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

Pangdra Vang,Rebecca Barok,Alexie A Larson,Dawn A Lowe,Brendan J Dougherty,Cory W Baumann,Gerhard Wiche

doi:10.1371/journal.pone.0249472

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.

Highlights

Duchenne muscular dystrophy (DMD) is a devastating muscular dystrophy, affecting approximately 1 in 5,000 male births, where a complete absence of dystrophin causes progressive muscle degeneration and weakness, leading to death from respiratory or cardiac failure [1,2,3,4]
There were no significant changes in respiratory rate (RR), VT, and VE, across time (Pre, 8, and 24 wk) or between sham and OVX mice during eupnea (p 0.163) except for duty cycle, which was ~20% higher at 8 and 24 wk than Pre
Because only effects of time were detected across the ventilatory parameters, these results indicate that estrogen deficiency has no impact on ventilatory function of adult female mdx mice

Summary

Introduction

Duchenne muscular dystrophy (DMD) is a devastating muscular dystrophy, affecting approximately 1 in 5,000 male births, where a complete absence of dystrophin causes progressive muscle degeneration and weakness, leading to death from respiratory or cardiac failure [1,2,3,4]. Despite DMD occurring predominantly in males, female carriers (i.e., females who carry a mutation of the DMD gene on one of their X-chromosomes) may display symptoms of DMD [5,6]. Women displaying symptoms are referred to as manifesting carriers [5,6]. Moser and Emery cites the first case of a manifesting carrier of DMD was in 1934 by Kryschowa and Abowjan [6]. While the majority of female carriers do not manifest symptoms, studies have shown that 2–17% develop DMD symptomology [5,7,8]. Similar to males with DMD, manifesting carriers present with skeletal muscle weakness and cardiomyopathy, with the gravity of skeletal muscle weakness ranging from mild muscle weakness to more severe DMD-like progression [8,9,10,11]

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