Inspiratory pressure-generating capacity is preserved during ventilatory and non-ventilatory behaviours in young dystrophic mdx mice despite profound diaphragm muscle weakness.

KEY POINTS: Respiratory muscle weakness is a major feature of Duchenne muscular dystrophy (DMD), yet little is known about the neural control of the respiratory muscles in DMD and animal models of dystrophic disease. Substantial diaphragm muscle weakness is apparent in young (8-week-old) mdx mice, although ventilatory capacity in response to maximum chemostimulation in conscious mice is preserved. Peak volume- and flow-related measures during chemoactivation are equivalent in anaesthetized, vagotomized wild-type and mdx mice. Diaphragm and T3 external intercostal electromyogram activities are lower during protracted sustained airway occlusion in mdx compared to wild-type mice. Yet, peak inspiratory pressure generation is remarkably well preserved. Despite profound diaphragm weakness and lower muscle activation during maximum non-ventilatory efforts, inspiratory pressure-generating capacity is preserved in young adult mdx mice, revealing compensation in support of respiratory system performance that is adequate, at least early in dystrophic disease. ABSTRACT: Diaphragm dysfunction is recognized in the mdx mouse model of muscular dystrophy; however, there is a paucity of information concerning the neural control of dystrophic respiratory muscles. In young adult (8 weeks of age) male wild-type and mdx mice, we assessed ventilatory capacity, neural activation of the diaphragm and external intercostal (EIC) muscles and inspiratory pressure-generating capacity during ventilatory and non-ventilatory behaviours. We hypothesized that respiratory muscle weakness is associated with impaired peak inspiratory pressure-generating capacity in mdx mice. Ventilatory responsiveness to hypercapnic hypoxia was determined in conscious mice by whole-body plethysmography. Diaphragm isometric and isotonic contractile properties were determined ex vivo. In anaesthetized mice, thoracic oesophageal pressure, and diaphragm and EIC electromyogram (EMG) activities were recorded during baseline conditions and sustained tracheal occlusion for 30-40s. Despite substantial diaphragm weakness, mdx mice retain the capacity to enhance ventilation during hypercapnic hypoxia. Peak volume- and flow-related measures were also maintained in anaesthetized, vagotomized mdx mice. Peak inspiratory pressure was remarkably well preserved during chemoactivated breathing, augmented breaths and maximal sustained efforts during airway obstruction in mdx mice. Diaphragm and EIC EMG activities were lower during airway obstruction in mdx compared to wild-type mice. We conclude that ventilatory capacity is preserved in young mdx mice. Despite profound respiratory muscle weakness and lower diaphragm and EIC EMG activities during high demand in mdx mice, peak inspiratory pressure is preserved, revealing adequate compensation in support of respiratory system performance, at least early in dystrophic disease. We suggest that a progressive loss of compensation during advancing disease, combined with diaphragm dysfunction, underpins the development of respiratory system morbidity in dystrophic diseases.