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Sex Differences in Human Skeletal Muscle Fatigue

Hicks, Audrey L.1; Kent-Braun, Jane2; Ditor, David S.1

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Exercise and Sport Sciences Reviews: July 2001 - Volume 29 - Issue 3 - p 109-112
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Muscle fatigue is a topic that has fascinated physiologists for much of the 20th century. It has been defined many ways, but perhaps the most common definition is the one proposed by Bigland-Ritchie et al. (2), in which fatigue is defined a decrease in the maximum force-generating capacity of the muscle. The ability to resist fatigue is sometimes expressed as muscle endurance, which can be defined as the time to failure to maintain target tension. Muscle fatigue can originate in any one of a number of sites within the human neuromuscular system, and in all likelihood a failure in force-generating capacity results from multiple events occurring at central and peripheral sites. The purpose of this review was not to describe the potential sites and mechanisms of human skeletal muscle fatigue (there are many good reviews on this topic) but rather to explore the suggestion that males and females differ in their ability to resist fatigue.

Sex differences in muscle fatigue have been reported frequently, with females generally exhibiting a greater relative fatigue resistance than males (5,11,12,15). This phenomenon has been observed in a variety of muscles with the use of various fatigue protocols, yet the mechanisms for the apparent sex difference are not completely understood. The purpose of this review was to examine the mechanisms that might underlie the apparent effect of biological sex on the fatigability of skeletal muscle.


As mentioned, the female advantage in fatigue resistance has been fairly well documented, especially in fatigue protocols that incorporate submaximal contractions (Table 1). Females have been shown to have significantly greater fatigue resistance than males in protocols involving sustained submaximal contractions of the knee extensors (11), the elbow flexors (12), the handgrip muscles (15), and the adductor pollicis muscle (5). Each of these studies used fatigue paradigms that incorporated contraction intensities of 20–70% of maximum voluntary contraction (MVC), and the relative increase in time to fatigue in the female subjects was 47–86%. Closer examination of the literature, however, suggests that the apparent magnitude of the female advantage in fatigue resistance declines as the intensity of the contractions increases (Figure 1). For example, no difference in fatigability between the sexes was noted at contraction intensities above 80% of one repetition maximum (1RM) in the knee extensors (9,11), nor in a recent study in the adductor pollicis muscle incorporating intermittent maximal contractions (3).

Table 1
Table 1:
Summary of research related to sex differences in human muscle fatigue
Figure 1
Figure 1:
The effect of contraction intensity on the magnitude of the female advantage in fatigue resistance. Most studies that have reported significantly greater fatigue resistance in females compared with males have used submaximal contraction intensities to induce fatigue. The magnitude of this female advantage appears to decline as the contraction intensity increases. Based on the available literature on young adults (numbers in parentheses correspond to references), the nature of the relationship between contraction intensity and the magnitude of the female advantage has been estimated. * Data that were not statistically different.


Several mechanisms have been hypothesized to explain the observed sex differences in fatigue resistance, of which the most popular can be classified into three general themes: (1) muscle mass, (2) substrate utilization, and (3) muscle morphology. The evidence supporting each of these hypotheses will be discussed, and the role of neuromuscular activation as a potential mechanism will be addressed.

Muscle Mass

One of the more commonly suggested explanations for the female advantage in fatigue resistance relates to the lower absolute muscle forces that females generate when performing the same relative work as males. These lower absolute forces involve a lower muscle oxygen demand and, assuming a similar specific tension (force per mm2 muscle) between males and females, less mechanical compression of the local vasculature (11,12). In support of this hypothesis, Barnes (1) reported a significant negative correlation between MVC strength and the percent of MVC necessary to produce intramuscular vascular occlusion during isometric handgrip exercise. Because females are generally weaker than males, they should experience less occlusion at a given submaximal percentage of their MVC and therefore would have both enhanced availability of oxygen and clearance of metabolic byproducts during exercise, thereby delaying fatigue. Although Barnes (1) studied only males, high-strength subjects experienced intramuscular occlusion at a lower percentage of MVC compared with low-strength subjects (51.5% versus 75.5% in high- and low-strength groups, respectively). A recent study by Fulco and coworkers (5), however, disputed this apparent effect of initial strength on vascular occlusion threshold when they found females to be significantly less fatigable than males during intermittent submaximal contractions, even when the two sexes were matched for maximum strength of the adductor pollicis muscle. Furthermore, initial absolute muscle force was not found to be a significant predictor of fatigue resistance in sustained submaximal handgrip contractions (15) or in intermittent MVCs of the adductor pollicis muscle (3).

It is important to point out that although it has been suggested that intramuscular occlusion of blood flow occurs at ∼ 60% of MVC (1), there will be significant variability in muscle blood flow and intramuscular pressure both within and between muscle groups at any given submaximal contraction intensity. Before any definitive conclusions can be made regarding the relationships among sex, absolute muscle force, relative contraction intensity, and muscle blood flow, further studies (possibly using imaging technology to monitor blood flow) are warranted. Furthermore, when exploring possible mechanisms for differences in muscle blood flow between the sexes, differences in sympathetic vascular control cannot be overlooked. Although the effects of estrogen on the hyperemic response during exercise are equivocal, there is evidence to suggest that estrogen enhances blood flow to active muscle. For example, males treated with long-term high-dose estrogen therapy were shown to have a greater hyperemic response (greater increases in brachial artery diameter) compared with untreated age-matched controls, and this hyperemic response was equal to that of age-matched females (4). It has also been shown that compared with males, females have an attenuated sympathetic outflow in response to exercise (4), which could reduce vasoconstriction. These findings should be interpreted with caution, however, because a reduction in sympathetic outflow may not strictly translate into an enhanced hyperemic response; rather, it could also impair the redirection of blood flow to the working muscle from the inactive muscle and viscera.

Substrate Utilization

Sex differences in metabolism have been studied quite thoroughly (14), and it appears that males have a greater glycolytic capacity and a greater reliance on glycolytic pathways than females. Females have a respiratory exchange ratio that is 4–5% lower than that in males during submaximal endurance exercise (< 70% V̇o2max), which amounts to a comparatively greater fat oxidation in females compared with males (14). Muscle biopsy data have shown that although there does not appear to be any sex difference in muscle glycogen content, lower activities of common glycolytic enzymes (pyruvate kinase, phosphofructokinase, and lactate dehydrogenase) have been reported in women, which would decrease their potential for anaerobic glycolysis (14). These differences may translate into a greater reliance on the β-oxidation of fatty acids for metabolism in females, which could prolong endurance during certain types of activity.

The female hormone estrogen has also been proposed to influence fuel metabolism during exercise, especially during exercise of long duration. The observation that females tend to have a lower reliance on carbohydrate metabolism during long-duration, mild-moderate intensity exercise, even when on carbohydrate-loaded diets, has led to the suggestion that estrogen has glycogen-sparing properties (14). This contention is supported by work in animals; the administration of estradiol to oophorectomized female rats resulted in a significantly lower glycogen depletion and significantly greater times to exhaustion during treadmill running (8). During exercise of short duration, however, where glycogen depletion does not play a role in the development of fatigue, it is unclear how estrogen might offer any distinct advantage in terms of fatigue resistance. It is likely that other mechanisms are far more important, especially because a greater fatigue resistance in females compared with males has been reported in postmenopausal women who were not on any hormone replacement therapy (7).

Muscle Morphology

There has been some suggestion in the literature that fiber type distribution may be different between men and women, which may in part, explain the sex differences in fatigability. Although higher proportions of the more fatigable type II fibers have been found in the vastus lateralis of men compared with women (12), this sex difference has not been found in other muscles, such as the biceps brachii. Furthermore, no relationship between sex-based differences in morphology and fatigability has been clearly established. There certainly is a need for further studies to examine the morphological properties of a variety of muscle groups from males and females and to expand this analysis to include measurements of muscle capillarization and ultrastructure.

Neuromuscular Activation

Finally, one cannot ignore the possibility of a sex difference in neuromuscular activation as a contributor to the apparent differences in fatigue resistance between males and females. Although this area has not been explored extensively, there are two studies that have provided evidence for a potential male-female difference in neuromuscular activation. After heavy resistance exercise resulting in similar declines in maximal force in both sexes, Hakkinen (6) found significant decreases in the maximum voluntary electromyogram (EMG) in the male subjects but not in the female subjects. This suggests a greater impairment in neuromuscular activation in males compared with females after fatiguing exercise. More recently, a significant increase in endurance time during a sustained submaximal (15% MVC) contraction of the elbow flexors was noted in females compared with males after a 4-wk period of immobilization, and this enhanced fatigue resistance was associated with an altered pattern of muscle activation (13). In the latter study, the postimmobilization EMG pattern in the female subjects during the fatigue task was characterized by a lack of the typical progressive increase in EMG during the course of fatigue. Furthermore, an intermittent activation pattern of the recruited motor units was observed in the females. It is possible, therefore, that there are subtle differences between the two sexes in the way the neuromuscular system adapts to various stressors (i.e., exercise, immobilization), which may ultimately influence fatigue resistance.


It is not clear whether the sex difference in fatigue resistance persists in the aged population. Although the age-related loss in muscle mass and strength is well documented, there is considerable discrepancy in the literature regarding (a) the fatigue characteristics of muscles in older adults and (b) any potential sex differences in muscle function or fatigue. Postmenopausal women have been shown to have greater fatigue resistance than age-matched men while performing intermittent MVCs in the elbow flexors (7), ankle dorsiflexors (7), and knee extensors (10); however, when the velocity demands of the task increase, the female endurance advantage is no longer apparent (9).

The postmenopausal woman can be used as a model to test the various mechanisms that have been discussed to explain the sex effect in young adults. The muscle force hypothesis should conceivably explain any sex differences in fatigue resistance in both younger and older adults. It is well known that older women have smaller muscles and are weaker than older men; the lower absolute muscle forces generated by older women would therefore result in less vascular occlusion and local muscle ischemia. It is noteworthy that Ditor and Hicks (3) recently found no sex differences in fatigue resistance between older men and women when both groups were matched for initial strength of the adductor pollicis. However, they found that when looking at the entire subject sample of young and old males and females, baseline muscle force had no independent effect on the ability of subjects to resist fatigue (3); rather, age was the only significant predictor of fatigue resistance.

With regard to the substrate metabolism hypothesis, it is unclear whether the apparent differences in substrate preference and metabolic enzymes seen in younger adults also exist in the older population. These studies still need to be done. However, the fact that older women (not on hormonal replacement therapy) have been shown to have greater fatigue resistance than men (7,10) would tend to minimize the potential role of estrogen in mediating any endurance advantage through its putative glycogen-sparing properties.

Not only is older muscle smaller and weaker; significant changes in fiber-type distribution occur as well. These age-related changes in muscle morphology have been well documented, and the shift toward a greater type I fiber area representation has been offered as an explanation for the maintenance or enhancement of fatigue resistance with aging. We do not yet know, however, whether there are any sex differences in these age-related changes or whether the slightly greater type I fiber representation observed by some in young females persists during the aging process.


Table 1 summarizes the literature in this review pertaining to the influence of sex on human skeletal muscle fatigue. The specific mechanisms that have been proposed for the apparent female advantage in fatigue resistance are illustrated in Figure 2. The most obvious source of the difference in fatigability between males and females is likely related to muscle mass, which theoretically will affect oxygen demand and perfusion (oxygen delivery) during muscle contractions at the same relative force level. Studies that address this issue by controlling for muscle mass or by using current imaging technology to examine muscle blood flow during fatigue tasks are warranted. It is also important that future studies continue to examine the relative reliance on oxidative versus glycolytic sources in the working muscle of men and women and the precise role that differences in substrate utilization play in fatigue. Furthermore, the specific role that estrogen might play in conferring any advantage in fatigue resistance should be clarified. Although overt sex differences in neuromuscular activation are not apparent, these have not been thoroughly studied. In particular, the possible role of central motor drive in sex-related differences in fatigue resistance needs clarification.

Figure 2
Figure 2:
Proposed mechanisms to account for female advantage in fatigue resistance. Schematic illustration of the various mechanisms that could underlie enhanced fatigue resistance in females.Solid arrows indicate mechanisms that have considerable supportive evidence;dotted arrows represent mechanisms that have only limited support in the literature.

It is quite interesting that similar mechanisms have often been proposed to explain either sex or aging differences in muscle fatigue. There is a growing body of literature suggesting that females have a greater resistance to fatigue than males, but it is not yet clear whether this apparent sex difference is maintained during aging. In this regard, there is a definite need for further research exploring muscle fatigue characteristics and mechanisms to control for both sex and aging effects.


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muscle activation; metabolism; blood flow; strength

© 2001 Lippincott Williams & Wilkins, Inc.