Estradiol Replacement or Wheel Running Reverses Skeletal Muscle Contractile Dysfunction in Mature Ovariectomized Mice

Abstract

Loss of ovarian hormones in mature female mice causes a decline in muscle force generation due to a decrease in the fraction of strong-binding myosin (Moran et al, JAP; In press). However, it is unknown which ovarian hormone is responsible for the decline and whether the decline can be reversed. PURPOSE: Determine if estradiol (E2) replacement or wheel running reverses the decline in muscle force generation caused by the loss of ovarian hormones. METHODS: Adult C57BL/6 mice (3 mo) were randomly assigned to (1) sham-operation (Control, n=20) (2) ovariectomy with placebo replacement (OVX, n=20) (3) ovariectomy with 17β-estradiol replacement (OVX+E2, n=20). Five days post-surgery, one-half of the mice in each group were given access to exercise wheels and distance run per day was monitored. The remaining mice maintained normal cage activity for the rest of the study. After 4 wk of normal cage activity or wheel running, placebo or 17β-estradiol time-release pellets were implanted. Four weeks after pellet implantation, in vitro contractile function of soleus muscles was determined. An eccentric injury protocol was also performed to determine if E2 replacement or wheel running reduced susceptibility to injury. Data were analyzed by one-way ANOVA with Dunnett's post-hoc tests with significance accepted at P<0.05. Data are reported as means ± SE. RESULTS: Maximal isometric force (Po) was 16% lower in muscles from OVX mice compared with Controls (152 ± 3 vs 176 ±5 mN), but was restored by wheel running (183 ± 7 mN) or E2 replacement (178 ± 7 mN). The combination of estradiol and wheel running increased Po 25% above Controls (219 ± 8 mN). Active stiffness was 10% lower in muscles from OVX mice compared with Controls (292 ± 3 vs 320 ± 3 N/m), but was restored by wheel running (314 ± 3 N/m) or E2 replacement (319 ± 6 N/m). Rates of isometric force development and relaxation were also greater in wheel running OVX+E2 mice compared with Controls (2.05 ± 0.24 vs 1.55 ± 0.59 N/s; 2.99 ± 0.68 vs 2.20 ± 0.83 N/s). Eccentric force was 15% greater in wheel runners and OVX+E2 mice compared with Controls (414 ± 16 and 408 ± 16 vs 347 ± 14 mN). However, neither wheel running nor E2 status affected susceptibility to muscle injury as indicated by Po loss and enzyme release following eccentric contractions (P>0.54). CONCLUSION: Loss of ovarian hormones reduced muscle force generation but E2 replacement restored force indicating it is a key hormone influencing muscle function. Wheel running also restored muscle function suggesting that physical activity may be as important as E2 replacement in reversing muscle contractile dysfunction induced by the loss of ovarian hormones. Supported by NIH Grants AG20990 and T32 AR07612.