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Recovery of respiratory function in mdx mice co-treated with neutralizing interleukin-6 receptor antibodies and Urocortin-2
Burns, David P.
Drummond, Sarah E.
O'Halloran, Ken D.
John Wiley & Sons, Inc. on behalf of the Physiological Society
The mdx mouse model of Duchenne muscular dystrophy shows evidence of hypoventilation and pronounced diaphragm dysfunction. Six‐week‐old male mdx (n = 32) and wild‐type (WT; n = 32) mice received either saline (0.9% w/v) or a co‐administration of neutralizing interleukin‐6 receptor antibodies (xIL‐6R; 0.2 mg/kg) and corticotrophin‐releasing factor receptor 2 agonist (Urocortin‐2; 30 μg/kg), subcutaneously over 2 weeks. Breathing and diaphragm muscle contractile function (ex vivo) were examined. Diaphragm structure was assessed using histology and immunofluorescence. Muscle cytokine concentration was determined using a multiplex assay. Minute ventilation and diaphragm muscle peak force at 100 Hz were significantly depressed in mdx compared with WT. Drug treatment completely restored ventilation in mdx mice during normoxia and significantly increased mdx diaphragm force‐ and power‐generating capacity. The number of centrally‐nucleated muscle fibres and the areal density of infiltrates and collagen content were significantly increased in mdx diaphragm; all indices were unaffected by drug co‐treatment. The abundance of myosin heavy chain (MyHC) type IIx fibres was significantly decreased in mdx diaphragm; drug co‐treatment preserved MyHC type IIx complement in mdx muscle. Drug co‐treatment increased the cross‐sectional area of MyHC type I and IIx fibres in mdx diaphragm. The cytokines IL‐1β, IL‐6, KC/GRO and TNF‐α were significantly increased in mdx diaphragm compared with WT. Drug co‐treatment significantly decreased IL‐1β and increased IL‐10 in mdx diaphragm. Drug co‐treatment had no significant effect on WT diaphragm muscle structure, cytokine concentrations or function. Recovery of breathing and diaphragm force in mdx mice was impressive in our studies, with implication for human dystrophinopathies.
DMD , mdx , Corticotrophin releasing factor , Diaphragm muscle b , Breathing , Interleukin-6 , Urocortin-2
Burns, D. P., Canavan, L., Rowland, J., O'Flaherty, R., Brannock, M., Drummond, S. E., O'Malley, D., Edge, D. and O'Halloran, K. D. (2018) 'Recovery of respiratory function in mdx mice co-treated with neutralizing interleukin-6 receptor antibodies and Urocortin-2', Journal of Physiology. doi:10.1113/JP276954
© 2018, the Physiological Society. Published by John Wiley & Sons Inc. This is the peer reviewed version of the following article: Burns, D. P., Canavan, L., Rowland, J., O'Flaherty, R., Brannock, M., Drummond, S. E., O'Malley, D., Edge, D. and O'Halloran, K. D. (2018) 'Recovery of respiratory function in mdx mice co-treated with neutralizing interleukin-6 receptor antibodies and Urocortin-2', Journal of Physiology. doi:10.1113/JP276954, which has been published in final form at https://doi.org/10.1113/JP276954 . This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.