Maxwell Michael N, Marullo Anthony L, Valverde-Pérez Esther, Slyne Aoife D, Murphy Ben T, O'Halloran Ken D
Department of Physiology, University College Cork, Cork, Ireland.
Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain.
Exp Physiol. 2024 Aug;109(8):1370-1384. doi: 10.1113/EP091862. Epub 2024 Jun 12.
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.
杜兴氏肌营养不良症（DMD）的特征是呼吸肌损伤、炎症、纤维化和无力，最终导致呼吸衰竭。DMD的肌营养不良蛋白缺陷小鼠模型（mdx）显示出呼吸肌重塑和功能障碍的证据，这导致呼吸系统性能受损。抗氧化剂N-乙酰半胱氨酸（NAC）已被证明在包括mdx小鼠在内的一系列肌肉功能障碍动物模型中，短期给药（2周）后具有抗炎和抗纤维化作用，从而改善呼吸肌性能。我们试图在先前工作的基础上，探索长期给予NAC（3个月）对mdx小鼠呼吸系统性能的影响。将1月龄雄性mdx小鼠随机分为两组，一组饮用正常饮用水（n = 30），另一组饮用含1%NAC的饮用水（n = 30），持续3个月。在4月龄时，我们通过体积描记法评估清醒小鼠的呼吸，随后对膈肌产生力的能力进行离体评估。此外，还进行了膈肌组织学检查。在单独的研究中，对麻醉小鼠测定了一系列行为中的呼吸肌电图（EMG）活动和吸气压力，包括对峰值吸气压力产生能力的评估。NAC治疗对mdx膈肌产生力的能力没有影响。与mdx膈肌相比，mdx + NAC组的胶原蛋白含量和免疫细胞浸润没有变化。此外，从基础状态到系统性能峰值的一系列行为中，NAC对呼吸、通气反应性、吸气EMG活动或吸气压力均无显著影响。我们得出结论，长期给予NAC对DMD的mdx小鼠模型的呼吸系统性能没有明显的有益作用，这表明单独使用NAC治疗人类DMD的潜力有限。
