17Alpha-estradiol stimulates running wheel activity in gonadectomized mice

Sarcopenia, the age-related loss of muscle mass and strength, affects females in part from decreased circulating estrogen. This is due, in part, to direct effects of estrogen on skeletal muscle and to well-established roles of estrogen stimulating physical activity through the central nervous system. Estradiol exists in two forms: the more prevalent 17beta-estradiol (17β-E2) and the less well-characterized 17alpha-estradiol (17α-E2), which the National Institute on Aging Interventions Testing Program has shown to extend life- and health-span in male mice. The purpose of this study was to test the hypothesis that 17α-E2 stimulates voluntary exercise contributing to enhanced healthspan in gonadectomized mice. It was hypothesized that 17α-E2 will increase average daily wheel running to a similar extent as 17β-E2, in both females and males. Four month old mice were singly-housed and acclimatized to running wheel cages for 10 days, and then baseline running wheel activity was recorded for one week. Gonads were surgically removed from all mice, and then mice recovered in normal cages for one week before going back into running wheel cages. Wheel running activity was recorded for one week. Mice were then treated with placebo, 17α-E2, or 17β-E2 by implanting a 60-day time-release 0 or 0.18mg E2 pellet into the base of the neck. A fourth group received 17α-E2 in food, at a dose comparable to the pellet. Wheel running activity was recorded for 4 weeks, at the end of which mice were euthanized and tissues harvested. In female mice, average daily running distance at baseline was 10.8 + 1.4 km/24 hours and did not differ between the four groups (p=0.984). Distance decreased 36-64% following ovariectomy. After four weeks of E2 treatment, running distance was different across groups (p0.401). During the 4-week E2 treatment period, body weight of the three E2 treatment groups stayed relatively constant (-2.1 to 5.5%), while body weight of mice receiving placebo increased by 26%. Serum levels of 17α-E2 and 17β-E2 in these mice are being measured via LC/MS. These results support the hypothesis that 17α-E2 stimulates voluntary physical activity similar to 17β-E2 in mice, building the case for the potential use of 17α-E2 as an alternative to traditional estrogen treatment and improving healthspan. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.