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Letter to the Editor: Mechanisms of sex differences in exercise capacity.

TO THE EDITOR: We read with great interest the recent findings of Oydanich et al. (12) on the article “Mechanisms of sex differences in exercise capacity.” The goals are important because there are significant differences in exercise physiology between male and female mice. There is little evidence exploring these contrasts; C57BL6/J female mice performed similarly to our recent work (2). We further observed that the estrous cycle did not influence the female mice’s maximal running power while modifying submaximal V̇O2 and V̇CO2 and thermoregulation induced by exercise (2). However, we have evidence and discordant opinions about the exercise performance of male mice in Oydanich’s study (12). The gold standard measurement of exercise capacity depends on three key points: an ergometer, fatigue index, and exercise capacity (15). The authors used a graded treadmill for subjective evaluation of fatigue and estimation of total work. The authors did not include the method of work to exhaustion, which is an important measure of exercise capacity. We project that this was vertical work, based on the information of body mass, treadmill inclination, and belt speed (Fig. 1A). The equation can be found in our recent manuscript (2). Each step of the exercise test (speed time) multiplied by greater body weight of male mice reflects large V̇O2peak and vertical works in the treadmill test (2). Thus, the submaximal treadmill work of male mice was higher at all comparable speeds (4 ¡ 24 m/min, Fig. 1B). The authors’ conclusion concentrates on all the treadmill work, because of the improved endurance of the female mice. However, the conclusions are intriguing because of the poor performance of male mice on the graded treadmill. We believe that the study’s subjective fatigue assessment methodology was inadequate. The authors showed a maximum male speed of 26 m/min after 23 min of graded treadmill test (6°, corresponding to report 10% grade) (12). Exhaustion was defined as spending time (10 s) on an electric rod (end of a treadmill) without attempting to reengage the treadmill belt (12). The intensity and duration of the shock were also not reported (12). However, a mouse could stop exercising due to fear, distraction, depression, heightened muscle pain perception, or fatigue, to name a few reasons (15). Thus, the subjective evaluation of fatigue should be replaced by objective and reproducible physiological and biochemical parameters, such as lactate threshold, maximal oxygen consumptions (V̇O2peak or V̇O2max), or respiratory exchange ratio (RER V̇CO2/V̇O2) (1–3, 5, 6, 13–15). Previous studies using these parameters found higher maximal speed (28–42 m/min) at the graded treadmill test (5°–28°) for adult male mice (2, 4, 7, 8, 11). We describe a maximum speed of 42 m/min (5° slope) at V̇O2peak in the same mouse lineage (2). Similar results were shown by Kinugawa et al. (8) at 10° slope. Speed was a little slower (39 m/min) at 12.5° slope (11). Even at higher grade, the maximum speed of male mice was 38 m/min at 20° slope for Ishihara and Taniguchi (7) and 27.5 m/min at 28° slope for Desai et al. (4). In the discussion, the authors argued that female mice showed better running performance because of higher work to exhaustion and race distance at the graded treadmill, but they presented evidence of another ergometer-voluntary running wheels (9, 10, 16). These papers evaluated submaximal exercise adaptations to long-term running wheels and not maximal acute exercise capacity at the treadmill. The authors further reinforced the different distributions of muscle fibers in the soleus muscle, faster fibers in male mice, and slower fibers in female mice. However, the evaluation of the estrous cycle is crucial for studies involving female mice, although it does not seem to influence the maximum vertical work of mice on the treadmill (12). We support the initiative of the authors to evaluate exercise sex gap. This is an important scientific and social field. However, it is crucial to recognize the adequate and reproducible methodology (ergometer, fatigue index, and exercise capacity) for assessment of exercise capacity (submaximal and maximum). Address for reprint requests and other correspondence: A. S. Aguiar, Jr., Universidade Federal de Santa Catarina, UFSC, Departamento de Ciências da Saúde, 88905-120 Araranguá–SC, Brazil (e-mail: aderbal.aguiar@ufsc. br, aderbalaguiar@gmail.com). Fig. 1. A: heavier male mice develop further submaximal vertical work on the graded treadmill at all comparable speeds (4¡24 m/min). B: great work observed in female mice occurred because of greater distance, although the result is controversial. Am J Physiol Regul Integr Comp Physiol 318: R156–R157, 2020; doi:10.1152/ajpregu.00187.2019.