Neuromuscular coupling of obligatory respiratory muscles to inspiratory pressure is reduced in dystrophic (mdx) mice

Neuromuscular coupling (NMC) is a recognised clinical index of inspiratory muscle function which reflects the efficiency of conversion of neural activation to inspiratory pressure. Duchenne muscular dystrophy (DMD) is characterised by respiratory insufficiency culminating in respiratory failure. We investigated inspiratory pressure generating capacity and electrical activation of obligatory inspiratory muscles in X-linked muscular dystrophy (mdx) mice, to evaluate NMC of diaphragm, external intercostal and parasternal intercostal to inspiratory pressure across a range of behaviours in early established to late progressive disease.In urethane anaesthetised mice (1.7 g/kg i.p.), inspiratory pressure was recorded via a pressure transducer positioned in the thoracic oesophagus. Diaphragm EMG activity was recorded using needle electrodes. Studies were performed in male wildtype (WT) and mdx mice at 4, 8, 12 and 16 months old. Recordings were made at baseline and during sustained tracheal occlusion to task failure, defined as an inability to sustain peak pressure. Peak pressure was determined from the average of five successive peak efforts at the maximum response. The corresponding peak inspiratory EMG activities were determined. Two factor (age x genotype) analysis of variance was performed.Obligatory muscle EMG activities were significantly lower in mdx mice from 4 months of age. Peak inspiratory pressure was significantly greater in mdx at 4 months of age. At 8 months, peak inspiratory pressure was equivalent between WT and mdx followed by a significant decrease in peak inspiratory pressure in 12- and 16-month-old mdx. NMC was lower in mdx mice across the ventilatory and non-ventilatory range, emerging early in dystrophic disease. Reduced NMC of obligatory muscles to inspiratory pressure in mdx mice reveals a greater reliance on accessory muscles to support respiratory performance in dystrophic disease. Remarkably, this burden is adequately accommodated in early disease with a preserved capacity to generate peak inspiratory pressure. We reason that the loss of compensation afforded by accessory muscles to peak inspiratory pressure generation underpins the emergence of respiratory compromise in advanced disease. Our results may have implications for the understanding and treatment of DMD.