Proceedings of The Physiological Society

Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCB062

Poster Communications

Carotid body dysfunction and hypoventilation in the dystrophin deficient mdx mouse

D. P. Burns1, A. Roy3, J. Rowland2, E. Lucking1, F. McDonald3, D. Edge2, R. Wilson3, K. D. O' Halloran1

1. Physiology, School of Medicine, University College Cork, Cork, Ireland. 2. Physiology, Trinity Biomedical Sciences Institute, Trinity College Dublin, the University of Dublin, Dublin, Ireland. 3. Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.


Duchenne muscular dystrophy (DMD) is a fatal X-linked neuromuscular disease. Patients have severe respiratory muscle wasting and chronic respiratory insufficiency. Hypoventilation and sleep disordered breathing are both common features of the disease and are known to culminate in periods of hypoxaemia and hypercapnia. There is a paucity of information regarding the control of breathing in pre-clinical models of DMD. We measured ventilation, oxygen consumption (VO2) and carbon dioxide production (VCO2) in freely behaving mdx (C57BL/10ScSn-Dmdmdx/J; n=12) and wild-type (C57BL/10ScSn; n=9) mice at 8 weeks of age during normoxia (FiO2=0.21) and in response to a graded hypoxic challenge (FiO2=0.15, 0.12, 0.1 & 0.08). Carotid sinus nerve activity was measured ex vivo in an artificially perfused preparation in WT (n=6) and mdx (n=6) mice during normoxia (Po2=100 Torr) and graded hypoxia (Po2=80, 60, 40 Torr). Diaphragm muscle force-frequency relationship was examined ex vivo. qRT-PCR was used to examine gene expression in diaphragm muscle from WT (n=8) and mdx (n=8) mice. Data were expressed as mean±SD and were statistically compared by unpaired Student t-test unless otherwise stated. Minute ventilation (VE) was significantly reduced in mdx (0.7±0.2 ml/min/g; p<0.001) mice compared with WT (1.2±0.3) controls. There was no significant difference in VO2 and VCO2 between WT and mdx when expressed in absolute terms. Inspiratory drive (VT/Ti) was significantly reduced in mdx (0.06± 0.02 ml/sec/g; p<0.001) compared with WT (0.1±0.02). Carotid sinus nerve unitary discharge was significantly depressed during normoxia in mdx (1.6±0.4 Hz; p<0.01) compared with WT (2.4±0.4) ex vivo. Diaphragm force was significantly reduced in mdx versus WT across all stimulation frequencies (p<0.0001; two-way ANOVA). Immunofluorescence for MHC fibre types revealed transition from type 2B to 2A in mdx diaphragm. NF-kB and TNF-α mRNA expression were both significantly increased in mdx diaphragm. HIF-1α expression was significantly increased, while HIF-2α was significantly decreased in mdx diaphragm. A significant respiratory phenotype presents at a young age in the mdx mouse. Mdx mice hypoventilate during normoxia (decreased VE/VCO2), which is likely related to hypo-activity of the carotid body during normoxia. We report unaltered chemosensory and ventilatory responsiveness to hypoxia in mdx. Mdx diaphragm muscle has severe mechanical dysfunction, is in a pro-inflammatory state with differential expression of hypoxia associated genes. The gene expression data is consistent with a pro-inflammatory and pro-oxidant status. Current interventional studies focused on anti-oxidant and anti-inflammatory strategies are yielding promising results. We reveal that respiratory control is altered in the mdx mouse model of DMD at a young age.

Where applicable, experiments conform with Society ethical requirements