雌激素对肥胖致上气道肌群结构和功能变化的影响及机制研究

The upper airway muscles are recognized as the main participant in the pathogenesis of obstructive sleep apnea (OSA), due to the change of physiological properties related to the different fiber types. Estrogen may partially explain the gender difference of the OSAHS incidence. The protective effects of estrogen on skeletal muscle in response to stressors such as chronic intermittent hypoxia, and higher level glucose have been reported. Most studies focus on how estrogen affects the upper airway muscles of OSA to clarify the role of estrogen on CIH-induced muscle change. However, it is more important to explore how estrogen affects the upper airway muscle changes related to obesity, which will help to clarify the pathogenesis of OSA. It has been found that there are gender difference in obesity-induced muscles physiologic changes, which are related to the flux through the ubiquitin-proteasome system (UPS) and autophagic/lysosomal pathways (ALP). However, there is still no study focus on the effects and mechanisms of estrogen on the obesity-induced fiber type and functional change of upper airway muscles. Thus, based on our previous study, we hypothesize that the estrogen affects the obesity-induced fiber type transformation by the ubiquitin-proteasome system (UPS) and autophagic/lysosomal system (ALP) pathways, or through the AMPK/PGC-1a pathway. Herein, we explore the mechanism of how estrogen affects the upper airway muscles, and provide a new insight on the targets of OSA treatment.

阻塞性睡眠呼吸暂停低通气综合征（OSAHS）上气道肌肉机制与肌纤维类型相关。OSAHS性别差异部分归因于雌激素。雌激素对上气道肌肉的影响表现在其应对各类应激时的保护作用。目前研究集中在慢性间歇低氧（CIH）刺激下雌激素的作用。然而，立足OSA的发病机制，探讨发病相关危险因素存在前提下雌激素的保护作用则意义更大。研究显示肥胖致骨骼肌纤维类型转化存在性别差异，雌激素可影响纤维类型转化过程。但是，关于雌激素对肥胖致上气道肌肉纤维类型转化的作用及机制尚无报道。因此，结合我们的前期研究结果，提出如下假说：雌激素影响肥胖致上气道肌群肌纤维的分化过程，可能机制一方面涉及AMPK/PGC-1a信号通路的活化，另一方面通过调节自噬-溶酶体系统/泛素化-蛋白酶体系统来实现。本研究拟应用高脂肥胖动物模型及脂肪因子致肌纤维分化的细胞模型，探讨雌激素对肥胖所致的上气道肌群肌纤维类型转化的影响及相关机制。

肥胖作为 OSA 主要危险因素之一，其参与 OSA 发病不仅包括了局部脂肪沉积效应，还涉及到脂肪因子对上气道肌肉结构和功能的影响。内脏脂肪素（Visfatin）作为一种脂肪因子及合成NAD+的关键酶最近广受关注，Visfatin作为脂肪因子如何影响上气道肌群及相关机制尚不清楚。已有研究表明，OSA的靶器官损伤及Visfatin对靶器官的作用均存在性别差异，而雌激素可能是其中的关键因素。本研究证实，Visfatin介导高脂导致的骨骼肌改变，并证明雌激素与Visfatin对骨骼肌的影响存在协同作用。