17β-Estradiol accentuates contractility of rat genioglossal muscle via regulation of estrogen receptor α

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Abstract

Objective

This study in rat genioglossus muscle (GG) was designed to test the hypothesis that the effects of estrogen are at least in part, meditated directly by the estrogen receptors (ERs) of muscle.

Design

Eighty-eight-week-old female Sprague–Dawley rats were randomly assigned to five groups: (1) normal animals (Normal); (2) sham operation animals (Sham); (3) ovariectomized animals without estrogen replacement (OVX); (4) ovariectomized animals with olive oil replacement (OVX + O); (5) ovariectomized animals with 17β-estradiol replacement (OVX + E2). Six weeks later, GG was assessed in vivo for contractile properties and further analysis for ERs expression was carried out including real-time quantitative RT-PCR, immunohistochemistry and Western blotting.

Results

The maximal twitch tension, 70%-decay time and fatigue index of GG decreased significantly in OVX group when compared with Normal group (P < 0.05, P < 0.05, P < 0.05). However, all the three parameters reversed in OVX + E2 group especially fatigue index. Further analysis showed a clear expression of ERα and ERβ in rat GG. The expression of both ERα protein and ERα mRNA was both significantly decreased in OVX group (P < 0.05) and recovered back to previous level after receiving 17β-estradiol replacement (P < 0.05). But neither ERβ protein nor ERβ mRNA was regulated by estrogen deprivation and replacement.

Conclusion

The results demonstrated that the contractility of GG was accentuated by estrogen. Moreover, these effects were at least in part, meditated directly via regulation of the expression of ERα. It might contribute to the protective effects of estrogen on the patency of upper airway and the pathogenesis of obstructive sleep apnea hypopnoea syndrome.

Introduction

Obstructive sleep apnea hypopnoea syndrome (OSAHS) is a serious, often debilitating disorder characterized by repetitive sleep-induced collapse of the upper airway (UA).1, 2 The prevalence of OSAHS has a strong male predominance. The male/female ratio of sleep apnea is between 2:1 and 4.9:1.3 And the prevalence of sleep apnea is higher in postmenopausal women without hormone replacement treatment (HRT) than in premenopausal women. In contrast, postmenopausal women with HRT had a prevalence of OSAHS similar to that of premenopausal women.4, 5

Although the causes of OSAHS are multi-factorial, it is generally thought to occur as a result of sleep-related decrements in UA muscle activity in individuals with abnormal airway anatomy. There is substantial evidence in both animals and humans that UA dilator muscles play an important role in maintaining airway patency6 and that the diminished UA dilator muscle activity may be responsible for the higher incidence of OSAHS in men and postmenopausal women.7, 8 It has been hypothesized that estrogen may have some impact on UA dilator muscle contractility. However, the actual interaction between estrogen and UA muscle activity is poorly understood as are the underlying molecular mechanisms.

The genioglossus (GG) is an important pharyngeal muscle and plays an important role in maintaining an open upper airway for effective breathing.9 GG is composed of skeletal muscle fibers. Skeletal muscle tissue is estrogen responsive because it has estrogen receptors with properties similar to those in classical target organs.10, 11, 12 The specific objective of the present study was to investigate the effects of estrogen deprivation and replacement on genioglossus muscle contractility and expression of estrogen receptors (ERs) in female rats.

Section snippets

Animals

Eighty-eight-week-old female Sprague–Dawley rats (initial weight 220 ± 20 g) were randomly assigned to five groups: (1) normal animals (Normal); (2) sham operation animals (Sham); (3) ovariectomized animals without estrogen replacement (OVX); (4) ovariectomized animals with olive oil replacement (OVX + O); (5) ovariectomized animals with 17β-estradiol replacement (OVX + E2). All procedures, in this study, were approved by Animal Care Committee of Tongji University.

For the three OVX groups, animals

Serum concentrations of estradiol and progesterone

The mean values were neither different between Normal and Sham groups nor between OVX and OVX + O groups (Fig. 1A and B). Compared with Normal group, the estradiol and progesterone levels decreased significantly in OVX group (P < 0.05, P < 0.05). Compared with OVX group, there was a significant increase in serum estradiol level in OVX + E2 group (P < 0.05), and it was higher than the estradiol level in Normal group (P < 0.05). No significant difference in serum progesterone level was detected between OVX + E2

Discussion

Although the causes of OSAHS are multi-factorial, there is evidence for abnormalities of the UA dilator muscles contraction.2 Normally, the UA dilator muscles play a crucial role in maintaining the patency of the upper airway, but there is a tendency toward collapse if there is a decrease in muscles’ activity.2 The genioglossus muscle was chosen, as it is a representative UA dilator muscle that influences UA patency by dilating the airway.13, 14 Furthermore, it is known to demonstrate

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