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. 2019 Apr 24;316(6):R832–R838. doi: 10.1152/ajpregu.00394.2018

Mechanisms of sex differences in exercise capacity

Marko Oydanich 1, Denis Babici 1, Jie Zhang 1, Nicole Rynecki 1, Dorothy E Vatner 1, Stephen F Vatner 1,✉
PMCID: PMC6734069  PMID: 31017810

Abstract

Sex differences are an important component of National Institutes of Health rigor. The goal of this investigation was to test the hypothesis that female mice have greater exercise capacity than male mice, and that it is due to estrogen, nitric oxide, and myosin heavy chain expression. Female C57BL6/J wild-type mice exhibited greater (P < 0.05) maximal exercise capacity for running distance (489 ± 15 m) than age-matched male counterparts (318 ± 15 m), as well as 20% greater work to exhaustion. When matched for weight or muscle mass, females still maintained greater exercise capacity than males. Increased type I and decreased type II myosin heavy chain fibers in the soleus muscle from females are consistent with fatigue resistance and better endurance in females compared with males. After ovariectomy, female mice no longer demonstrated enhanced exercise, and treatment of male mice with estrogen resulted in exercise capacity similar to that of intact females (485 ± 37 m). Nitric oxide synthase, a downstream target of estrogen, exhibited higher activity in female mice compared with male mice, P < 0.05, whereas ovariectomized females exhibited nitric oxide synthase levels similar to males. Nitric oxide synthase activity also increased in males treated with chronic estrogen to levels of intact females. Nitric oxide synthase blockade with Nω-nitro-l-arginine methyl ester eliminated the sex differences in exercise capacity. Thus estrogen, nitric oxide, and myosin heavy chain expression are important mechanisms mediating the enhanced exercise performance in females.

Keywords: estrogen, exercise capacity, l-NAME, nitric oxide, sex

INTRODUCTION

The National Institutes of Health (NIH) review process has recently emphasized rigor, with a major component of rigor involving the study of sex differences. The goal of this investigation was to study sex differences in exercise capacity. In view of the fact that the majority of basic research in animals funded by the NIH involves rodent models (25), it becomes important to address mechanisms of sex differences in exercise capacity in male and female mice. Although differences in exercise capacity in male and female rodents have been studied extensively, the results are controversial, with most studies finding enhanced exercise in female mice (14, 18, 28), while others show superior exercise in male mice and rats (23). Relatively little is known about the mechanisms mediating the differences in exercise capacity. One complicating factor comparing exercise in male and female mice is that most studies compare animals of the same age, but there are significant differences in body weight and muscle mass in male and female animals of the same age. Therefore, our goal was to compare exercise capacity in male and female mice, matched, not only for the same age, but also for the same body weights or muscle mass. The next goal was to investigate the different hormonal and biochemical mechanisms of the sex differences in exercise capacity. First, the role of estrogen was studied by surgically removing the ovaries in female mice and also by administering estrogen chronically to male mice. Since there is a known link between estrogen and nitric oxide (4, 12), another goal was to investigate the role of nitric oxide in mediating the enhanced exercise performance in female mice. Finally, the role of myosin heavy chain expression was also analyzed in the skeletal muscle in male and female mice to determine whether differences in myosin heavy chain expression also contribute to the mechanism of differences in exercise between male and female mice.

METHODS

Animal experimental procedures.

For mouse exercise studies, male and female C57BL/6J mice (Jackson Laboratories, Bar Harbor, ME) were matched for age, body weight, or skeletal muscle mass. Age-matched mice were 5 mo old. Weight-matched males and females were 6–7 wk old and 14–15 wk old, respectively. A separate subset of male and female NIHBL (S), Black Swiss mice, were also used for mouse exercise studies and were matched for weight. Animals used in this study were maintained, and all experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, 8th ed., 2011). These studies were approved by the Institutional Animal Care and Use Committee of Rutgers University-New Jersey Medical School. Animals were all placed on standard chow for the length of the study and had access to fresh water. All animals were kept on a standard 12:12-h light-dark cycle.

Exercise protocol and indexes of exercise capacity.

Mice were exercised on a treadmill (AN5817474, Accuscan Instruments) to measure indexes defining exercise capacity. All mice were subjected to a practice trial 3 days before the experiment to adapt to the treadmill testing environment. Food was withdrawn at least 3 h before exercise testing. Mice were exercised at the same time (12:00 PM) for each experiment. All exercise testing was done by the same investigator to maintain consistency between all experimental groups. At the time of the experiment, each mouse was placed on a treadmill with a constant 10% grade. The treadmill was started at 4 m/min, and the speed incrementally increased by 2 m/min every 2 min until the mice reached exhaustion. At the end of each treadmill lane was a rod, which delivered a shock when contacted that would entice the mice to run. Exhaustion was defined as spending time (10 s) on the rod without attempting to reengage the treadmill belt. The indexes of exercise capacity measured were maximal distance, maximal speed reached, and work to exhaustion. C57BL/6J mice were also treated 15 min before maximal treadmill testing with Nω-nitro-l-arginine methyl ester (l-NAME; 1.43 μmol, 2 μl ip) to determine the effects of nitric oxide on exercise performance (8, 15).

Ovariectomy.

Female mice were anesthetized with tribromoethanol (Avertin, 12.5 mg/ml). Ovaries were removed in a sterilized manner to prevent infection. Cefazolin (100 mg/ml) was given intramuscularly in the quadriceps after surgery. Mice were given 2 wk to properly heal after the surgery before any exercise testing was repeated. Upon euthanasia, ovariectomy was confirmed.

Estrogen treatment.

17β-Estradiol (estrogen) treatment was administered to male C57BL/6J mice, aged 5 mo. On preparation, 17β-estradiol (Sigma-Aldrich, St. Louis, MO) was dissolved in USP-propylene glycol (Fisher Scientific, Pittsburgh, PA) to allow effective infusion via drug implantation pumps, as previously described (21, 24). The vehicle solution was composed only of the USP-propylene glycol without the 17β-estradiol. ALZET pumps (0.11 µl/h, 28 days, model 1004, Durect, Cupertino, CA) were used to deliver 17β-estradiol to the animal at a concentration of 0.2 mg·kg−1·day−1(13). After preparation, the pumps were incubated overnight and implanted subcutaneously onto the back of the mouse the following day. Cefazolin (100 mg/ml) was given intramuscularly in the quadriceps after surgery. The mice were allowed to recover for 2 wk before exercise testing began.

Tissue collection and biochemistry.

Mice were euthanized by CO2 gas inhalation. The gastrocnemius muscle was removed from both legs, weighed, and immediately placed in liquid nitrogen in preparation for biochemical analysis. Other muscles, such as the quadriceps, tibialis anterior, soleus, and extensor digitorum longus muscles, were weighed to determine total hindlimb muscle mass. Total nitric oxide synthase activity was measured at a wavelength of 540 nm in the gastrocnemius using a nitric oxide synthase activity assay kit (Colorimetric, K205, BioVision). For histochemical analysis, the soleus muscle was removed after euthanasia because of its common use in muscle biology and exercise physiology. After removal, muscles were embedded in OCT compound (Tissue-Tek), frozen in liquid nitrogen-cooled isopentane, and stored at −80°C. All samples were cut into 10-µm cryosections using a cryostat (Thermo Electronic) and maintained at −20°C.

Immunofluorescence and histochemical analysis.

Immunofluorescence and histochemical analysis of myosin heavy chain muscle expression was conducted as previously described (3). Immunofluorescence analysis of myosin heavy chain expression was performed with primary antibodies against type I (BA-F8), type IIa (SC-71, 2F7), and type-IIb (BF-F3) fibers. Primary antibodies were purchased from the Developmental Studies Hybridoma Bank (University of Iowa), whereas secondary antibodies were purchased from Invitrogen. After OCT-embedded muscle was cut into 10-µm cross sections, all samples were air-dried for 10 min. Samples were then blocked with 10% goat serum in PBS for 60 min. Primary antibody (BA-F8, SC-71, or BF-F3) was then applied for 120 min. Samples were then washed with PBS three times for 5 min, followed by application of secondary antibody for 60 min. After incubation with secondary antibody, slides were washed with PBS three times for 5 min and mounted with ProlongH Gold Antifade reagent. Slides were visualized with an Olympus BX51 microscope (Olympus America, Scientific Solutions Group) using conventional wide-field fluorescence microscopy. The microscope was equipped with a red filter, an Olympus DP73 camera, and CellSens Standard software (Olympus America, Scientific Solutions Group). Total muscle fibers were quantified as positive fibers per field. The slides for immunofluorescence analysis were prepared individually for each myosin heavy chain isoform.

Data analysis and statistics.

All results are expressed as means ± SE. Comparisons between males and females within each group were analyzed using one-way ANOVA, followed by Bonferroni post hoc analysis. Comparisons between individual groups were analyzed using Student’s t-test. Two-way ANOVA was used to analyze exercise capacity between males treated with estrogen/vehicle. P < 0.05 was taken as the level of significance.

RESULTS

Enhanced exercise capacity in age-matched female mice compared with males.

Age-matched female mice (n = 6) ran significantly longer than male mice (n = 7) (489 ± 15 vs. 318 ± 15 m; Fig. 1A) and demonstrated 20% more work to exhaustion (Fig. 1B). Age-matched males weighed roughly 7.5 g more than age-matched females (Fig. 1C) and had a higher skeletal muscle mass of the hindlimb (426 ± 13 vs. 359 ± 5 mg; Fig. 1D). All animals in this group were matched at 5 mo of age (Fig. 1E).

Fig. 1.

Fig. 1.

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Female mice have enhanced exercise capacity compared with males of the same age. In 5-mo-old male (open bars) and female (solid bars) mice, female mice ran longer distances (A) and did more work (B) than males in age-matched (n = 6–7) groups. Male mice had greater body weight (C) and total hindlimb muscle mass than their female, age-matched counterparts (D). E: all mice were matched at 5 mo of age. Values are means ± SE. *P < 0.05, male vs. female.

Enhanced exercise capacity in female mice persists, even when matching males for weight and skeletal muscle mass.

Since age-matched males outweighed females by 32% (Fig. 1C), exercise capacity was also compared in weight-matched male (n = 10) and female mice (n = 10). To properly match for weight (23 g; Fig. 2A), males and females were at different ages (6–7 vs. 14–15 wk old; Fig. 2B). However, even with this discrepancy in age, body weight-matched female mice still demonstrated greater running distance (527 ± 9 vs. 482 ± 7 m; Fig. 2C) and work to exhaustion (20.4 ± 0.4 vs. 19.0 ± 0.4 J; Fig. 2D) compared with males. Skeletal muscle mass was also examined, finding similar results to the weight-matched groups. When matched for muscle mass (340 mg; Fig. 3A), there was no difference in body weight (Fig. 3B) between males (n = 5) and females (n = 5), but males were at a younger age (6–7 vs. 14–15 wk; Fig. 3C). When matched for skeletal muscle mass, females still ran 11% farther and performed 14% more work until exhaustion compared with males (Figs. 3, D and E).

Fig. 2.

Fig. 2.

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Female mice maintain enhanced exercise capacity even when matched for body weight. A: male (open bars) and female (solid bars) mice were matched at the same body weight (23 g, n = 10/group). B: to equalize body weight, males were 6–7 wk old, whereas females were 14–15 wk old. Even when matching for body weight, females still ran longer distances (C) and did more work than their male counterparts (D). Values are means ± SE. *P < 0.05, male vs. female.

Fig. 3.

Fig. 3.

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Female mice maintain enhanced exercise capacity even when matched for skeletal muscle mass. A: total hindlimb muscle mass was matched between male (open bars) and female (solid bars) mice (340 mg, n = 6/group). B: there was also no difference in body weight when matching for muscle mass. C: however, females were 14–15 wk old, whereas males were 6–7 wk old. Similar to weight-matched mice, females still ran longer distances (D) and did more work (E) compared with males. Values are means ± SE. *P < 0.05, male vs. female.

Ovariectomy eliminates the enhanced exercise capacity in female mice, while estrogen treatment improves exercise capacity in intact male mice.

Ovariectomy was conducted in 5-mo-old female mice (n = 8). Age was matched at 5 mo (Fig. 4A). After ovariectomy, females lost their enhanced exercise capacity and demonstrated similar running distance (349 ± 24 vs. 318 ± 15 m; Fig. 4B) to that observed in intact males. Estrogen was infused in 5-mo-old male mice (n = 5) for a treatment period of 4 wk. At the end of the 4 wk, males treated with estrogen exhibited an improvement in running distance compared with males treated for the same time with vehicle (485 ± 38 vs. 359 ± 22 m; Fig. 4C). Furthermore, the exercise capacity of males treated with estrogen was similar to that of intact females.

Fig. 4.

Fig. 4.

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The enhanced exercise capacity in females was abolished by either ovariectomy (OVX) in females or by estrogen treatment in male mice. A: all animals were matched for age at 5 mo. B: females with OVX (diagonal hatched bar) (n = 8) lost their enhanced exercise capacity in running distance compared with intact females (solid bar). C: exercise capacity in males chronically treated with estrogen (horizontal striped bar) increased compared with males treated with vehicle (dotted bar) and matched the exercise capacity observed in intact females (solid bar). Values are means ± SE. *P < 0.05.

Nitric oxide mediates the enhanced exercise capacity in intact females and in males with estrogen.

Female mice demonstrated an increase in nitric oxide synthase activity compared with male mice (0.11 ± 0.02 vs. 0.05 ± 0.01 mU/mg, P < 0.05; Fig. 5A). After ovariectomy, nitric oxide synthase activity (0.05 ± 0.01 mU/mg, Fig. 5A) was similar to that in males. Males treated with estrogen had a significant increase in nitric oxide synthase activity compared with vehicle-treated males (0.09 ± 0.02 vs. 0.05 ± 0.01 mU/mg; Fig. 5B) similar to that observed in intact females. l-NAME eliminated all differences in running distance among males, females, females with ovariectomy, and males treated with estrogen (Figs. 5, C and D). These data confirm the role of nitric oxide, the downstream target of estrogen, in mediating the enhanced exercise capacity in females with intact ovaries and in males chronically treated with estrogen.

Fig. 5.

Fig. 5.

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Enhanced exercise capacity is mediated through increased nitric oxide synthase activity. A: total nitric oxide synthase activity was higher in females (solid bar) compared with males (open bar) (n = 6/group), but was no longer higher after females had ovariectomy (OVX; diagonal hatched bar). B: after chronic estrogen treatment, males had increased nitric oxide synthase activity (horizontal striped bar), compared with vehicle treatment (dotted bar) and to a level similar to intact females. C: after Nω-nitro-l-arginine methyl ester (l-NAME; shaded bar), females no longer demonstrated enhanced exercise capacity, observed in intact females (solid bar). However, l-NAME (shaded bar) did not affect the reduced exercise capacity in females with OVX (diagonal striped bar). D: males treated with vehicle (dotted bar) showed no difference in exercise capacity after l-NAME treatment (shaded bar). However, l-NAME (shaded bar) eliminated the enhanced exercise capacity in males treated with estrogen (horizontal striped bar). Values are means ± SE. *P < 0.05.

Myosin heavy chain expression mediates greater exercise capacity in females compared with males.

Type I, IIa, and IIb fibers were analyzed in the soleus muscle of both C57BL6/J male (n = 4) and female (n = 6) age-matched mice. Analysis of type I fibers revealed females having greater (P < 0.05) type I expression when compared with males (54.2 ± 2.6 vs. 42.0 ± 1.9 positive fibers/field; Fig. 6). However, analysis of both type IIa and IIb fibers revealed the opposite trend, with males showing increased type IIa (29.5 ± 2.9 vs. 13.3 ± 1.8 positive fibers/field, P < 0.05) and type IIb (32.5 ± 2.1 vs. 19.0 ± 3.7 positive fibers/field, P < 0.05).

Fig. 6.

Fig. 6.

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MHC expression in the skeletal muscle promotes the enhanced exercise capacity observed in female mice. Myosin heavy chain type I expression was higher in females (solid bars), compared with males (open bars), whereas type IIa and IIb myosin heavy chain expression was higher in males. The high type I fibers (slow) and low type II fibers (fast) in females are supportive of fatigue resistance, consistent with the enhanced exercise capacity found in females (n = 4–6). Values are means ± SE. *P < 0.05.

DISCUSSION

The current policy for NIH grants involves rigor, which not only includes adequate statistics, but also examination of both males and females (11, 30). This is important because male animals have been used almost exclusively in preclinical studies (25), which allows for biases to arise and can lead to unexpected outcomes when the results of these studies are translated to clinical trials (11). Moreover, the overwhelming majority of basic studies are conducted in rodents, because of ease of handling, cost, and availability of genetically altered models. Accordingly, the current investigation on exercise performance was conducted in mice, focusing on male/female differences, since this species is studied most frequently in NIH grant applications.

Although it is generally assumed that exercise capacity is enhanced in male vs. female humans and most large mammals, the results on exercise in mice are controversial, with most studies finding enhanced exercise in female mice (14, 18, 28), whereas some studies showed superior exercise in male mice and rats (23). In addition, in some prior studies, work to exhaustion was not found to be significantly higher in females than males (5, 17), which differs from the results in the present investigation. In part, this is because body weight is an important component of calculated work, and females of the same age as male mice weigh significantly less. It was precisely for this reason that we compared male and female mice of the same age, same body weight, and same muscle mass. In the present investigation, we observed a 54% increase in running distance, and a 20% increase in work to exhaustion in female vs. male mice of the same age, all of which are measures of total maximal exercise capacity. These results are not strain specific, as similar results were found in the FVB strain as well (14). It could also be argued that the results in this investigation are due to the specific inbred characteristics of the wild-type mice studied. Accordingly, in addition to studying the inbred C57BL6/J strain, an outbred NIHBL(S) Black Swiss mouse strain was also studied. Comparing body weight-matched outbred Black Swiss males vs. females, a similar pattern was observed with females outperforming males, as was observed in C57BL6/J mice, with one difference. The increases in running distance and work to exhaustion in female Black Swiss mice compared with males were greater than observed in the C57BL6/J mice, i.e., the female Black Swiss mice ran for 42% longer distance and performed 40% more work than did males, confirming that the enhanced exercise performance in female vs. male C57BL6/J mice was not simply a factor of their breeding.

To explain the enhanced exercise capacity in female mice studied at the same age as male mice, we examined the mechanisms involved. First of all, we examined the role of body weight. Whereas most studies compared exercise at similar ages, it is important to appreciate that female mice of the same age weigh less than male mice. This is important for two reasons. First, mice that weigh less generally run better, as shown in Fig. 1. Second, work to exhaustion is generally proportionate to body weight, since the formula for work includes body mass. Despite the importance of comparisons at similar weights, no other study examined this. When we examined male and female mice of the same weight, females still ran farther distances, but the increase in running distance (10%), and work to exhaustion (8%) were significantly less than observed with exercise at the same age. Another physical factor that can affect exercise performance is skeletal muscle mass, since increased skeletal muscle mass is associated with enhanced exercise performance in humans (1, 29). This was also examined in the current investigation, finding that hindlimb skeletal muscle mass was proportionate to body weight and, accordingly, exercise performance differences between males and females of the same skeletal muscle mass corresponded to the data for body weight, i.e., with increases in running distance (11%) and work to exhaustion (14%).

Although all of these physical factors, such as age, weight, and muscle mass, play a role in mediating sex differences in exercise capacity, there are many other mechanisms that can also explain these differences. One mechanism that has been studied is the role of estrogen in mediating the enhanced exercise performance in female rodents (2, 6, 7, 16, 19, 20, 27) and humans (22). The importance of this mechanism was demonstrated in the current investigation by examining exercise performance in females with and without ovariectomy and in males comparing the effects of chronic estrogen treatment with chronic vehicle treatment. Ovariectomy eliminated the enhanced exercise capacity in females, whereas chronic estrogen increased exercise capacity in males to the same level as intact females. Although it is recognized that administration of estrogen to males is not identical to the role of estrogen in intact females, it is interesting that, in our data, either eliminating the increased estrogen in females by ovariectomy, or increasing levels of estrogen in males with chronic estrogen administration, resulted in identical outcomes, i.e., elimination of the enhanced exercise capacity in females compared with males.

One mechanism that has not been studied at all to explain the sex difference in exercise capacity in mice is the role of nitric oxide, even though there is a known link between estrogen and nitric oxide (4, 12). In the present investigation, we observed a 111% increase in nitric oxide synthase activity in females compared with age-matched males. l-NAME, an inhibitor of nitric oxide synthase, reduced exercise capacity in females by 27% while not having any negative effect on exercise capacity in males, thereby equalizing the running distance between the two groups (Fig. 5). To further substantiate the key role of nitric oxide synthase in mediating the sex differences in exercise performance, we studied the activity of nitric oxide synthase in female mice with ovariectomy and in male mice chronically treated with estrogen. We found that female mice exhibited a 53% decrease in nitric oxide synthase activity after ovariectomy, and that male mice chronically treated with estrogen exhibited an 80% increase in nitric oxide synthase activity. Blockade of nitric oxide with l-NAME eliminated the sex differences in exercise performance among all groups, demonstrating the key role of nitric oxide in mediating the sex differences. However, intact females and males treated with estrogen did show significant decreases in exercise capacity after nitric oxide blockade, whereas males and females with ovariectomy did not, further confirming the tight connection between estrogen and nitric oxide, as well as the importance of nitric oxide in regulating enhanced exercise capacity in these two groups. While estrogen has been shown to increase levels of nitric oxide in females through the upregulation of endothelial nitric oxide synthase (4), this is the first time the key role of nitric oxide in mediating the enhanced exercise performance in females is demonstrated.

In an effort to further understand the exercise differences between male and female mice, analysis of the myosin heavy chain expression of the soleus skeletal musculature was conducted. Females exhibited increased expression of type I fibers and decreased expression of type IIa and IIb fibers compared with males. Type I fibers are known to be slow oxidative fibers and contribute to prolonged muscle contractility, whereas type II fibers, specifically type IIb, are fast glycolytic fibers responsible for swift muscle contraction (9). Increased type I and decreased type IIb fibers are consistent with a fatigue-resistant state and enhanced endurance (10), which we found in the female mice. Furthermore, estrogen has been shown to increase type I fiber expression, further supporting the role of fatigue resistance in intact females compared with males (26).

In summary, we identified several mechanisms responsible for the differences in exercise capacity observed between male and female mice, including physical, hormonal, and molecular factors. We show, for the first time, that the enhanced exercise capacity in female mice remains present, even when matched for physical factors, such as body weight and muscle mass. This is crucial, given that males and females at the same age are not of the same body weight and skeletal muscle mass, which can influence exercise performance, such as running distance and work to exhaustion. We also demonstrated the importance of sex hormones, as ovariectomy reduced exercise capacity in females to levels observed in intact males and, conversely, chronic estrogen administered to males improved their exercise performance to that of intact females. Finally, we show for the first time that nitric oxide is a key mechanism mediating the enhanced exercise capacity in intact females and in males treated with estrogen, since these differences were no longer observed after nitric oxide blockade.

GRANTS

This study was supported by National Institutes of Health Grants R01HL102472, R01HL106511, R01HL119464, R01HL124282, R01HL130848, R01HL137368, R01HL137405, and R21AG053514.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

D.E.V. and S.F.V. conceived and designed research; M.O., D.B., and N.R. performed experiments; M.O., D.B., J.Z., and N.R. analyzed data; M.O., D.B., J.Z., and S.F.V. interpreted results of experiments; M.O. and J.Z. prepared figures; M.O. and J.Z. drafted manuscript; M.O., D.B., J.Z., N.R., D.E.V., and S.F.V. edited and revised manuscript; D.E.V. and S.F.V. approved final version of manuscript.

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