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Endurance Exercise Capacity and Substrate Metabolism in Male and Female Mice

The investigation of sex‐specific differences in physiological and pathophysiological processes is of increased importance in scientific research. Previous studies, in both rodents and humans, observed that females generally have a higher endurance exercise capacity (EEC) than males. Additional research suggests that the increased EEC in females is mediated, in part, by differences in substrate metabolism during exercise. The objective of this study was to determine whether changes in exercise substrate metabolism contributed to sex‐specific differences in EEC in mice. To evaluate EEC, male and female, C57BL/6‐NCrl mice (n=9 each group) were subjected to a graded exercise test on a motorized treadmill. The treadmill was set at a 10% incline and the speed gradually increased from 10.2 m/min to 22.2 m/min at fixed intervals for up to 2.5 hrs. At exhaustion, blood glucose (BG) was measured from a tail clip using a hand‐held glucometer. Blood and tissues (heart, liver, skeletal muscle, and adipose) were harvested from all mice. Serum levels of non‐esterified fatty acids (NEFA), triglycerides (TG), cholesterol (CHOL), lactate (LAC), and ketone bodies (KET) were measured using commercially available kits. Endurance exercise times were ~25% higher in females compared to males (121.2 ± 4.0 min vs. 97.3 ± 4.3 min, P<0.05). At exhaustion, BG was significantly lower in females (66.7 ± 3.0 mg/dl) vs. males (75.8 ± 2.4 mg/dl); however, there was no significant difference in LAC. Although post‐exercise serum TG levels were similar, CHOL was significantly lower in females (40.3 ± 2.5 mg/dl vs. 50.6 ± 3.0 mg/dl). Interestingly, serum levels of both NEFA and KET were ~50% higher in females at exhaustion. Although body weight was significantly greater in males (25.6 ± 0.8g vs. 20.1 ± 0.6g), the quadriceps to body weight ratio was similar, suggesting that body or muscle mass was not a factor in the differences. In conclusion, female mice have higher EEC than male mice, which may be due to the supply of exogenous substrates. In particular, female mice have elevated serum levels of fatty acids and ketone bodies at exhaustion, which may reflect an increased ability to mobilize these substrates to prolong endurance exercise. Additional studies will investigate whether endogenous cellular metabolism, especially glycogen and triglycerides in skeletal muscle, contribute to the enhanced endurance capacity phenotype.