Understanding fundamental aspects of respiratory control in dystrophin‐deficient mice

Abstract

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease associated with respiratory‐related morbidity and mortality. DMD is characterised by severe skeletal muscle weakness, which extends to the striated muscles of breathing. Our recent research has explored deficits and compensation in the respiratory control network governing respiratory homeostasis in a pre‐clinical model of DMD, the mdx mouse. Deficits at multiple sites of the network provide considerable challenges to respiratory control, including carotid body hypo‐activity (sensory deficit) and diaphragm dysfunction ( Burns et al., 2017). 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 ( Burns et al., 2019). Our findings point to a considerable reserve in the capacity of the respiratory neuromuscular system to perform a broad range of function, resulting from the recruitment of auxiliary muscles in support of peak respiratory‐related performance. We propose that a progressive loss of compensation during advancing disease, combined with diaphragm dysfunction, underpins the development of respiratory morbidity in dystrophic diseases. Studies utilising anti‐inflammatory, anti‐stress and anti‐oxidant pharmacotherapy strategies indicate that interventions aimed at preserving muscle fibre complement and promoting muscle fibre quality in mdx respiratory muscles can alleviate breathing and muscle functional deficits ( Burns et al. 2018). Dr. Burns will discuss current knowledge gaps and the need to better appreciate fundamental aspects of respiratory control in pre‐clinical models so as to better inform intervention strategies in human DMD.Support or Funding InformationDepartment of Physiology, University College Cork and The Physiological Society.