Department of Physiology, University College Cork, Cork, Ireland.
Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
J Physiol. 2017 Nov 1;595(21):6653-6672. doi: 10.1113/JP274792. Epub 2017 Oct 9.
Respiratory failure is a leading cause of mortality in Duchenne muscular dystrophy (DMD), but little is known about the control of breathing in DMD and animal models. We show that young (8 weeks of age) mdx mice hypoventilate during basal breathing due to reduced tidal volume. Basal CO production is equivalent in wild-type and mdx mice. We show that carotid bodies from mdx mice have blunted responses to hyperoxia, revealing hypoactivity in normoxia. However, carotid body, ventilatory and metabolic responses to hypoxia are equivalent in wild-type and mdx mice. Our study revealed profound muscle weakness and muscle fibre remodelling in young mdx diaphragm, suggesting severe mechanical disadvantage in mdx mice at an early age. Our novel finding of potentiated neural motor drive to breathe in mdx mice during maximal chemoactivation suggests compensatory neuroplasticity enhancing respiratory motor output to the diaphragm and probably other accessory muscles.
Patients with Duchenne muscular dystrophy (DMD) hypoventilate with consequential arterial blood gas derangement relevant to disease progression. Whereas deficits in DMD diaphragm are recognized, there is a paucity of knowledge in respect of the neural control of breathing in dystrophinopathies. We sought to perform an analysis of respiratory control in a model of DMD, the mdx mouse. In 8-week-old male wild-type and mdx mice, ventilation and metabolism, carotid body afferent activity, diaphragm muscle force-generating capacity, and muscle fibre size, distribution and centronucleation were determined. Diaphragm EMG activity and responsiveness to chemostimulation was determined. During normoxia, mdx mice hypoventilated, owing to a reduction in tidal volume. Basal CO production was not different between wild-type and mdx mice. Carotid sinus nerve responses to hyperoxia were blunted in mdx, suggesting hypoactivity. However, carotid body, ventilatory and metabolic responses to hypoxia were equivalent in wild-type and mdx mice. Diaphragm force was severely depressed in mdx mice, with evidence of fibre remodelling and damage. Diaphragm EMG responses to chemoactivation were enhanced in mdx mice. We conclude that there is evidence of chronic hypoventilation in young mdx mice. Diaphragm dysfunction confers mechanical deficiency in mdx resulting in impaired capacity to generate normal tidal volume at rest and decreased absolute ventilation during chemoactivation. Enhanced mdx diaphragm EMG responsiveness suggests compensatory neuroplasticity facilitating respiratory motor output, which may extend to accessory muscles of breathing. Our results may have relevance to emerging treatments for human DMD aiming to preserve ventilatory capacity.
呼吸衰竭是杜兴氏肌营养不良症（DMD）患者死亡的主要原因，但人们对 DMD 患者和动物模型的呼吸控制知之甚少。我们发现，年轻（8 周龄）mdx 小鼠在基础呼吸时会出现通气不足，这是由于潮气量减少所致。野生型和 mdx 小鼠的基础 CO 产生量相当。我们发现，mdx 小鼠的颈动脉体对高氧的反应迟钝，表明在正常氧合下活动减弱。然而，野生型和 mdx 小鼠的颈动脉体、通气和代谢对缺氧的反应是相当的。我们的研究揭示了年轻 mdx 膈肌中严重的肌肉无力和纤维重塑，这表明 mdx 小鼠在早期就存在严重的机械劣势。我们的新发现表明，在最大化学刺激下，mdx 小鼠呼吸的神经运动驱动增强，这表明神经可塑性增强，从而增强了对膈肌和可能其他辅助呼吸肌的呼吸运动输出。
杜兴氏肌营养不良症（DMD）患者通气不足，导致动脉血气紊乱，与疾病进展有关。尽管人们已经认识到 DMD 膈肌的缺陷，但在肌营养不良症中，呼吸的神经控制知识仍然匮乏。我们试图在 DMD 的模型，mdx 小鼠中进行呼吸控制分析。在 8 周龄的雄性野生型和 mdx 小鼠中，测定了通气和代谢、颈动脉体传入活动、膈肌产生力量的能力、肌肉纤维大小、分布和中央核化。还测定了膈肌肌电图活动和对化学刺激的反应性。在正常氧合下，mdx 小鼠通气不足，这是由于潮气量减少所致。野生型和 mdx 小鼠的基础 CO 产生量没有差异。mdx 中颈动脉窦神经对高氧的反应迟钝，表明活动减弱。然而，颈动脉体、通气和代谢对缺氧的反应在野生型和 mdx 小鼠中是相当的。mdx 小鼠的膈肌力量严重下降，有纤维重塑和损伤的证据。mdx 小鼠的膈肌肌电图对化学刺激的反应增强。我们的结论是，年轻的 mdx 小鼠有慢性通气不足的证据。膈肌功能障碍导致 mdx 机械缺陷，导致在休息时产生正常潮气量的能力受损，在化学刺激时绝对通气量减少。增强的 mdx 膈肌肌电图反应性表明代偿性神经可塑性促进呼吸运动输出，这可能扩展到呼吸的辅助肌肉。我们的研究结果可能与旨在保持人类 DMD 患者通气能力的新兴治疗方法有关。
