Influence of Ovarian Hormones on Strength Loss in Healthy and Dystrophic Female Mice

Abstract

Purpose The primary objective of this study was to determine if strength loss and recovery following eccentric contractions is impaired in healthy and dystrophic female mice with low levels of ovarian hormones. Methods Female C57BL/6 (wildtype) or mdx mice were randomly assigned to ovarian-intact (Sham) and ovariectomized (Ovx) groups. Anterior crural muscles were tested for susceptibility to injury from 150 or 50 eccentric contractions in wildtype and mdx mice, respectively. An additional experiment challenged mdx mice with a 2-wk treadmill running protocol followed by an eccentric contraction injury to posterior crural muscles. Functional recovery from injury was evaluated in wildtype mice by measuring isometric torque 3, 7, 14, or 21 days following injury. Results Ovarian hormone deficiency in wildtype mice did not impact susceptibility to injury as the ~50% isometric torque loss following eccentric contractions did not differ between Sham and Ovx mice (p=0.121). Similarly in mdx mice, hormone deficiency did not affect percent of pre injury isometric torque lost by anterior crural muscles following eccentric contractions (p=0.952), but the percent of pre injury torque in posterior crural muscles was lower in Ovx compared to Sham mice (p=0.014). Recovery from injury in wildtype mice was affected by hormone deficiency. Sham mice recovered pre injury isometric strength by 14 days (96 ± 2%) while Ovx mice maintained deficits at 14 and 21 days post injury (80 ± 3% and 84 ± 2%; p<0.001) Conclusion Ovarian hormone status did not impact the vulnerability of skeletal muscle to strength loss following eccentric contractions. However, ovarian hormone deficiency did impair the recovery of muscle strength in female mice.

Effects of the selective inhibition of proteasome caspase-like activity by CLi a derivative of nor-cerpegin in dystrophic mdx mice

“…This exercise protocol is recommended for pre-clinical studies (Treat-NMD, DMD_M.2.1.001). However, we found that muscle weakness and fragility were not exacerbated in the Run mdx as compared to Sed mdx mice, confirming a previous study [28]. These results indicate that the use of a more severe murine Duchenne muscular dystrophy model than the exercised mdx mice would be more useful in pre-clinical studies.…”

Estrogen Regulates the Satellite Cell Compartment in Females

“…Serum estradiol concentration declines dramatically at the average age of 51 in women, corresponding to the time of menopause (Baber et al, 2016). Estradiol deficiency reduces skeletal muscle mass and force generation in women (Greising et al, 2009; Phillips et al, 1993, 1996; Qaisar et al, 2013; Taaffe et al, 2005) and female rodents (Greising et al, 2011; Moran et al, 2007) and prevents the recovery of strength following contraction-induced muscle injury (Kosir et al, 2015; Rader and Faulkner, 2006) and traumatic muscle injury in female mice (Le et al, 2018). However, evidence that this regenerative phenotype involves effects of estradiol directly on satellite cells is lacking.…”

Estrogen Regulates the Satellite Cell Compartment in Females

“…Serum estradiol concentration declines dramatically at the average age of 51 in women, corresponding to the time of menopause (Baber et al, 2016). Estradiol deficiency reduces skeletal muscle mass and force generation in women (Greising et al, 2009;Phillips et al, 1993;Phillips et al, 1996;Qaisar et al, 2013;Taaffe et al, 2005) and female rodents (Greising et al, 2011;Le et al, 2017;Moran et al, 2007) and prevents full recovery of strength following contraction-induced injury (Kosir et al, 2015;Rader and Faulkner, 2006).…”

“…Mechanistically, it has been hypothesized that the regulation of muscle inflammation (Le et al, 2015;McClung et al, 2007;Tiidus et al, 2001) and protein synthesis (Kamanga-Sollo et al, 2010;Kosir et al, 2015;McClung et al, 2007;McClung et al, 2006) is perturbed by estradiol deficiency and may contribute to impaired recovery . Previous work has also indicated that exercise-induced activation of satellite cells is less effective in the absence of estradiol , and that androgens contribute to the regulation of juvenile satellite cells during growth (Kim et al, 2016), but it has yet to be determined if there are cell autonomous mechanisms which involve estradiol acting directly on satellite cells .…”