Abstract 16806: Mechanisms of Sex Differences in Exercise Capacity

Abstract

The current policy for NIH grants involves rigor, which not only includes adequate statistics, but also examination of both males and females. The reason for the priority to examine sex differences is because male rodents have been used almost exclusively in pre-clinical studies, which allows for biases to arise. Accordingly, the goal of this investigation was to determine sex differences in exercise capacity in mice and the mechanisms mediating these differences. C57 female wild-type (WT) mice (5 months old) exhibited greater, p<0.05, maximal exercise capacity for running distance (469 ± 24 m; n=7) than age-matched male WT mice (337 ± 14 m; n=8) as well as a 21% improvement in work to exhaustion. The first goal was to look at the effect of physical factors, such as weight and muscle mass, on exercise capacity. When matched for weight females still out-performed males in both running distance (541 ± 21 vs. 456 ± 18m, p<0.05; n=10/group) and demonstrated an 18% improvement in work to exhaustion. Similar outcomes were observed when matching for hind-limb muscle mass. The second goal was to study the effects of estrogen on exercise capacity. After ovariectomy (OVX), female mice no longer demonstrated enhanced exercise compared with males. Conversely, chronic administration of estrogen to male mice improved capacity in running distance and work to exhaustion by 35% after 4 weeks of treatment. Next, we investigated nitric oxide (NO), a downstream target of estrogen, a mechanism which has not been examined previously for mediating sex differences in exercise capacity. Total NO synthase (NOS) activity was higher in female mice compared with male mice (207 ± 14 U/mg vs. 138 ± 4 U/mg, p<0.05), but was no longer different after OVX. Furthermore, males chronically treated with estrogen exhibited a 47% increase in NOS activity. NO blockade with L-NAME eliminated the enhanced exercise capacity observed in both females and males treated with estrogen. Thus, as expected, estrogen is a key mechanism mediating the enhanced exercise capacity in female mice. However, this investigation also demonstrated another, novel key mechanism, increased nitric oxide activity.