Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, C006

Oral Communications

Breathing with neuromuscular disease: insights from pre-clinical studies

D. P. Burns1, E. O'Driscoll2, J. Rowland2, L. Canavan2, K. H. Murphy1, K. M. O'Connor1,3,5, D. O'Malley1,3, G. Clarke3,4, D. Edge2, K. D. O'Halloran1

1. Physiology, School of Medicine, University College Cork, Cork, Ireland. 2. Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, the University of Dublin, Dublin, Ireland. 3. APC Microbiome Ireland, University College Cork, Cork, Ireland. 4. Psychiatry and Neurobehavioural Science, School of Medicine, University College Cork, Cork, Ireland. 5. Anatomy and Neuroscience, University College Cork, Cork, Ireland.


Duchenne muscular dystrophy (DMD) is characterised by severe skeletal muscle weakness, which extends to the striated muscles of breathing. Hypoventilation, carotid body hypo-activity (sensory deficit) and diaphragm dysfunction have been described in the mdx mouse model of muscular dystrophy (Burns et al., 2017), however there is a paucity of information concerning neuromechanical control of the respiratory muscles. Since inflammation is a major pathological feature of DMD, we assessed the potential of a combined anti-inflammatory and anti-stress interventional strategy in ameliorating respiratory deficits in mdx mice. Young (8-week-old) wild-type (WT; n=41) and mdx (n=37) mice were studied. Respiratory stability and ventilatory capacity were determined. Diaphragm EMG activity and inspiratory pressure generating capacity was examined in anaesthetised (1.7 g/kg i.p. urethane) spontaneously breathing mice in vivo. Diaphragm muscle structure and force-generating capacity were assessed. Monoamine concentrations, density of glial cells, and pro-inflammatory gene expression was determined in the spinal cord (C3-C5), containing the phrenic motor nucleus. Interventional studies consisted of a combinational treatment of a neutralizing interleukin-6-receptor antibody and urocortin 2 (corticotrophin releasing factor receptor 2 agonist), or saline in WT (n=32) and mdx (n=32) mice for 2 weeks. Ventilation and diaphragm muscle form and function were determined. Data were statistically compared by unpaired Student's t test. Poincaré analysis of respiratory timing revealed no evidence of perturbed respiratory rhythm in mdx mice, which retained a capacity to enhance ventilation despite diaphragm weakness and structural remodelling. Peak inspiratory oesophageal pressure generation was preserved during basal breathing and was greater during augmented breaths in mdx (P<0.05) compared to WT mice, probably due to recruitment of accessory muscles of breathing. Diaphragm EMG activity was not potentiated compared with WT across ventilatory behaviours. Serotonin and noradrenaline concentrations were elevated in mdx (P<0.05) spinal cord. There was no evidence of spinal neuroinflammation. Combinational therapy in mdx mice completely restored ventilation during normoxia, improved diaphragm muscle force-generating capacity and restored myosin heavy chain complement in diaphragm muscle. We reason that compensatory neuroplasticity in accessory motor pathways preserves ventilatory capacity in mdx mice despite profound diaphragm muscle weakness. Interventional studies indicate that strategies aimed at preserving muscle fibre complement and promoting muscle fibre quality in mdx respiratory muscles can alleviate breathing and muscle functional deficits. These data may have relevance to the development of interventional strategies designed to alleviate respiratory insufficiency in the human dystrophinopathies.

Where applicable, experiments conform with Society ethical requirements