Effects of ovarian hormones and estrogen receptor α on physical activity and skeletal muscle fatigue in female mice

Menopause is associated with declines in physical activity and skeletal muscle strength. Physical activity is also reduced in rodents after ovariectomy (OVX) and whole-body estrogen receptor alpha (ER alpha) knockout. However, it is unclear if the effects are estradiol (E-2) specific. Thus, the overall purpose of this study was to investigate the effects of the ovarian hormones, E-2 and progesterone (P4), and skeletal muscle ER alpha (skmER alpha) on physical activity and skeletal muscle contractility in female mice. Methods: Study 1: Forty female C57B1/6J mice were given free access to running wheels for 2 weeks to assess baseline running and randomized into 4 treatment groups: OVX, OVX + E-2, OVX + P4, OVX E-2 + P4. All mice underwent OVX, returned to wheels for 2 weeks, received hormone pellet implants and returned to running wheels for 6 weeks, after which soleus muscle contractility testing was completed. Study 2: Thirty-two skeletal muscle specific ER alpha knock-out (skmER alpha KO) mice and wildtype (WT) littermates were randomized into 4 groups: skmER alpha KO-Run, skmER alpha WT-Run, skmER alpha KO-Sed, and skmER alpha WT-Sed. Run mice were given free access to wheels for 20 wk and sedentary (Sed) mice maintained normal cage activities. At the end point, muscle contractility was tested. Results: Study 1: OVX + E-2 + P4 group ran greater distances than both the OVX and OVX + P4 groups (p <= 0.009). After fatiguing contractions, soleus muscles of the OVX + E-2 + P4 group maintained greater submaximal force than those of other groups (p = 0.023). Immediately after the fatiguing contractions, OVX + E2 + P4 muscles had greater maximal force production than the OVX + E2 group (p = 0.027). Study 2: There were no differences in running distance between skmER alpha WT and skmER alpha KO mice (p = 0.240). Soleus muscles of skmER alpha KO mice were more fatigable (p < 0.001) and did not recover force as well as skmER alpha WT mice (p < 0.001). In vivo isometric, concentric and eccentric torque was decreased in skmER alpha KO mice com- pared to skmER alpha WT mice (p <= 0.029). Conclusions: Combined treatment of E-2 + P4 in OVX mice restored physical activity, predominantly driven by E-2, and protected soleus muscles against fatigue. Muscle of skmER alpha KO mice was weak regardless of physical activity. Although 20 wk of wheel running partially prevented force loss during fatigue in skmER alpha KO mice, force production during recovery remained low, indicating that estradiol functions through ER alpha in skeletal muscle.