Aspects of Respiratory Control in the Dystrophin‐deficient mdx Mouse

Abstract

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease characterised by skeletal muscle weakness which extends to the respiratory musculature. Although deficits in the diaphragm muscle of dystrophin‐deficient mdx mice are well described, there is a paucity of information pertaining to central control of breathing in dystrophinopathies. We have previously reported hypoventilation in mdx mice with reserved capacity to increase ventilation in response to chemoactivation (Burns et al., 2017). Systemic and muscle inflammation are reported in mdx mice and human DMD. We sought to examine aspects of respiratory system control in the mdx mouse model of DMD including electrical activity of the diaphragm muscle and markers of inflammation in putative phrenic motor nuclei.Young adult (8 week old) wild‐type (WT) and mdx mice were studied. Inspiratory (Ti) and expiratory (Te) durations were assessed in conscious WT and mdx mice using whole‐body plethysmograpghy. Diaphragm EMG activity was assessed in WT and mdx mice using fine concentric needle electrodes in anaesthetised spontaneously breathing mice. Basal EMG and responsiveness to chemoactivation were determined. Diaphragm muscle function was examined ex vivo. Cervical spinal cord (C3–C5 region) segments of WT and mdx mice were examined for immunohistochemical and gene expression analyses.Poincaré analysis of Ti and Te revealed no evidence of perturbed respiratory rhythm in young mdx mice based on short‐ and long‐term variability of breathing. Diaphragm muscle force was severely depressed in mdx diaphragm within the frequency range of both ventilatory and airway protective behaviours. Mdx diaphragm had potentiated EMG activity during chemoactivation compared to WT mice. Dystrophin mRNA is expressed in the C3–C5 region of WT spinal cords and expression is significantly reduced in mdx mice, with no indication of altered inflammatory gene expression. Putative phrenic motornuclei in mdx mice had unaltered expression of microglia and astrocytes compared to WT.Our study revealed a potentiated neural drive to breathe in mdx mice during chemoactivation suggesting compensatory neuroplasticity facilitating respiratory motor output. Although systemic and muscle inflammation are present in mdx mice, there is no evidence of neuroinflammation in the cervical spinal cord (C3–C5) of young mdx mice. If neuroplasticity is a feature of DMD, it may be possible to boost motor facilitation of breathing through safe interventions and thus preserve or limit deficiencies in respiratory capacity.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.