Immune and stress factors in the pathophysiology of the mdx mouse model of Duchenne Muscular Dystrophy

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dc.contributor.advisor O'Malley, Dervla en Manning, Jennifer 2015-08-13T11:21:57Z 2015-08-13T11:21:57Z 2014 2014
dc.identifier.citation Manning, J. 2014. Immune and stress factors in the pathophysiology of the mdx mouse model of Duchenne Muscular Dystrophy. PhD Thesis, University College Cork. en
dc.identifier.endpage 245
dc.description.abstract Duchenne Muscular Dystrophy (DMD) is a fatal multi-system neuromuscular disease caused by loss of dystrophin. The loss of dystrophin from membranes of contractile muscle cells and the dysregulation of the DAPC, induces chronic inflammation due to tissue necrosis and eventual replacement with collagen which weakens muscular force and strength. Dystrophin deficiency may cause under-diagnosed features of DMD include mood disorders such as depression and anxiety and dysfunction of the gastrointestinal tract. The first study in the thesis examined mood in the dystrophin-deficient mdx mouse model of DMD and examined the effects of the tri-cyclic antidepressant, amitriptyline on behaviours. Amitriptyline had anti-depressant and anxiolytic effects in the mdx mice possibly through effects on stress factors such as corticotrophin-releasing factor (CRF). This antidepressant also reduced skeletal muscle inflammation and caused a reduction in circulating interleukin (IL)-6 levels. In the second and third studies, we specifically blocked IL-6 signalling and used Urocortin 2, CRFR2 agonist to investigate their potential as therapeutic targets in mdx mice pathophysiology. Isometric and isotonic contractile properties of the diaphragm, were compared in mdx mice treated with anti IL-6 receptor antibodies (anti IL-6R) and/or Urocortin 2. Deficits in force production, work and power detected in mdx mice were improved with treatment. In study three I investigated contractile properties in gastrointestinal smooth muscle. As compared to wild type mice, mdx mice had slower faecal transit times, shorter colons with thickened muscle layers and increased contractile activity in response to recombinant IL-6. Blocking IL-6 signalling resulted in an increase in colon length, normalised faecal output times and a reduction in IL-6-evoked contractile activity. The findings from these studies indicate that for both diaphragm and gastrointestinal function in a dystrophin-deficient model, targeting of IL-6 and CRFR2 signalling has beneficial therapeutic effects. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2014, Jennifer Manning. en
dc.rights.uri en
dc.subject Muscle en
dc.subject Muscular Dystrophy en
dc.subject Stress en
dc.subject Inflammation en
dc.subject Interleukin - 6 en
dc.title Immune and stress factors in the pathophysiology of the mdx mouse model of Duchenne Muscular Dystrophy en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname Doctor of Medicine en
dc.internal.availability Full text available en No embargo required en
dc.description.version Accepted Version
dc.contributor.funder Muscular Dystrophy Ireland en
dc.contributor.funder Physiology, College of Medicine and Health, University College Cork en
dc.description.status Not peer reviewed en Physiology en
dc.check.type No Embargo Required
dc.check.reason No embargo required en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false
dc.check.embargoformat Not applicable en
dc.internal.conferring Autumn Conferring 2014

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