Sex differences in human fatigability: mechanisms and insight to physiological responses

Performance fatigability differs between men and women for a range of fatiguing tasks. Women are usually less fatigable than men, and this is most widely described for isometric fatiguing contractions and some dynamic tasks. The sex difference in fatigability is specific to the task demands so that one mechanism is not universal, including any sex differences in skeletal muscle physiology, muscle perfusion, and voluntary activation. However, there are substantial knowledge gaps about the task dependency of the sex differences in fatigability, the involved mechanisms, and the relevance to clinical populations and with advanced age. The knowledge gaps are in part due to the significant deficits in the number of women included in performance fatigability studies despite a gradual increase in the inclusion of women for the last 20 yr. Therefore, this review 1) provides a rationale for the limited knowledge about sex differences in performance fatigability, 2) summarizes the current knowledge on sex differences in fatigability and the potential mechanisms across a range of tasks, 3) highlights emerging areas of opportunity in clinical populations, and 4) suggests strategies to close the knowledge gap and understanding the relevance of sex differences in performance fatigability. The limited understanding about sex differences in fatigability in healthy and clinical populations presents as a field ripe with opportunity for high-impact studies. Such studies will inform on the limitations of men and women during athletic endeavors, ergonomic tasks, and daily activities. Because fatigability is required for effective neuromuscular adaptation, sex differences in fatigability studies will also inform on optimal strategies for training and rehabilitation in both men and women.

Several studies have shown that women can present with greater muscle endurance (less fatigability) compared with men ([3][1], [5][2], [10][3], [12][4]), although this is not always the case ([4][5], [8][6]). Most of these studies have focused on peripheral physiological mechanisms, mostly those

Contraction intensity and sex differences in knee-extensor fatigability

Females demonstrate greater fatigue resistance than males during contractions at intensities relative to maximum force. However, previous studies have not accounted for the influence of metabolic thresholds on fatigability. This study is the first to test whether sex differences in fatigability exist when exercise intensity is normalised relative to a metabolic threshold: the critical intensity derived from assessment of the intensity-duration relationship during intermittent, isometric knee extensor contractions. We show that critical intensity in females occurred at a higher percentage of maximum force compared to males. Furthermore, females demonstrated greater fatigue resistance at exercise intensities above and below this metabolic threshold. Our data suggest that the sex difference was mediated by lesser deoxygenation of the knee extensors during exercise. These data highlight the importance of accounting for metabolic thresholds when comparing fatigability between sexes, whilst emphasising the notion that male data are not generalisable to female populations. Females are less fatigable than males during isometric exercise at intensities relative to maximal voluntary contraction (MVC); however, whether a sex difference in fatigability exists when exercise is prescribed relative to a critical intensity is unknown. This study established the intensity-duration relationship, and compared fatigability and recovery between sexes following intermittent isometric contractions normalised to critical intensity. Twenty participants (10females) completed four intermittent isometric knee extension trials to task failure to determine critical intensity and the curvature constant (W'), followed by fatiguing tasks at +10% and -10% relative to critical intensity. Neuromuscular assessments were completed at baseline and for 45min post-exercise. Non-invasive neurostimulation, near-infrared spectroscopy, and non-invasive haemodynamic monitoring were used to elucidate the physiological mechanisms responsible for sex differences. Females demonstrated a greater critical intensity relative to MVC than males (25 ± 3 vs. 21 ± 2% MVC, P=0.003), with no sex difference for W' (18,206 ± 6331 vs. 18,756 ± 5762Ns, P=0.850). Time to task failure was greater for females (62.37 ± 17.25 vs. 30.43 ± 12.75min, P<0.001) during the +10% trial, and contractile function recovered faster post-exercise (P=0.034). During the -10% trial females experienced less contractile dysfunction (P=0.011). Throughout the +10% trial, females demonstrated lesser decreases in deoxyhaemoglobin (P=0.007) and an attenuated exercise pressor reflex. These data show that a sex difference in fatigability exists even when exercise is matched for critical intensity. We propose that greater oxygen availability during exercise permits females to sustain a higher relative intensity than males, and is an explanatory factor for the sex difference in fatigability during intermittent, isometric contractions.

ABSTRACTObjectives:With a relatively high percentage of type I fibers in the vastus medialis (VM), itsfatigability may be more sensitive to the effects of muscle activity in the quadriceps.However, sex-related differences in the muscle fatigability of the VM remain unknown.The purpose of the present study was to assess the differences in fatigability of the VMbetween healthy adult men and women.Methods:Surface electromyographic (EMG) activities of VM oblique (VMO) and VM long (VML) wererecorded during sustained isometric contraction on a leg press machine. The results ofEMG power spectral analysis were compared between healthy adult men and women. Thedecline in the median frequency (MF), defined as MF slope, was calculated using spectrumanalysis after fast Fourier transform of the raw EMG signals of VMO and VML.Results:The endurance time and the MF slopes of the VMO and VML were significantly longer andlower, respectively, in women than in men. The present results demonstrated that bothVMO and VML are more fatigue-resistant in women than in men.Conclusions:Understanding the sex differences in fatigability could help to design more effectiveexercise regimens for VMO and VML in healthy individuals. A similar approach should beconsidered when prescribing practical exercise regimens for patients with muscleatrophy.

Females demonstrate greater fatigue resistance compared to males in tasks ranging from single-limb contractions to whole-body exercise, including running. Many of the studies investigating sex differences in fatigability following running, however, occur after long duration, low-intensity tasks and it is unknown whether there is a sex difference in fatigability following high-intensity running. This study compared fatigability and recovery following a 5 km running time trial in young males and females. Sixteen recreationally active participants (8 males, 8 females, age: 23 ± 4 years) completed a familiarisation and experimental trial. Knee-extensor maximal voluntary contractions (MVCs) were performed before and up to 30 min after a 5 km time trial on a treadmill. Heart rate and rating of perceived exertion (RPE) were recorded after every kilometre during the time trial. Although not significantly different, males completed the 5 km time trial 15% faster than females (p = 0.095). Heart rate (p = 0.843) and RPE (p = 0.784) were similar between the sexes during the trial. Prior to running, males had larger MVCs (p = 0.014). The relative decrease in MVC force was less in females than males immediately post-exercise (−4.6 ± 2.4% vs. −15.1 ± 3.0%, p < 0.001) and at 10-minutes post-exercise (p = 0.018). At 20- and 30-minutes recovery, however, relative MVC force was not different between the sexes (p ≥ 0.129). These data demonstrate that females experienced less fatigability of the knee extensors than males following a high-intensity 5 km running time trial. The findings highlight the need to understand responses to exercise in both sexes and have implications for recovery from training and exercise prescription. Highlights Data regarding sex differences in fatigability following high-intensity running is relatively sparse. Therefore, this study quantified the decrease in knee-extensor maximum voluntary contraction force (MVC) following a 5-km self-paced running time trial. Despite similar heart rates and ratings of perceived exertion, the percentage decrease in MVC was three times greater in males compared to females. Relative MVCs remained greater in females compared to males until 20 min post-exercise.

What is the topic of this review? Women are usually less fatigable than men for isometric fatiguing contractions of similar intensity, but whether this occurs for dynamic tasks is less clear. This review presents evidence that the sex difference in muscle fatigue of repeated dynamic contractions is specific to the task requirements, including the velocity of shortening and the muscle group involved. What advances does it highlight? Contractile mechanisms are responsible for the sex differences in muscle fatigue for slow-velocity and low-load dynamic tasks. The variability of the sex difference in fatigability among dynamic tasks has implications for fatiguing contractions prescribed in training and rehabilitation to men and women. Women are usually less fatigable than men during single-limb isometric contractions, primarily because of sex-related differences in contractile mechanisms. It is less clear whether these sex differences in muscle fatigue occur for dynamic fatiguing tasks. This review highlights new findings that the sex difference in fatigability for dynamic shortening contractions with a single limb is dependent on the contraction velocity and the muscle group involved. Recent studies demonstrate that women are less fatigable than men for a dynamic task as follows: (i) the elbow-flexor muscles at slow- but not high-velocity contractions; and (ii) the knee-extensor muscles when muscle fatigue was quantified as a reduction in the maximal voluntary isometric contraction force after the dynamic fatiguing task. Contractile mechanisms are responsible for the sex difference in muscle fatigue of the dynamic contractions, with no evidence for a sex difference in the reduction in voluntary activation (i.e. central fatigue). Thus, these findings indicate that the sex difference in muscle fatigue of dynamic contractions is task specific. These data also challenge the assumption that men and women respond in a similar manner to training and rehabilitation that involve fatiguing contractions to overload the neuromuscular system. There is, however, a tremendous opportunity for conducting high-impact studies to gain insight into those factors that define the sex-based differences in muscle fatigue during dynamic tasks. Such studies can define the boundaries to human performance in both men and women during athletic endeavours, ergonomic tasks and rehabilitation.

No sex differences in fatigability or neuromuscular responses during one set of maximal intended velocity muscle actions to failure at 30 % one-repetition maximum

Exercise-induced neuromuscular fatigue is well known for being specific. This specificity, which determines both the magnitude and aetiology of fatigue, includes multiple parameters such as the nature of the task (i.e. contraction mode, muscle mass involved), the intensity–duration of the task, but also individual characteristics such as the participants’ sex (Hunter, 2016). However, similarly to other research areas, sex differences in neuromuscular fatigue are still under-investigated (Hunter, 2016). In a recent article published in The Journal of Physiology, Ansdell and colleagues aimed to clarify the sex differences in fatigue during whole-body exercise (Ansdell et al. 2020a). A classic question when comparing independent groups in exercise physiology is the methodological approach to normalize exercise intensity. One approach is to use an absolute exercise intensity (e.g. 100 W on a cycle ergometer), which is particularly relevant for clinical outcomes since daily living activities such as climbing stairs or doing grocery shopping are driven by the environment and are not relative to the individual's maximal capacity. Alternatively, or additionally, relative intensity is often utilized to match the exercise demands between groups, which also provides important mechanistic insights. In this context, exercise intensity can be relative to the maximal voluntary contraction force (% of MVC) or the maximal oxygen uptake (% of ), for single-joint or whole-body exercise modalities, respectively. If this normalization is insightful, it is not devoid of confounding factors when comparing males and females. Indeed, in this scenario (matching exercise at a specific percentage of ), metabolic thresholds are neglected and the metabolic rate can be drastically different between individuals. As a result, males and females could experience substantial differences in time to task failure, which would be a serious limitation as the intensity and duration of the exercise task are known to influence the magnitude and aetiology of neuromuscular fatigue (Ducrocq et al. 2021). In order to circumvent this limitation, Ansdell et al. (2020a) normalized exercise intensity to critical power, a metabolic threshold derived from the power–time relationship, with the intention to match the metabolic rate between males and females. The power–time relationship for high-intensity exercise is well known to be hyperbolic and generalizable to multiple exercise modalities in humans and other species. The critical power is mathematically defined as the asymptote of this hyperbola, while the curvature constant (W′) represents a fixed amount of work that can be performed above critical power before reaching exhaustion. Importantly, critical power delineates the heavy and severe intensity domains of exercise, characterized by distinct rates of metabolism and fatigue (Burnley & Jones, 2018). Indeed, critical power represents the highest intensity with a steady state, i.e. without a progressive loss of homeostasis. Therefore, and intramuscular metabolites fail to stabilize above the critical power. Given the tight relationship between intramuscular metabolic perturbation and peripheral fatigue, it is not surprising to observe drastic differences in fatigue development in the severe compared to the heavy intensity domain (Burnley & Jones, 2018). In their investigation, Ansdell et al. (2020a) aimed to clarify the sex differences in fatigue during exercise in both the heavy (90% of critical power) and the severe (110% of critical power) intensity domain. Critical power was similar between males and females when expressed in relative units (% of maximal power), leading to no sex difference in time to task failure for both the heavy and the severe exercises. In this context, peripheral fatigue, assessed by supramaximal electrical stimulation over the femoral nerve, was about 50% lower in females compared to males at task failure. Interestingly, this sex difference in peripheral fatigue persisted independently of the exercise intensity domain (severe: males ∼2.9% min−1 vs females ∼1.3% min−1; heavy: males ∼0.5% min−1 vs females ∼0.2% min−1). From this observation, females appear to be less fatigable than males, which is consistent with previous investigations matching exercise intensity at a defined percentage of maximal force or power between sexes (Hunter, 2016). Mechanisms to explain this sex difference include less locomotor muscle deoxygenation and contractile impairment in females, potentially related to discrepancies in skeletal muscle size and composition between males and females. However, it is important to note that males produced considerably more work than females in both exercise conditions. In fact, critical power and W′ were both ∼30% lower in females compared to males. Given the relationship between W′ and peripheral fatigue, one could hypothesize that the sex differences in fatigability are driven by the total work performed. Interestingly, when peripheral fatigue was normalized to W′, the sex differences were cancelled. In other words, females developed less neuromuscular fatigue because they performed less work, likely due to a smaller skeletal muscle mass. It seems therefore questionable to characterize females as ‘more fatigue-resistant’. Indeed, this (common) terminology seems quite illogical. Females would resist to a negative phenomenon for performance (i.e. acute fatigue), which should lead, in fine, to a positive outcome for performance. In contrast, the opposite is observed, with a lower exercise capacity for females compared to males. This is why describing females as ‘more fatigue-resistant’ might not be an appropriate terminology in this context, similarly to what was suggested previously for ageing (Zarzissi et al. 2020). The ‘greater fatigue-resistance’ terminology should describe individuals combining less fatigue development associated to a better, or at least preserved, exercise performance compared to their counterparts, such as what was documented in elite compared to recreationally trained cyclists (Ducrocq et al. 2021). Regardless, from an integrative perspective, Ansdell et al. (2020a) describe substantial sex differences in the relative contribution of several muscle groups in task failure during whole-body exercise. The concept of a sensory tolerance limit suggests that the sum of all feedback and feedforward signals is processed within the CNS and ultimately regulates the intensity of exercise to ensure that voluntary activity remains tolerable (self-paced exercise) or determines task failure (constant-load exercise) (Hureau et al. 2018). Therefore, as speculated by Ansdell et al. (2020b), with less metabolic perturbation in locomotor muscles but heightened work of breathing and dyspnoea, the sensory tolerance limit was likely reached with lower firing of afferent feedback from locomotor muscles but greater firing from respiratory muscles, in females compared to males (Ansdell et al. 2020b). Using an integrative physiological approach during exercise normalized to critical power, the study performed by Ansdell et al. (2020a) provides new mechanistic insights into the sex differences in fatigability. While it is methodologically impossible to match simultaneously all physiological characteristics dissociating males and females that influence exercise-induced neuromuscular fatigue, their study provides a major contribution that advances the field by matching exercise intensity between sex groups to critical power. This investigation highlights perfectly the need to investigate through different normalization paradigms exercise intensity of independent groups for a comprehensive understanding. As suggested by the authors, future studies normalizing exercise to fat-free mass might be interesting to circumvent the effect of muscle mass on sex and provide further insights into the fatigue-related sex differences. While neuromuscular fatigue might be an important acute stimulus for chronic adaptations to training, and considering that females developed 50% less fatigue than males, it is currently unclear if females would also get only 50% of the adaptations for a given training load (Ansdell et al. 2020b). In our opinion, this is a very important question that might be highly impactful for training and rehabilitation programmes. As exercise physiologists working with athletes and disease populations from both sexes, we are looking forward to investigations researching this topic. No competing interests declared. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None. Due to Journal imposed reference limits, we apologize for not citing all relevant articles. We thank all attendees of The Journal of Physiology’s Virtual Journal Club as well as the focus article authors Dr Kirsty Hicks and Dr Paul Ansdell (panellists) for their participation and the interesting discussions resulting from this scientific meeting.

Eccentric exercise-induced muscle weakness abolishes sex differences in fatigability during sustained submaximal isometric contractions

Women have been shown to experience less neuromuscular fatigue than men in knee extensors (KE) and less peripheral fatigue in plantar flexors (PF) after ultratrail running, but it is unknown if these differences exist for shorter trail running races and whether this may impact running economy. The purpose of this study was to characterize sex differences in fatigability over a range of running distances and to examine possible differences in the postrace alteration of the cost of running (Cr). Eighteen pairs of men and women were matched by performance after completing different races ranging from 40 to 171 km, divided into SHORT versus LONG races (<60 and >100 km, respectively). Neuromuscular function and Cr were tested before and after each race. Neuromuscular function was evaluated on both KE and PF with voluntary and evoked contractions using electrical nerve (KE and PF) and transcranial magnetic (KE) stimulation. Oxygen uptake, respiratory exchange ratio, and ventilation were measured on a treadmill and used to calculate Cr. Compared with men, women displayed a smaller decrease in maximal strength in KE (-36% vs -27%, respectively, P < 0.01), independent of race distance. In SHORT only, women displayed less peripheral fatigue in PF compared with men (Δ peak twitch: -10% vs -24%, respectively, P < 0.05). Cr increased similarly in men and women. Women experience less neuromuscular fatigue than men after both "classic" and "extreme" prolonged running exercises but this does not impact the degradation of the energy Cr.

This study investigated whether the sex difference in fatigability of the knee extensors (KE) is explained by the sex difference in fatigue-induced changes in the shear modulus of one or more muscles of KE in 18 young men and 23 young women. The shear moduli of the resting rectus femoris and medial and lateral vastus muscles (VL) were measured before and after a sustained contraction at 20% peak torque during a maximal voluntary isometric contraction of KE until the endurance limit, in addition to evoked torque and voluntary activation (VA%). The fatigue-induced decrease in maximal muscle strength was more prominent in men than in women. Only the VL shear modulus for men increased after the fatiguing task, and a sex difference was observed in the percentage change in the VL shear modulus before and after the fatiguing task. The fatigue-induced decreased ratio was greater for men than for women in evoked torque, but not in VA%. These results suggest that although peripheral and central fatigue both influenced the fatigue-induced decrease in maximal muscle strength regardless of sex, the sex difference in KE fatigability is explained by that in peripheral fatigue, particularly the degree of peripheral VL fatigue.

Objective.This study examined sex-related differences in fatigability and neuromuscular responses using surface electromyographic (sEMG) and mechanomyographic (sMMG) amplitude (AMP) and frequency (MPF) during fatiguing, maximal, bilateral isometric leg extensions.Approach.Twenty recreationally active males and females with resistance training experience performed continuous, maximal effort, bilateral isometric leg extensions until their force reduced by 50%. Linear mixed effect models analyzed patterns of force, sEMG, and sMMG AMP and MPF responses in the dominant limb. An independent samples t-test compared time-to-task failure (TTF) between sexes.Main Results.There were no significant differences in TTF between males and females. However, males experienced a greater rate of force loss compared to females. Furthermore, sEMG AMP and MPF and sMMG AMP responses followed similar linear trends for both sexes, while sMMG MPF showed non-linear responses with sex-dependent differences.Significance.These data suggest that although TTF was similar, males had a higher rate of force reduction, likely due to greater absolute strength. Furthermore, despite parallel changes in sEMG AMP and MPF, as well as sMMG AMP, the divergent responses observed in sMMG MPF highlight sex-dependent differences in how males and females experience changes in the firing rates of active motor units during sustained maximal contractions.

Objectives:Females tend to fatigue less than males after isometric exercise, but less is clear for isotonic exercise. Further, there have been relatively few sex comparisons for fatigability of the plantar flexors (PFs). We sought to investigate potential sex differences in contractile properties after a sustained maximal voluntary isometric contraction (MVIC) and isotonic contractions.Methods:Twenty-seven physically active males (n=14; 22±2 yrs) and females (n=13; 21±2 yrs) randomly performed a 2 min MVIC and 120 concentric isotonic (30% MVIC) contractions for the PFs on separate visits. Before and after each fatiguing task, muscle activation was obtained from brief MVICs, which was followed (~2 sec) by tibial nerve stimulation at rest. Contractile properties including peak twitch, absolute and normalized time to peak twitch, and half relaxation time were calculated.Results:No sex differences existed for fatigue-induced changes in muscle activation (p=0.09-0.41; d=0.33-0.69) or contractile properties (p=0.19-0.96; d=0.06-0.94).Conclusions:Peripheral fatigue, as indicated by contractile parameters, did not differ between sexes after isometric or isotonic exercise. The PFs similar fiber type proportions between sexes or greater fiber type heterogeneity may explain why sex differences in fatigability, though common in other muscle groups (e.g., knee extensors), were not expressed in this muscle group.

Knee-extensors demonstrate greater fatigue resistance in females compared to males during single-limb and whole-body exercise. For single-limb exercise, the intensity-duration relationship is different between sexes, with females sustaining a greater relative intensity of exercise. This study established the power-duration relationship during cycling, then assessed fatigability during critical power-matched exercise within the heavy and severe intensity domains. When critical power and the curvature constant were expressed relative to maximal ramp test power, no sex difference was observed. No sex difference in time to task failure was observed in either trial. During heavy and severe intensity cycling, females experienced lesser muscle de-oxygenation. Following both trials, females experienced lesser reductions in knee-extensor contractile function, and following heavy intensity exercise, females experienced less reduction in voluntary activation. These data demonstrate that whilst the relative power-duration relationship is not different between males and females, the mechanisms of fatigability during critical power-matched exercise are mediated by sex. Due to morphological differences, females demonstrate greater fatigue resistance of locomotor muscle during single-limb and whole-body exercise modalities. Whilst females sustain a greater relative intensity of single-limb, isometric exercise than males, limited investigation has been performed during whole-body exercise. Accordingly, this study established the power-duration relationship during cycling in 18 trained participants (eight females). Subsequently, constant-load exercise was performed at critical power (CP)-matched intensities within the heavy and severe domains, with the mechanisms of fatigability assessed via non-invasive neurostimulation, near-infrared spectroscopy and pulmonary gas exchange during and following exercise. Relative CP (72±5 vs. 74±2% Pmax , P=0.210) and curvature constant (51±11 vs. 52±10JPmax-1 , P=0.733) of the power-duration relationship were similar between males and females. Subsequent heavy (P=0.758) and severe intensity (P=0.645) exercise time to task failures were not different between sexes. However, females experienced lesser reductions in contractile function at task failure (P≤0.020), and greater vastus lateralis oxygenation (P≤0.039) during both trials. Reductions in voluntary activation occurred following both trials (P<0.001), but were less in females following the heavy trial (P=0.036). Furthermore, during the heavy intensity trial only, corticospinal excitability was reduced at the cortical (P=0.020) and spinal (P=0.036) levels, but these reductions were not sex-dependent. Other than a lower respiratory exchange ratio in the heavy trial for females (P=0.039), no gas exchange variables differed between sexes (P≥0.052). Collectively, these data demonstrate that whilst the relative power-duration relationship is not different between males and females, the mechanisms of fatigability during CP-matched exercise above and below CP are mediated by sex.