Estradiol (E2) treatment in young adult, ovariectomized mice increases physical activity and reverses deleterious effects on skeletal muscle. Here we test the hypothesis that E2 treatment improves muscle function and physical activity in aged, ovarian-senescent mice. Plasma E2 levels and vaginal cytology confirmed ovarian senescence in 20-month-old C57BL/6 mice. Mice were then randomly divided into activity groups, having access to a running wheel or not, and further into those receiving E2 or placebo. Placebo-treated mice wheel ran more than E2-treated mice (P=0.03), with no difference between treatment groups in cage activities such as time spent being active and ambulation distance (P≥0.55). Soleus muscles from aged mice that wheel ran adapted by getting larger and stronger, irrespective of E2 status (P≤0.02). Soleus muscle fatigue resistance was greater in mice treated with E2 (P=0.02), but maximal isometric tetanic force was not affected (P≥0.79). Because E2 treatment did not improve physical activity or overall muscle function in the aged, ovarian-senescent mice as predicted, a second study was initiated to examine E2 treatment of young adult mice prematurely ovarian senescent from exposure to the chemical, 4-vinylcyclohexene diepoxide (VCD). 4-month-old C57BL/6 female mice were dosed with oil (control) or VCD. Vaginal cytology confirmed ovarian senescence in all mice treated with VCD 63 days after the onset of dosing, and then a subset of the VCD mice received E2 (VCD+E2). Wheel running distance did not differ among control, VCD, and VCD+E2 mice (P≥0.34). Soleus muscle concentric, isometric, and eccentric in vitro forces were greater in VCD+E2 than VCD mice (P<0.04), indicating beneficial estrogenic effects on muscle function. In general, aged and young mice with senescent ovaries were less responsive to E2 treatment, in terms of physical activities and muscle function, than what has previously been shown for young, ovariectomized mice. These results bring forth the possibility that some component of the residual, follicle-depleted ovarian tissue influences physical activity in mice or that aging diminishes the responsiveness of skeletal muscle and related tissues to E2 treatment.

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