Respiratory control in the mdx mouse model of Duchenne muscular dystrophy

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Burns, David P.
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University College Cork
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Duchenne muscular dystrophy (DMD) is a genetic disease that occurs in males due to the absence of the dystrophin (427 kDa) protein. Comprehensive studies on the control of breathing in DMD and animal models of the dystrophinopathies are lacking. We examined the integrated respiratory control system in a pre-clinical model of DMD – the mdx mouse. Young (8-week-old) wild-type and mdx mice were studied. During normoxia, mdx mice hypoventilated, due to decreased tidal volume with no evidence of perturbed respiratory rhythm. Carotid sinus nerve responses to hyperoxia were blunted in mdx, suggesting hypoactivity (sensory deficit). Mdx mice retained a remarkable capacity to increase ventilation during hypercapnic hypoxic breathing despite profound diaphragm muscle weakness and major structural remodelling. Peak inspiratory oesophageal pressure generation was preserved in mdx compared to wild-type mice, probably due to recruitment of accessory muscles of breathing. Monoamine concentrations were elevated in the C3-C5 spinal cord of mdx mice, and the density of activated immune cells and pro-inflammatory gene expression was unchanged, indicating no evidence of neuroinflammation. xIL-6R and Ucn2 co-treatment in mdx mice completely restored ventilation and significantly improved diaphragm and sternohyoid muscle strength. Combinational therapy restored myosin heavy chain complement in respiratory muscles. Considerable deficits arising from dystrophin lack are partly compensated, limiting ventilatory deficits in young mdx mice. Strategies aimed at preserving muscle fibre complement and quality in mdx respiratory muscles can alleviate breathing and muscle functional deficits. These data may have relevance to the development of treatments for the human dystrophinopathies.
Duchenne muscular dystrophy , mdx , Breathing , Diaphragm , EMG , Upper airway , Interleukin-6 , Urocortin
Burns, D. P. 2018. Respiratory control in the mdx mouse model of Duchenne muscular dystrophy. PhD Thesis, University College Cork.