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Title: Heart function in mouse models of muscular dystrophy
Author: Crisp, Edmund Alastair D.
ISNI:       0000 0004 2716 5446
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2011
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Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused, in most cases, by the complete absence of the 427 kD cytoskeletal protein, dystrophin. Without dystrophin, the dystrophin-associated protein complex (DAPC) does not form and the plasma membrane is destabilised. There is no effective treatment and affected individuals die from respiratory failure and cardiomyopathy by age 30. This thesis describes experiments in which in vivo cardiac function was measured using non-invasive magnetic resonance imaging in a number of mouse models relevant to muscular dystrophy. As syncoilin forms a link from the DAPC to the cytoskeleton, it was postulated in Chapter 3 that the syncoilin knockout mouse would have cardiac defects similar to those caused by the loss of dystrophin. However, the loss of syncoilin did not alter the protein levels of its binding partners, measured by western blotting, and caused no defect in heart function or structure, measured using histological staining. Similarly, in Chapter 4, a mouse with a mutation in the transient receptor potential channel canonical type 3 (TRPC3), a receptor/stretch-activated cation channel thought to be involved in the pathogenesis of DMD, was found to have no functional or morphological cardiac defect. In the mdx mouse, a mouse model of DMD that lacks dystrophin, cardiomyopathy was prevented by either increasing levels of the dystrophin related protein, utrophin, or of dystrophin, in the diaphragm, which thereby restored diaphragm function. In Chapter 5 it was found that in a transgenic mdx mouse in which utrophin was over-expressed in skeletal muscle and diaphragm, but not in the heart, cardiac function was restored to wild-type levels. However, histologically the transgenic heart showed more fibrosis and immune cell infiltration than that of untreated mdx controls. In Chapter 6 it was found that in mdx mice treated with a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO), that resulted in high dystrophin restoration in skeletal muscle and diaphragm only, cardiac function was also restored to wild-type levels. In Chapter 6 it was also found that in dystrophin/utrophin-deficient double-knockout (dKO) mice, a more severely affected animal model of DMD, treatment with a PPMO again produced high levels of dystrophin only in skeletal muscle and diaphragm, and once more restored cardiac function to wild-type levels. In the dKO mouse, there was no difference in heart function between treatment of the diaphragm plus the heart and treatment of the diaphragm alone. Restoration of diaphragm and other respiratory muscle function, irrespective of the method used, was sufficient to prevent cardiomyopathy in dystrophic mice. The novel mechanism of treating respiratory muscles to prevent cardiomyopathy in dystrophic mice has implications for the study of heart function in the current DMD mouse models and suggests a new approach to treatment.
Supervisor: Davies, Kay ; Clarke, Kieran Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Disease (zoology) ; Physiology and anatomy ; Biology ; heart function ; muscular dystrophy