Does sleep apnea exacerbate respiratory muscle dysfunction in muscular dystrophy?

描述(申请人提供)：Duchenne肌营养不良症(DMD)是一种致命性和致残性疾病，由膜稳定蛋白dystrophin突变引起。营养不良蛋白缺乏的肌肉比正常肌肉更容易受到各种压力的影响。呼吸肌是生存的关键，呼吸肌衰竭是导致DMD死亡的主要原因。睡眠呼吸障碍(SDB)很常见，据报道，80%的DMD患者存在夜间气体交换异常和睡眠结构紊乱，这是SDB的特征。睡眠时通气量的减少会导致动脉血氧分压(缺氧)的周期性降低，包括肿瘤坏死因子-1在内的多种炎性细胞因子的升高，以及活性氧物种(ROS)的产生，所有这些都可能影响肌肉细胞的功能。此外，对伴随着SDB的氧气水平周期性变化的生理反应包括交感神经放电增加和呼吸肌(上呼吸道和呼吸肌)的激活，这些因素也可以影响肌肉功能。尽管SDB在DMD患者中普遍存在，但SDB对DMD患者呼吸肌功能的影响尚不清楚。我们假设SDB加重了DMD的呼吸肌功能障碍。营养不良小鼠(Dmdmdx)的初步数据显示，实验性睡眠呼吸暂停加剧了横隔膜收缩功能的下降。拟议的研究将描述在DMD动物模型中SDB导致呼吸肌功能障碍的机械和生化机制。更具体地说，拟议的研究将评估1)针对间歇性低氧而增加的肌肉招募(机械应激)对呼吸肌功能的可能影响；2)评估由肿瘤坏死因子-1机制介导的可能的作用；以及3)评估氧化应激在介导营养不良蛋白缺乏的呼吸肌的SDB功能障碍中的作用。为此，将在长期(长达12周)每天(每天8小时，每周5天)暴露于实验性睡眠呼吸暂停(间歇性低氧)的Dmdmdx小鼠中模拟SDB。呼吸肌的功能障碍将通过测量功能参数(呼吸策略、力量输出和分离肌束的疲劳性)、生化标记物(胶原含量、脂质过氧化和炎症细胞因子)以及组织学/形态计量学标记物(中央成核、纤维大小和纤维丢失和纤维化的程度)来评估。与公共卫生相关。睡眠呼吸障碍(SDB)在Duchenne肌营养不良症(DMD)中很常见，可能会加重呼吸肌功能障碍。研究将使用Dmdmdx-小鼠来研究几种可能导致呼吸肌功能障碍的机制(机械和生化应激源)。由于呼吸肌衰竭是DMD死亡的主要原因，这些研究将揭示旨在预防DMD呼吸肌衰竭的新的治疗方法。

DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD), a fatal and crippling disease, results from a mutation of the membrane stabilizing protein dystrophin. Dystrophin-deficient muscles are more susceptible than normal to a variety of stresses. The respiratory muscles are critical for survival and their failure is a leading cause of death in DMD. Sleep disturbed breathing (SDB) is common and nocturnal gas exchange abnormalities and disrupted sleep architecture, hallmarks of SDB, have been reported in > 80% of DMD patients. Reduced ventilation during sleep results in cyclic decreases in arterial oxygen tensions (hypoxia), in elevations of several inflammatory cytokines including TNF-1, and in the production of reactive oxygen species (ROS), all of which can putatively impact muscle cell function. In addition, physiologic responses to cyclic alterations in oxygen levels that accompany SDB include increased sympathetic discharge and enhanced activation of the respiratory muscles (upper airway and ventilatory), factors which can also impact muscle function. Despite the pervasiveness of SDB in DMD patients, the effects of SDB on respiratory muscle function in DMD remain unknown. We hypothesize that SDB exacerbates dysfunction of the respiratory muscle in DMD. Preliminary data in dystrophic mice (Dmdmdx) reveal that experimental sleep apnea intensifies functional declines in diaphragm contractility. Proposed studies will delineate mechanical and biochemical mechanisms responsible for SDB induced respiratory muscle dysfunction in an animal model of DMD. More specifically, the proposed studies will assess 1) the putative impact of enhanced muscle recruitment (mechanical stress) in response to episodic hypoxia on respiratory muscle function; 2) to assess the putative role mediated by TNF-1 mechanisms; and 3) to assess the role attributed to oxidative stress in mediating SDB dysfunction of dystrophin-deficient respiratory muscles. To this end, SDB will be simulated in Dmdmdx- mice with long term (up to 12 weeks) diurnal (8 hrs per day, 5 days a week) exposure to experimental sleep apnea (episodic hypoxia). The dysfunction of the respiratory muscles will be assessed by measuring functional parameters (breathing strategies, force output and fatigability of isolated muscle bundles), biochemical markers (collagen content, lipid peroxidation, and inflammatory cytokines), and histological/ morphometric markers (central nucleation, fiber size, and extent of fiber loss and fibrosis). PUBLIC HEALTH RELEVANCE. Sleep disordered breathing (SDB) is prevalent in Duchenne Muscular Dystrophy (DMD) and may exacerbate dysfunction of the respiratory muscles. Studies will investigate several putative mechanisms (mechanical and biochemical stressors) that contribute to respiratory muscle dysfunction using Dmdmdx-mice. Since respiratory muscle failure is a leading cause of death in DMD, these studies will reveal new therapeutic modalities aimed at preventing respiratory muscle failure in DMD.