performed at the same workload. Finally, although active muscle mass has little influence on the age-related difference in the rate of fatigue at a given relative intensity, it substantially impacts the comparison during exercise at a given absolute intensity.

Acetazolamide, a carbonic anhydrase (CA) inhibitor used clinically and to prevent acute mountain sickness, worsens skeletal muscle fatigue in animals and humans. In animals, methazolamide, a methylated analog of acetazolamide and an equally potent CA inhibitor, reportedly exacerbates fatigue less than acetazolamide. Accordingly, we sought to determine, in humans, if methazolamide would attenuate diaphragm and dorsiflexor fatigue compared with acetazolamide. Healthy men (dorsiflexor: n = 12; diaphragm: n = 7) performed fatiguing exercise on three occasions, after ingesting acetazolamide (250 mg three times a day) and then in random order, methazolamide (100 mg twice a day) or placebo for 48 h. For both muscles, subjects exercised at a fixed intensity until exhaustion on acetazolamide, with subsequent iso-time and -workload trials. Diaphragm exercise was performed using a threshold-loading device, while dorsiflexor exercise was isometric. Neuromuscular function was determined pre- and postexercise by potentiated transdiaphragmatic twitch pressure and dorsiflexor torque in response to stimulation of the phrenic and fibular nerve, respectively. Diaphragm contractility 3-10 min postexercise was impaired more for acetazolamide than methazolamide or placebo (82 ± 10, 87 ± 9, and 91 ± 8% of pre-exercise value; P < 0.05). Similarly, dorsiflexor fatigue was greater for acetazolamide than methazolamide (mean twitch torque of 61 ± 11 vs. 57 ± 13% of baseline, P < 0.05). In normoxia, methazolamide leads to less neuromuscular fatigue than acetazolamide, indicating a possible benefit for clinical use or in the prophylaxis of acute mountain sickness. NEW & NOTEWORTHY Acetazolamide, a carbonic anhydrase inhibitor, may worsen diaphragm and locomotor muscle fatigue after exercise; whereas, in animals, methazolamide does not impair diaphragm function. Compared with both methazolamide and the placebo, acetazolamide significantly compromised dorsiflexor function at rest and after exhaustive exercise. Similarly, diaphragm function was most compromised on acetazolamide followed by methazolamide and placebo. Methazolamide may be preferable over acetazolamide for clinical use and altitude illness prophylaxis to avoid skeletal muscle dysfunction.

Key Points: Acute exposure and acclimatization to hypoxia are associated with an impairment and partial recovery, respectively, of the capability of the central nervous system to drive muscles during prolonged efforts. Motoneurones play a vital role in muscle contraction and in fatigue, although the effect of hypoxia on motoneurone excitability during exercise has not been assessed in humans. We studied the impact of fatigue on motoneurone excitability in normoxia, acute and chronic exposure (5050 m) to hypoxia. Performance was worse in acute hypoxia but recovered to the normoxic standard in chronic hypoxia, in parallel with an increased excitability of the motoneurones compared to acute exposure to hypoxia. These findings reveal that prolonged hypoxia causes a heightened motoneurone responsiveness during fatiguing exercise; such an adaptation might favour the restoration of performance where low pressures of oxygen are chronically present., Abstract: The fatigue-induced failure of the motor cortex to drive muscles maximally increases in acute hypoxia (AH) compared to normoxia (N) but improves with acclimatization (chronic hypoxia; CH). Despite their importance to muscle output, it is unknown how locomotor motoneurones in humans are affected by hypoxia and acclimatization. Eleven participants performed 16 min of submaximal [25% maximal torque (maximal voluntary contraction, MVC)] intermittent isometric elbow flexions in N, AH (environmental chamber) and CH (7-14 days at 5050 m) (P I O 2  = 140, 74 and 76 mmHg, respectively). For each minute of the fatigue protocol, motoneurone responsiveness was measured with cervicomedullary stimulation delivered 100 ms after transcranial magnetic stimulation (TMS) used to transiently silence voluntary drive. Every 2 min, cortical voluntary activation (cVA) was measured with TMS. After the task, MVC torque declined more in AH (∼20%) than N and CH (∼11% and 14%, respectively, P < 0.05), with no differences between N and CH. cVA was lower in AH than N and CH at baseline (∼92%, 95% and 95%, respectively) and at the end of the protocol (∼82%, 90% and 90%, P < 0.05). During the fatiguing task, motoneurone excitability in N and AH declined to ∼65% and 40% of the baseline value (P < 0.05). In CH, motoneurone excitability did not decline and, late in the protocol, was ∼40% higher compared to AH (P < 0.05). These novel data reveal that acclimatization to hypoxia leads to a heightened motoneurone responsiveness during fatiguing exercise. Positive spinal and supraspinal adaptations during extended periods at altitude might therefore play a vital role for the restoration of performance after acclimatization to hypoxia., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

Purpose: It is uncertain if sex influences central fatigue because the reduction in voluntary activation (VA) has been reported as not different between the sexes for elbow flexors (EF) but greater in males compared with females for knee extensors. This disparity could result from the facilitatory and inhibitory effects of group III/IV muscle afferents on flexor versus extensor motoneurons, respectively. The purpose of this study was to examine central fatigue and motoneuron responsiveness of EF and elbow extensors (EE) in males and females., Methods: Twenty-two participants (11 females) performed a 2-min isometric maximal voluntary contraction of EF and EE (on separate days) followed by 2 min of recovery. EMG potentials were recorded from biceps or triceps brachii in response to the stimulation of the brachial plexus (Mmax), corticospinal tract (cervicomedullary motor evoked potential [CMEP]), and motor cortex (motor evoked potential [MEP]). Superimposed and resting doublets (for determining VA) were evoked via muscle belly stimulation of biceps or triceps brachii. Only CMEP and superimposed doublets were recorded during fatigue., Results: There was no effect of sex on CMEP area for either muscle group during fatigue or recovery. During the 2 min after EE fatigue, mean normalized CMEP and MEP area were ∼85% and ∼141% of control, indicating inhibition and facilitation of the motoneurons and motor cortex, respectively. VA during recovery was significantly reduced in males but not females for the EF, and unchanged in either sex for the EE., Conclusion: The findings do not support the concept that equivocal findings regarding sex differences in central fatigue are related to augmented effects of group III/IV afferent feedback in males compared with females.

New Findings: What is the central question of this study? Do group III and IV muscle afferents act at the spinal or cortical level to affect the ability of the central nervous system to drive quadriceps muscles during fatiguing exercise? What is the main finding and its importance? The excitability of the motoneurone pool of vastus lateralis was unchanged by feedback from group III and IV muscle afferents. In contrast, feedback from these afferents may contribute to inhibition at the cortex. However, the excitability of the corticospinal pathway was not directly affected by feedback from these afferents. These findings are important for understanding neural processes during fatiguing exercise. In upper limb muscles, changes in afferent feedback, motoneurone excitability, and motor cortical output can contribute to failure of the central nervous system to recruit muscles fully during fatigue. It is not known whether similar changes occur with fatigue of muscles in the lower limb. We assessed the corticospinal pathway to vastus lateralis during fatiguing sustained maximal voluntary contractions (MVCs) of the knee extensors and during firing of fatigue-sensitive group III/IV muscle afferents maintained by postexercise ischaemia after fatiguing MVCs of the knee extensors and, separately, the flexors. In two experiments, subjects (n = 9) performed brief knee extensor MVCs before and after 2-min sustained MVCs of the knee extensors (experiment 1) or knee flexors (experiment 2). During MVCs, motor evoked potentials (MEPs) were elicited by transcranial magnetic stimulation over the motor cortex and thoracic motor evoked potentials (TMEPs) by electrical stimulation over the thoracic spine. During the 2-min extensor contraction, the size of vastus lateralis MEPs normalized to the maximal M-wave increased (P < 0.05), but normalized TMEPs were unchanged (P = 0.16). After the 2-min MVC, maintained firing of group III/IV muscle afferents had no effect on vastus lateralis MEPs or TMEPs (P = 0.18 and P = 0.50, respectively). Likewise, after the 2-min knee flexor MVC, maintained firing of these afferents showed no effect on vastus lateralis MEPs or TMEPs (P = 0.69 and P = 0.34, respectively). Motoneurones of vastus lateralis do not become less excitable during fatiguing isometric MVCs. Moreover, fatigue-sensitive group III/IV muscle afferents fail to affect the overall excitability of vastus lateralis motoneurones during MVCs., (© 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.)

This study determined whether short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) change during a sustained submaximal isometric contraction. On 2 days, 12 participants (6 men, 6 women) performed brief (7-s) elbow flexor contractions before and after a 10-min fatiguing contraction; all contractions were performed at the level of integrated electromyographic activity (EMG) which produced 25 % maximal unfatigued torque. During the brief 7-s and 10-min submaximal contractions, single (test) and paired (conditioning-test) transcranial magnetic stimuli were applied over the motor cortex (5 s apart) to elicit motor-evoked potentials (MEPs) in biceps brachii. SICI and ICF were elicited on separate days, with a conditioning-test interstimulus interval of 2.5 and 15 ms, respectively. On both days, integrated EMG remained constant while torque fell during the sustained contraction by ~51.5 % from control contractions, perceived effort increased threefold, and MVC declined by 21-22 %. For SICI, the conditioned MEP during control contractions (74.1 ± 2.5 % of unconditioned MEP) increased (less inhibition) during the sustained contraction (last 2.5 min: 86.0 ± 5.1 %; P < 0.05). It remained elevated in recovery contractions at 2 min (82.0 ± 3.8 %; P < 0.05) and returned toward control at 7-min recovery (76.3 ± 3.2 %). ICF during control contractions (conditioned MEP 129.7 ± 4.8 % of unconditioned MEP) decreased (less facilitation) during the sustained contraction (last 2.5 min: 107.6 ± 6.8 %; P < 0.05) and recovered to 122.8 ± 4.3 % during contractions after 2 min of recovery. Both intracortical inhibitory and facilitatory circuits become less excitable with fatigue when assessed during voluntary activity, but their different time courses of recovery suggest different mechanisms for the fatigue-related changes of SICI and ICF.

With fatiguing exercise, firing of group III/IV muscle afferents reduces voluntary activation and force of the exercised muscles. These afferents can also act across agonist/antagonist pairs, reducing voluntary activation and force in nonfatigued muscles. We hypothesized that maintained firing of group III/IV muscle afferents after a fatiguing adductor pollicis (AP) contraction would decrease voluntary activation and force of AP and ipsilateral elbow flexors. In two experiments (n = 10) we examined voluntary activation of AP and elbow flexors by measuring changes in superimposed twitches evoked by ulnar nerve stimulation and transcranial magnetic stimulation of the motor cortex, respectively. Inflation of a sphygmomanometer cuff after a 2-min AP maximal voluntary contraction (MVC) blocked circulation of the hand for 2 min and maintained firing of group III/IV muscle afferents. After a 2-min AP MVC, maximal AP voluntary activation was lower with than without ischemia (56.2 ± 17.7% vs. 76.3 ± 14.6%; mean ± SD; P < 0.05) as was force (40.3 ± 12.8% vs. 57.1 ± 13.8% peak MVC; P < 0.05). Likewise, after a 2-min AP MVC, elbow flexion voluntary activation was lower with than without ischemia (88.3 ± 7.5% vs. 93.6 ± 3.9%; P < 0.05) as was torque (80.2 ± 4.6% vs. 86.6 ± 1.0% peak MVC; P < 0.05). Pain during ischemia was reported as Moderate to Very Strong. Postfatigue firing of group III/IV muscle afferents from the hand decreased voluntary drive and force of AP. Moreover, this effect decreased voluntary drive and torque of proximal unfatigued muscles, the elbow flexors. Fatigue-sensitive group III/IV muscle nociceptors act to limit voluntary drive not only to fatigued muscles but also to unfatigued muscles within the same limb.

Data are equivocal on whether voluntary activation is preserved or decreased in old compared to young adults. Further, data are scant on the effect of age on the rate of muscle relaxation when the muscle is contracting voluntarily. Assessment of both measures with transcranial magnetic stimulation (TMS) yields information which cannot be obtained with traditional peripheral nerve stimulation. Hence, voluntary activation and peak relaxation rate of the elbow flexors were assessed with TMS during repeated maximal efforts in 30 men and 28 women between the ages of 22-84 years. Voluntary activation was similar for the two sexes (P = 0.154) and was not affected by age in men (96.2 ± 2.7 %; P = 0.887) or women (95.1 ± 3.0 %; P = 0.546). Men had a significantly faster peak rate of relaxation than women in absolute units (-880.0 ± 223.2 vs. -360.2 ± 78.5 Nm/ s, respectively; P < 0.001) and when normalized to subject strength (-12.5 ± 2.1 vs. -8.7 ± 1.0 s(-1), respectively; P < 0.001). Absolute and normalized relaxation rates slowed with age in men (P = 0.002 and P = 0.006, respectively), but not women (P = 0.142 and P = 0.950, respectively). Across the age range studied, all subjects, regardless of age or sex, were able to achieve high voluntary activation scores for the elbow flexors (~95 %). In contrast, peak relaxation rate was markedly faster in men than women and slowed with age in men but not women. Normalization of relaxation rates to strength did not affect the influence of age or sex.

During muscle fatigue, firing of small-diameter muscle afferents can decrease voluntary activation of the fatigued muscle. However, these afferents may have a more widespread effect on other muscles in the exercising limb. We examined if the firing of fatigue-sensitive afferents from elbow extensor muscles in the same arm reduces torque production and voluntary activation of elbow flexors. In nine subjects we examined voluntary activation of elbow flexors by measuring changes in superimposed twitches evoked by transcranial magnetic stimulation of the motor cortex during brief (2-3 s) maximal voluntary contractions (MVC). Inflation of a blood pressure cuff following a 2-min sustained MVC blocked blood flow to the fatigued muscle and maintained firing of small-diameter afferents. After a fatiguing elbow flexion contraction, maximal flexion torque was lower (26.0 ± 4.4% versus 67.9 ± 5.2% of initial maximal torque; means ± s.d.; P < 0.001) and superimposed twitches were larger (4.1 ± 1.1% versus 1.8 ± 0.2% ongoing MVC, P = 0.01) with than without ischaemia. After a fatiguing elbow extensor contraction, maximal flexion torque was also reduced (82.2 ± 4.9% versus 91.4 ± 2.3% of initial maximal torque; P = 0.007), superimposed twitches were larger (2.7 ± 0.7% versus 1.3 ± 0.2% ongoing MVC; P = 0.02) and voluntary activation lower (81.6 ± 8.2% versus 95.5 ± 6.9%; P = 0.04) with than without ischaemia. After a fatiguing contraction, voluntary drive to the fatigued muscles is reduced with continued input from small-diameter muscle afferents. Furthermore, fatigue of the elbow extensor muscles decreases voluntary drive to unfatigued elbow flexors of the same arm. Therefore, firing of small-diameter muscle afferents from one muscle can affect voluntary activation and hence torque generation of another muscle in the same limb.

The assessment of voluntary activation of human muscles usually depends on measurement of the size of the twitch produced by an interpolated nerve or cortical stimulus. In many forms of fatiguing exercise the superimposed twitch increases and thus voluntary activation appears to decline. This is termed 'central' fatigue. Recent studies on isolated mouse muscle suggest that a peripheral mechanism related to intracellular calcium sensitivity increases interpolated twitches. To test whether this problem developed with human voluntary contractions we delivered maximal tetanic stimulation to the ulnar nerve (≥60 s at physiological motoneuronal frequencies, 30 and 15 Hz). During the tetani (at 30 Hz) in which the force declined by 42%, the absolute size of the twitches evoked by interpolated stimuli (delivered regularly or only in the last second of the tetanus) diminished progressively to less than 1%. With stimulation at 30 Hz, there was also a marked reduction in size and area of the interpolated compound muscle action potential (M wave). With a 15 Hz tetanus, a progressive decline in the interpolated twitch force also occurred (to ∼10%) but did so before the area of the interpolated M wave diminished. These results indicate that the increase in interpolated twitch size predicted from the mouse studies does not occur. Diminution in superimposed twitches occurred whether or not the M wave indicated marked impairment at sarcolemmal/t-tubular levels. Consequently, the increase in superimposed twitch, which is used to denote central fatigue in human fatiguing exercise, is likely to reflect low volitional drive to high-threshold motor units, which stop firing or are discharging at low frequencies.

Motoneurone excitability is rapidly and profoundly reduced during a sustained maximal voluntary contraction (MVC) when tested in the transient silent period which follows transcranial magnetic stimulation (TMS) of the motor cortex. One possible cause of this reduction in excitability is a fatigue-induced withdrawal of excitatory input to motoneurones from muscle spindle afferents. We aimed to test if muscle spindle input produced by tendon vibration would ameliorate suppression of the cervicomedullary motor-evoked potential (CMEP) in the silent period during a sustained MVC. Seven subjects performed a 2 min MVC of the elbow flexors. Stimulation of the corticospinal tract at the level of the mastoids was preceded 100 ms earlier by TMS. These stimulus pairs were delivered every 10 s during the 2 min MVC. Stimulus pairs at 30, 50, 70, 90 and 110 s were delivered while vibration (-80 Hz) was applied to the distal tendon of biceps. On a separate day, the protocol was repeated with both stimuli delivered to the motor cortex. The CMEP in the silent period decreased rapidly with fatigue (to -9% of control) and was not affected by tendon vibration (P = 0.766). The motor-evoked potential in the silent period also declined rapidly (to -5% of control) and was similarly unaffected by tendon vibration (P = 0.075). These data suggest motoneurone disfacilitation due to a fatigue-related decrease of muscle spindle discharge does not contribute significantly to the profound suppression of motoneurone excitability during the silent period. Therefore, a change to intrinsic motoneurone properties caused by repetitive discharge is most probably responsible.

During fatigue caused by a sustained maximal voluntary contraction (MVC), motoneurones become markedly less responsive when tested during the silent period following transcranial magnetic stimulation (TMS). To determine whether this reduction depends on the repetitive activation of the motoneurones, responses to TMS (motor evoked potentials, MEPs) and to cervicomedullary stimulation (cervicomedullary motor evoked potentials, CMEPs) were tested during a sustained submaximal contraction at a constant level of electromyographic activity (EMG). In such a contraction, some motoneurones are repetitively activated whereas others are not active. On four visits, eight subjects performed a 10 min maintained-EMG elbow flexor contraction of 25% maximum. Test stimuli were delivered with and without conditioning by TMS given 100 ms prior. Test responses were MEPs or CMEPs (two visits each, small responses evoked by weak stimuli on one visit and large responses on the other). During the sustained contraction, unconditioned CMEPs decreased ∼20% whereas conditioned CMEPs decreased ∼75 and 30% with weak and strong stimuli, respectively. Conditioned MEPs were reduced to the same extent as CMEPs of the same size. The data reveal a novel decrease in motoneurone excitability during a submaximal contraction if EMG is maintained. Further, the much greater reduction of conditioned than unconditioned CMEPs shows the critical influence of voluntary drive on motoneurone responsiveness. Strong test stimuli attenuate the reduction of conditioned CMEPs which indicates that low-threshold motoneurones active in the contraction are most affected. The equivalent reduction of conditioned MEPs and CMEPs suggests that, similar to findings with a sustained MVC, impaired motoneurone responsiveness rather than intracortical inhibition is responsible for the fatigue-related impairment of the MEP during a sustained submaximal contraction.

During maximal exercise, supraspinal fatigue contributes significantly to the decline in muscle performance but little is known about intracortical inhibition during such contractions. Long-interval inhibition is produced by a conditioning motor cortical stimulus delivered via transcranial magnetic stimulation (TMS) 50-200 ms prior to a second test stimulus. We aimed to delineate changes in this inhibition during a sustained maximal voluntary contraction (MVC). Eight subjects performed a 2 min MVC of elbow flexors. Single test and paired (conditioning-test interval of 100 ms) stimuli were delivered via TMS over the motor cortex every 7-8 s throughout the effort and during intermittent MVCs in the recovery period. To determine the role of spinal mechanisms, the protocol was repeated but the TMS test stimulus was replaced by cervicomedullary stimulation which activates the corticospinal tract. TMS motor evoked potentials (MEPs) and cervicomedullary motor evoked potentials (CMEPs) were recorded from biceps brachii. Unconditioned MEPs increased progressively with fatigue, whereas CMEPs increased initially but returned to the control value in the final 40 s of contraction. In contrast, both conditioned MEPs and CMEPs decreased rapidly with fatigue and were virtually abolished within 30 s. In recovery, unconditioned responses required <30 s but conditioned MEPs and CMEPs required 90 s to return to control levels. Thus, long-interval inhibition increased markedly as fatigue progressed. Contrary to expectations, subcortically evoked CMEPs were inhibited as much as MEPs. This new phenomenon was also observed in the first dorsal interosseous muscle. Tested with a high intensity conditioning stimulus during a fatiguing maximal effort, long-interval inhibition of MEPs was increased primarily by spinal rather than motor cortical mechanisms. The spinal mechanisms exposed here may contribute to the development of central fatigue in human muscles.

Background: Muscle power is more relevant to the activities of daily living than is isometric strength. However, dynamic contractions have received little attention as they relate to the effect of age on muscle fatigue, particularly in very old persons. Thus, the purpose of this study was to investigate fatigue of the dorsiflexors during a velocity-dependent (isotonic) power task in 12 young (26 years), 12 old (64 years), and 12 very old (84 years) men., Methods: The fatigue protocol involved 25 maximal (as fast as possible) contractions at a load of 20% maximum isometric strength through a 25 degrees range of motion. Electromyographic signals of the tibialis anterior and soleus muscles were recorded to assess agonist activation and antagonist coactivation, respectively., Results: Fatigability increased progressively with age as muscle power decreased by 13% in young men, 19% in old men, and 24% in very old men. In contrast, agonist activation and antagonist coactivation were unaffected by age. During the fatigue protocol, agonist activity decreased by 3%, 5%, and 4%, whereas antagonist activity increased by 11%, 13%, and 13% in young, old, and very old men, respectively., Conclusion: These results demonstrate that older adults are more fatigable than young adults during a velocity-dependent power task. This finding is in contrast to the majority of fatigue data previously reported from less functionally relevant isometric or isokinetic tasks.

The purpose of this study was to compare fatigue and recovery of maximal voluntary torque [maximal voluntary contraction (MVC)] and muscle oxygenation after voluntary (Vol) and electrically stimulated (ES) protocols of equal torque production. On 1 day, 10 male subjects [25 yr (SD 4)] completed a Vol fatigue protocol and, on a separate day, an ES fatigue protocol of the right dorsiflexors. Each task involved 2 min of intermittent (2-s on, 1-s off) isometric contractions at 50% of MVC. For the ES protocol, stimulation was delivered percutaneously to the common peroneal nerve at a frequency of 25 Hz. Compared with the Vol protocol, the ES protocol caused a greater impairment in MVC (75 vs. 83% prefatigue value; Pre) and greater increase in 50-Hz half relaxation time (165 vs. 117% Pre) postexercise. After acute (1 min) recovery, MVC impairment was similar for both protocols, whereas 50- Hz half relaxation time was still greater in the ES than Vol protocol. Total hemoglobin decreased to a similar extent in both protocols during exercise, but it was elevated above the resting value to a significantly greater extent for the ES protocol in recovery (18 vs. 11 microM). Oxygen saturation was significantly lower in the ES than Vol protocol during exercise (46 vs. 57% Pre), but it was significantly greater during recovery (120 vs. 105% Pre). These findings suggest that despite, equal torque production, ES contractions impose a greater metabolic demand on the muscle that leads to a transient greater impairment in MVC. The enforced synchronization and fixed frequency of excitation inherent to ES are the most likely causes for the exacerbated changes in the ES compared with the Vol protocol.

The influence of different work-to-rest (W:R) ratios during fatigue induced by maximal eccentric contractions is unknown. The present study sought to expand the understanding of the task-dependent nature of eccentric contractions, and the associated fatigue, during exercise and acute as well as extended recovery periods. Using a Biodex multi-joint dynamometer, the ankle dorsiflexors of eight men [26 (4) years] were fatigued with 150 maximal eccentric contractions. Set structure was manipulated such that one leg performed 3 sets of 50 repetitions (short rest protocol, SRP), and the other leg performed 15 sets of 10 repetitions (long rest protocol, LRP). A 1-min rest interval separated each set, which resulted in 2 and 14 min of total rest for the SRP and the LRP, respectively. At fatigue, the SRP demonstrated a marginally greater loss of average peak eccentric torque than the LRP ( P<0.05). In the acute period following fatigue, isometric peak torque loss and the degree of low-frequency fatigue (LFF) were not recovered ( P<0.05) and were equivalent for both protocols. Significant impairment of both eccentric and isometric torque was persistent and equal for each protocol at 96 h of recovery ( P<0.05). These findings suggest that the W:R ratio has a modest influence on the fatigue (torque loss) induced by maximal eccentric contractions, but maximal isometric torque during recovery and LFF are insensitive to changes in total rest time.