Contribution of extra‐diaphragmatic inspiratory muscles to peak inspiratory pressure in wild‐type and dystrophic ( mdx ) mice

Abstract

Peak inspiratory pressure-generating capacity is preserved in mdx dystrophic mice, despite profound diaphragm muscle weakness and a reduction in peak diaphragm electromyogram activity1. Our data reveal a capacity for compensation afforded by accessory muscles of breathing, adequate to sustain peak respiratory system performance, at least in early dystrophic disease1,2. We hypothesise that there is a greater contribution by extra-diaphragmatic inspiratory muscles to peak respiratory system performance in mdx mice, a compensation that is ultimately lost with advancing disease. In anesthetized 4-month old wild-type and mdx mice, inspiratory pressure and respiratory electromyogram activities were measured under baseline conditions and following unilateral and bilateral phrenic nerve section, confirmed by bilateral loss of phasic electrical activity in costal electromyogram recordings. Parasternal intercostal electromyogram was recorded in phrenicotomized mice during sustained tracheal occlusion to generate maximal respiratory muscle activation and peak inspiratory pressure. In separate 4-month-old mice with intact phrenic nerves, peak inspiratory pressure was -74±13 cmH20 (mean±SD) in wild-type control mice (n=12) and -90±21 cmH20 in mdx mice (n=13), confirming our previous observation of a retained capacity to achieve normal peak inspiratory pressure in mdx mice, despite diaphragm weakness (50% reduction in peak diaphragm force)1. In 4-month-old phrenicotomized mice, peak inspiratory pressure was -26±9 cmH20 in wild-type mice (n=8) and -55±10 cmH20 in mdx mice (n=8); p<0.05. Peak parasternal EMG activity coinciding with peak pressure generation during airway obstruction was greater in wild-type 34±22 mV.s compared to mdx 23±11 mV.s. Our results confirm the greater reliance on extra-diaphragmatic inspiratory muscles in support of peak inspiratory performance in mdx mice. Despite a 50% reduction in peak diaphragm force, mdx mice generate peak inspiratory pressures that match or exceed those of wild-type mice. Following acute paralysis of the diaphragm, mdx mice generate peak inspiratory pressures that are double that of wild-type mice. These findings suggest plasticity in extra-diaphragmatic motor pathways of breathing. Since there was no evidence of greater recruitment of the obligatory inspiratory parasternal intercostal muscles, we hypothesize a greater contribution by accessory motor pathways in support of peak inspiratory performance in dystrophic mice. We reason that this compensatory plasticity is progressively lost in advancing dystrophic disease, culminating in respiratory morbidity and ultimately failure.