Duchenne Muscular Dystrophy (DMD) is a fatal condition occurring in approximately 1 in 3500 male births and is due to the lack of a protein called dystrophin. Initially DMD was considered a skeletal myopathy, but the pathology and consequences of cardiomyopathy are being increasingly recognised. Fibrosis, resulting from continual cycles of degeneration of the muscle tissues followed by inadequate regeneration of the muscles, is progressive in both cardiac and skeletal dystrophic muscle. In the heart fibrosis interferes with contractility and rhythm whereas it affects contractile function and causes contractures in skeletal muscles. This study utilised the mdx mouse which exhibits a pathological loss of muscle fibres and fibrosis characteristic of DMD, to examine a range of mechanisms that can influence muscle function and fibrosis. Ageing and workload both appear to contribute to the development of dystrophic features in cardiac and skeletal muscle of the mdx mouse. Therefore the effect of eccentric exercise on cardiac and skeletal muscle was examined in older mdx mice. Mice ran in 30 minute sessions for five months, 5 days per week. Downhill treadmill running did not exacerbate the contractile function or fibrosis of the mdx heart or the EDL, SOL or diaphragm muscles suggesting that cytokines influence function and fibrosis to a greater extent than workload alone. The role of the cytokine TGF-beta was examined by treating mdx mice with the TGF-beta antagonist pirfenidone at 0.4, 0.8 or 1.2 per cent in drinking water for six months. Pirfenidone improved cardiac contractility (P<0.01) and coronary flow (P<0.05), to levels comparable to control mice, despite no reduction in cardiac fibrosis. Pirfenidone did not reduce fibrosis or improve function in skeletal muscle. A deficiency of neuronal nitric oxide synthase (nNOS) in DMD and mdx mice causes a lowered production of nitric oxide indicating that the substrate of nNOS, l-arginine, may be beneficial to cardiac and skeletal muscle function in mdx mice. Oral l-arginine (5 mg/g bw) improved cardiac contractility, coronary flow and reduced cardiac fibrosis (P<0.05) without improving skeletal muscle function or fibrosis. In contrast, 10 mg/g bw l-arginine improved cardiac function and coronary flow (P<0.01), despite also elevating cardiac collagen. This increment in collagen was prevented by co-administration of prednisone. The experiments described in this dissertation reveal for the first time that pharmacological treatments in mdx mice can improve cardiac structure and function. Further elucidation of the optimum time and doses of such treatments may result in future pharmacological treatments to improve cardiac function and fibrosis in DMD.
| Identifer | oai:union.ndltd.org:ADTP/178771 |
| Date | January 2005 |
| Creators | van Erp, Christel |
| Publisher | University of Southern Queensland, Faculty of Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://www.usq.edu.au/eprints/terms_conditions.htm, (c) Copyright 2005 Christel van Erp |
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