Estradiol treatment, physical activity, and muscle function in ovarian-senescent mice

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). Four-month-old C57BL/6 female mice were dosed with oil (control) or VCD. Vaginal cytology confirmed ovarian senescence in all mice treated with VCD 63days 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 in 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.