Impact of estrogen deficiency on diaphragm and leg muscle contractile function in female mdx mice

Abstract

Female carriers of Duchenne muscular dystrophy (DMD) presenting with DMD symptomology similar to males with DMD, such as skeletal muscle weakness and cardiomyopathy, are termed manifesting carriers. There is phenotypic variability among manifesting carriers including the age of onset, which can range from the first to fourth decade of life. In females, estrogen levels typically begin to decline during the fourth decade of life and estrogen deficiency contributes to loss of muscle strength and recovery of strength following injury. Thus, we questioned whether the decline of estrogen impacts the development of DMD symptoms in females. To address this question, we studied 6–8 month-old homozygous mdx female mice randomly assigned to a sham or ovariectomy (OVX) surgical group. In vivo whole-body plethysmography assessed ventilatory function and diaphragm muscle strength was measured in vitro before and after fatigue. Anterior crural muscles were analyzed in vivo for contractile function, fatigue, and in response to eccentric contraction (ECC)-induced injury. For the latter, 50 maximal ECCs were performed by the anterior crural muscles to induce injury. Body mass, uterine mass, hypoxia-hypercapnia ventilatory response, and fatigue index were analyzed by a pooled unpaired t-test. A two-way ANOVA was used to analyze ventilatory measurements. Fatigue and ECC-injury recovery experiments were analyzed by a two-way repeated-measures ANOVA. Results show no differences between sham and OVX mdx mice in ventilatory function, strength, or recovery of strength after fatigue in the diaphragm muscle or anterior crural muscles (p ≥ 0.078). However, OVX mice had significantly greater eccentric torque loss and blunted recovery of strength after ECC-induced injury compared to sham mice (p ≤ 0.019). Although the results show that loss of estrogen has minimal impact on skeletal muscle contractile function in female mdx mice, a key finding suggests that estrogen is important in muscle recovery in female mdx mice after injury.

Sensitivity to behavioral stress impacts disease pathogenesis in dystrophin‐deficient mice

“…These data indicate E2 directly regulates the stress response of female mdx mice to mild stressors such as forced downhill treadmill exercise but not to moderate stressors such as scruff restraint. These data build on several observations that E2 positively impacts other aspects of DMD pathophysiology 60,61 and it strengthens the basis for the selective estrogen receptor modulator study (tamoxifen; NCT03354039) on DMD. However, although female mdx mice were more physically active than males, there were no differences in the amount of central nucleated fibers, fat content, capillary density or utrophin expression; suggesting sex does not affect characteristic histopathological markers of DMD.…”

Global phosphoproteomic profiling of skeletal muscle in ovarian hormone-deficient mice

“…Appropriate autophagic ux is required to remove and degrade damaged proteins and cell organelles in muscle, and inhibition of autophagy induces atrophy and myopathies (49,50). Estrogen de ciency, via ovariectomy, aging, or in a diseased state, decreases the ability of skeletal muscle to generate force and reduces recovery of muscle strength from injury (10,(51)(52)(53)(54)(55)(56). Accordingly, the IPA predicted inhibition in contractility of muscle in estrogen-de cient mice supports what we and others have observed in vitro and in vivo in skeletal muscle and sheds light on underlying molecular mechanisms.…”

Time course changes in in vivo muscle mechanical function and Ca2+ regulation of force following experimentally induced gradual ovarian failure in mice

“…( 2021 ) observed no differences in the plantar flexor torque–frequency relationship between OVX mice, controls and OVX mice that received 17β‐estradiol. Others have also observed no differences in maximum isometric dorsiflexion torque between control and OVX mice 8 weeks following removal of the ovaries (Kosir et al., 2015 ; Vang et al., 2021 ). Cabelka et al.…”