Abstract：
Despite profound diaphragm weakness, peak inspiratory pressure-generating capacity is preserved in young mdx mice revealing adequate compensation by extra-diaphragmatic muscles of breathing in early dystrophic disease. We hypothesised that loss of compensation gives rise to respiratory system compromise in advanced dystrophic disease. Studies were performed in male wild-type (n = 196) and dystrophin-deficient mdx mice (n = 188) at 1, 4, 8, 12 and 16 months of age. In anaesthetised mice, inspiratory pressure and obligatory and accessory respiratory EMG activities were recorded during baseline and sustained tracheal occlusion for up to 30-40 s to evoke peak system activation to task failure. Obligatory inspiratory EMG activities were lower in mdx mice across the ventilatory range to peak activity, emerging in early dystrophic disease. Early compensation protecting peak inspiratory pressure-generating capacity in mdx mice, which appears to relate to transforming growth factor-β1-dependent fibrotic remodelling of the diaphragm and preserved accessory muscle function, was lost at 12 and 16 months of age. Denervation and surgical lesion of muscles of breathing in 4-month-old mice revealed a greater dependency on diaphragm for peak inspiratory performance in wild-type mice, whereas mdx mice were heavily dependent upon accessory muscles (including abdominal muscles) for peak performance. Accessory EMG activities were generally preserved or enhanced in young mdx mice, but peak EMG activities were lower than wild-type by 12 months of age. In general, ventilation was reasonably well protected in mdx mice until 16 months of age. Despite the early emergence of impairments in the principal obligatory muscles of breathing, peak inspiratory performance is compensated in early dystrophic disease due to diaphragm remodelling and facilitated contribution by accessory muscles of breathing. Loss of compensation afforded by accessory muscles underpins the emergence of respiratory system morbidity in advanced dystrophic disease. KEY POINTS: Despite diaphragm weakness, peak inspiratory performance is preserved in young dystrophin-deficient mdx mice revealing adequate compensation by extra-diaphragmatic muscles. Peak obligatory muscle (diaphragm, external intercostal, and parasternal intercostal) EMG activities are lower in mdx mice, emerging early in dystrophic disease, before the temporal decline in peak performance. Peak EMG activities of some accessory muscles are lower, whereas others are preserved. There is greater recruitment of the trapezius muscle in mdx mice during peak system activation. In phrenicotomised mice with confirmed diaphragm paralysis, there is a greater contribution made by extra-diaphragmatic muscles to peak inspiratory pressure in mdx compared with wild-type mice. Surgical lesion of accessory (including abdominal) muscles adversely affects peak pressure generation in mdx mice. Diaphragm remodelling leading to stiffening provides a mechanical advantage to peak pressure generation via the facilitated action of extra-diaphragmatic muscles in early dystrophic disease. Peak accessory EMG activities are lower in 12-month-old mdx compared to wild-type mice. Peak inspiratory pressure declines in mdx mice with advanced disease. We conclude that compensation afforded by accessory muscles of breathing declines in advanced dystrophic disease precipitating the emergence of respiratory system dysfunction.
摘要：
尽管隔膜严重薄弱，在年轻的mdx小鼠中，峰值吸气压力产生能力得以保留，这表明在早期营养不良性疾病中，diaphragm肌外的呼吸得到了充分的补偿。我们假设补偿的丧失会导致晚期营养不良性疾病的呼吸系统受损。在1、4、8、12和16月龄的雄性野生型(n=196)和肌营养不良蛋白缺陷型mdx小鼠(n=188)中进行研究。在麻醉小鼠中，在基线和持续气管闭塞长达30-40s期间记录吸气压力以及强制性和附属呼吸肌电图活动，以引起任务失败的峰值系统激活。mdx小鼠的强制性吸气EMG活动在通气范围至峰值活动期间较低，出现在早期的营养不良疾病。早期补偿保护mdx小鼠的峰值吸气压力产生能力，这似乎与隔膜的转化生长因子-β1依赖性纤维化重塑和保留的副肌功能有关，在12个月和16个月大的时候失去了。4月龄小鼠呼吸肌肉的神经支配和手术损伤显示，野生型小鼠的峰值吸气性能对隔膜的依赖性更大，而mdx小鼠在很大程度上依赖于副肌（包括腹部肌肉）的最佳表现。在年轻的mdx小鼠中，辅助EMG活动通常得到保留或增强，但是到12个月大时，峰值EMG活动低于野生型。总的来说,在16个月大之前，mdx小鼠的通气得到了相当好的保护。尽管呼吸的主要强制性肌肉早期出现了损伤，在早期的营养不良性疾病中，由于diaphragm肌重塑和呼吸辅助肌的促进作用，峰值吸气性能得到了补偿。辅助肌肉提供的补偿损失是晚期营养不良性疾病中呼吸系统发病率的出现。关键点：尽管隔膜薄弱，在年轻的肌营养不良蛋白缺乏的mdx小鼠中，峰值吸气性能得以保留，这表明膈外肌具有足够的补偿作用。峰值强制肌(膈肌，外部肋间,mdx小鼠的胸骨旁肋间）EMG活动较低，出现在营养不良疾病的早期，在峰值性能暂时下降之前。某些副肌的EMG活动峰值较低，而其他人则被保存下来。在峰值系统激活期间，mdx小鼠的斜方肌募集更多。在证实膈肌麻痹的膈肌切除小鼠中，与野生型小鼠相比，mdx的膈外肌对峰值吸气压力的贡献更大。附属（包括腹部）肌肉的手术病变会对mdx小鼠的峰值压力产生产生不利影响。导致硬化的膈肌重塑通过早期营养不良性疾病中膈外肌的促进作用为峰值压力产生提供了机械优势。与野生型小鼠相比，12月龄mdx的峰值辅助EMG活性较低。患有晚期疾病的mdx小鼠的峰值吸气压力下降。我们得出的结论是，晚期营养不良性疾病的呼吸辅助肌肉所提供的补偿下降，从而导致呼吸系统功能障碍的出现。
