Neuromuscular and neuromechanical assessments of respiratory performance in the mdx mouse model of Duchenne muscular dystrophy across the natural history of disease.

Abstract

Duchenne muscular dystrophy (DMD) is a severe life-limiting X-linked neuromuscular disorder characterised by progressive skeletal muscle degeneration and respiratory failure. The mdx mouse, lacking dystrophin, is the most widely used preclinical model of DMD, yet the trajectory of respiratory dysfunction in this model remains incompletely defined. We evaluated neural respiratory drive (NRD), neuromechanical efficiency (NME), tension-time index (TTI), inspiratory drive rate and electromyographic (EMG) frequency spectrum parameters in the diaphragm, external intercostal and parasternal muscles across the natural history of disease (aged 1-16 months). Despite early and persistent reductions in EMG activity and frequency spectrum parameters in mdx mice, NRD and TTI in respiratory muscles were largely equivalent to controls. NME was paradoxically increased in mdx mice, likely reflecting compensatory recruitment of accessory muscles rather than improved contractile efficiency of the major inspiratory muscles of breathing. The area under the pressure-time curve during sustained tracheal occlusion was reduced in mdx mice at 1 month of age but was equivalent to wild-type values at all other ages, demonstrating robust compensation even in advanced disease. No significant differences in inspiratory duty cycle, respiratory muscle effort or TTI were observed across groups. We conclude that assessments of integrative respiratory morbidity in mdx mice should focus on animals aged ≥16 months or alternative models with accelerated disease progression. Our results underscore the need for refined translational models and highlight the importance of integrating EMG-based indices for early detection and monitoring of respiratory compromise in DMD.