Obligatory and accessory respiratory muscle structure, function and control in early and advanced disease in the mdx mouse model of Duchenne muscular dystrophy.

Abstract

Peak inspiratory pressure-generating capacity is preserved in the mdx mouse model of Duchenne muscular dystrophy in early disease, despite profound diaphragm muscle weakness and reduced electrical activation, revealing adequate compensation by extra-diaphragmatic muscles. Respiratory system compensation is lost as disease progresses, with the emergence of reduced peak inspiratory pressure-generating capacity in advanced disease. We hypothesised that extra-diaphragmatic inspiratory muscles compensate for diaphragm dysfunction in early dystrophic disease, supporting the maintenance of peak respiratory performance in mdx mice. We reasoned that extra-diaphragmatic muscle dysfunction would emerge with progressive disease, leading to the loss of peak inspiratory pressure-generating capacity in advanced dystrophic disease. We measured ventilation, inspiratory pressure, and obligatory (diaphragm, intercostal and parasternal) and accessory (sternomastoid, cleidomastoid, scalene and trapezius) respiratory muscle form, function and EMG activity in early (4 months) and advanced (16 months) dystrophic disease. Despite obligatory and accessory muscle dysfunction, including structural remodelling, weakness and reduced EMG activity, peak inspiratory pressure-generating capacity and ventilation are preserved in early disease. Obligatory and accessory muscle dysfunction progressively declines with advanced disease, with the emergence of reduced peak inspiratory pressure-generating capacity. However, although there was evidence of progressive accessory muscle dysfunction, more profound remodelling was seen in the diaphragm muscle comparing early and advanced dystrophic disease. In conclusion, in early dystrophic disease, peak inspiratory performance is compensated. A progressive decline in diaphragm and extra-diaphragmatic muscles contributes to respiratory system compromise in advanced disease. Further loss of compensation afforded by extra-diaphragmatic muscles probably contributes to end-stage respiratory failure. KEY POINTS: We characterised obligatory and accessory respiratory muscle form, function and control in early and advanced disease in the mdx mouse model of Duchenne muscular dystrophy. Profound diaphragm muscle remodelling, immune cell infiltration, elevated cytokine concentrations and dysfunction present in early disease, but peak inspiratory performance is fully compensated. The burden of breathing is shared across many muscles, revealed as remodelling, elevated cytokine concentrations, weakness and impaired control in several obligatory and accessory muscles. Peak inspiratory performance declines in advanced disease with evidence of progressive remodelling in the diaphragm muscle with extensive fibrosis and further decline in the form, function and control of accessory muscles of breathing. Diaphragm remodelling with profound fibrosis, more so than progressive accessory muscle remodelling (although evident), is the striking phenotype at 16 months of age when the decline in peak inspiratory performance appears. The progressive decline to end-stage disease (∼20-22 months of age in mdx mice) probably relates to continued profound loss of diaphragm contractile function and loss of compensatory support provided by extra-diaphragmatic muscles. Logistically convenient models of rapid, progressive muscular dystrophy are required to facilitate the study of end-stage disease.