Abstract：
Duchenne muscular dystrophy (DMD) is characterised by respiratory muscle injury, inflammation, fibrosis and weakness, ultimately culminating in respiratory failure. The dystrophin-deficient mouse model of DMD (mdx) shows evidence of respiratory muscle remodelling and dysfunction contributing to impaired respiratory system performance. The antioxidant N-acetylcysteine (NAC) has been shown to exert anti-inflammatory and anti-fibrotic effects leading to improved respiratory muscle performance in a range of animal models of muscle dysfunction, including mdx mice, following short-term administration (2 weeks). We sought to build on previous work by exploring the effects of chronic NAC administration (3 months) on respiratory system performance in mdx mice. One-month-old male mdx mice were randomised to receive normal drinking water (n = 30) or 1% NAC in the drinking water (n = 30) for 3 months. At 4 months of age, we assessed breathing in conscious mice by plethysmography followed by ex vivo assessment of diaphragm force-generating capacity. Additionally, diaphragm histology was performed. In separate studies, in anaesthetised mice, respiratory electromyogram (EMG) activity and inspiratory pressure across a range of behaviours were determined, including assessment of peak inspiratory pressure-generating capacity. NAC treatment did not affect force-generating capacity of the mdx diaphragm. Collagen content and immune cell infiltration were unchanged in mdx + NAC compared with mdx diaphragms. Additionally, there was no significant effect of NAC on breathing, ventilatory responsiveness, inspiratory EMG activity or inspiratory pressure across the range of behaviours from basal conditions to peak system performance. We conclude that chronic NAC treatment has no apparent beneficial effects on respiratory system performance in the mdx mouse model of DMD suggesting limited potential of NAC treatment alone for human DMD.
摘要：
杜氏肌营养不良症（DMD）的特征是呼吸肌损伤，炎症,纤维化和虚弱，最终导致呼吸衰竭.DMD（mdx）的肌营养不良蛋白缺陷小鼠模型显示了呼吸肌重塑和功能障碍导致呼吸系统性能受损的证据。抗氧化剂N-乙酰半胱氨酸（NAC）已被证明可以发挥抗炎和抗纤维化作用，从而在一系列肌肉功能障碍的动物模型中改善呼吸肌的性能。包括MDX老鼠,短期给药（2周）后。我们试图通过探索慢性NAC给药（3个月）对mdx小鼠呼吸系统性能的影响来建立先前的工作。一个月大的雄性mdx小鼠随机接受正常饮用水(n=30)或饮用水中的1%NAC(n=30)3个月。在4个月大的时候，我们通过体积描记术评估清醒小鼠的呼吸,然后通过离体评估膈肌力产生能力.此外,进行膈肌组织学检查.在单独的研究中，在麻醉的老鼠身上，确定了一系列行为的呼吸肌电图（EMG）活动和吸气压力，包括峰值吸气压力产生能力的评估。NAC处理不影响mdx隔膜的力产生能力。与mdx隔膜相比，mdxNAC中的胶原蛋白含量和免疫细胞浸润没有变化。此外,NAC对呼吸没有显著影响,通气反应性，从基础条件到峰值系统性能的行为范围内的吸气EMG活动或吸气压力。我们得出的结论是，在DMD的mdx小鼠模型中，慢性NAC治疗对呼吸系统性能没有明显的有益作用，这表明仅NAC治疗对人DMD的潜力有限。
