Fibrotic pathways in the dystrophin deficient heart
Masters Thesis
Title | Fibrotic pathways in the dystrophin deficient heart |
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Type | Masters Thesis |
Authors | |
Author | Wakefield, Amanda |
Supervisor | Hoey, Andrew |
Institution of Origin | University of Southern Queensland |
Qualification Name | Master of Science |
Number of Pages | 206 |
Year | 2009 |
Abstract | Duchenne muscular dystrophy is the most prevalent and severe of the muscular dystrophies. A hallmark of dystrophic muscle is fibrosis which is a result of chronic cycles of degeneration and regeneration. Cardiac fibrosis interferes with contractility and rhythm of the heart and cardiomyopathy is a leading cause of mortality in DMD. While gene therapy may offer a cure in the future, there exists an immediate need to ameliorate the symptoms of DMD. The mdx mouse is the most widely used animal model in DMD research. The initial study of this dissertation examined cardiac parameters of the mdx mouse at different ages (3, 6 and 12 months) and found a progressive cardiac involvement. Compromised systolic and diastolic function was evident from 6 months of age. An underlying morphological link between diastolic dysfunction is cardiac fibrosis and this was significantly increased in all ages examined.The role of proinflammatory cytokine TGF-β in fibrosis was investigated and mRNA levels were found to be significantly elevated at 3 months of age, which did not continue with the other two age groups examined. This suggests that TGF-β may be involved in the initiation of fibrotic pathways, but not in the progression of fibrosis. These results were supported by mRNA levels of procollagen and fibronectin which significantly decreased at 12 months of age. This implies a shift away from the initial active collagen synthesis toward a decreased collagen degradation maintaining the high levels of fibrosis. Study 2 aimed to determine if insulin-like growth factor-1 could ameliorate the symptoms of the dystrophic heart by generating a novel transgenic mouse that overexpressed IGF-1 exclusively in the mdx heart. This study found IGF-1 overexpression to be beneficial to the dystrophic heart at 12 months of age. It mediated cardiac hypertrophy at 6 and 12 months of age which appeared to be a physiological adaptation as evidenced by the significantly improved cardiac function and rate of contractility at 12 months of age. IGF-1 mediated a dramatic reduction in ventricular fibrosis by 12 months of age to levels not significantly different than control mice. Thus IGF-1 appears to be capable of resolving the inflammatory response and thereby reducing fibrosis. This study supported the previous findings that at 6 and 12 months of age TGF-β mRNA levels do not correlate with the degree of ventricular fibrosis. The final study of this dissertation further characterised the mdx:MyoD(-/-) mouse as a model of the cardiomyopathy associated with DMD. MyoD is required for efficient muscle regeneration and its removal from the germline of the mdx mouse resulted in significantly higher levels of ventricular fibrosis. This implies that the milder phenotype of the mdx mouse may be due in part to increased regeneration. As MyoD is only expressed in skeletal muscle, this also suggests that skeletal muscle pathology plays a role in dystrophin deficient cardiomyopathy. One surprising finding from this study was an improvement in cardiac function in the face of increased ventricular fibrosis. This may be a compensatory mechanism due to the increased skeletal pathology placing an extra work load on the heart. Cardiac mRNA levels of TGF-β did not correlate with the increased levels of ventricular fibrosis observed in the mdx:MyoD(-/-) supporting the findings of the previous two studies. While procollagen gene expression also did not correlate with fibrosis, fibronectin mRNA levels did suggesting that fibronectin may be a better marker for active collagen synthesis than procollagen. |
Keywords | fibrosis; Duchenne Muscular Dystrophy; dystrophin deficiency |
ANZSRC Field of Research 2020 | 310507. Genetic immunology |
Byline Affiliations | Department of Biological and Physical Sciences |
https://research.usq.edu.au/item/q0x98/fibrotic-pathways-in-the-dystrophin-deficient-heart
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