Muscular dystrophies are a diverse group of genetic diseases characterized by progressive muscle weakness and deterioration with wide variability in severity and affected muscle groups. Some of the more devastating muscular dystrophies result from the absence of components of the dystrophin-glycoprotein complex (DGC). Disruption of the DGC compromises sarcolemmal integrity in striated muscle, leading to increased myocyte injury and death. These forms of muscular dystrophy often feature both skeletal muscle wasting and marked cardiomyopathy. The most common of these muscular dystrophies is Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene that result in the loss of this large membrane-stabilizing protein. DMD features a childhood onset and leads to premature death at ages ranging from the teens into the 30’s, often from cardiorespiratory failure. DMD is an X-linked disorder, and is usually inherited from carrier mothers who also face a high risk of cardiomyopathy. Sarcoglycanopathies are a rarer group of autosomal recessive Limb Girdle muscular dystrophies (LGMD) that arise from mutations in the sarcoglycan genes, sometimes leading to an aggressive Duchenne-like disease course in patients of both sexes. The heterotetrameric sarcoglycan complex is a key component of the DGC, and its loss induces significant myocyte pathology that can trigger childhood disease onset and premature death. Muscles and hearts devoid of the sarcolgycan complex display hallmark dystrophic pathology, including muscle wasting, loss of ambulation, and a high incidence of lethal dilated cardiomyopathy. The work presented here is driven by efforts to quantify the susceptibility of dystrophic hearts to acute injury caused by increased cardiac workload, and to understand the contribution of angiotensin signaling to dystrophic heart injury. It describes the following key findings: 1) angiotensin receptor blockers (ARBs) can markedly reduce acute injury in dystrophin-null and sarcoglycan-null mouse hearts; 2) female mouse hearts lacking the sarcoglycan complex are significantly protected compared to male hearts, and do not derive the same benefit from ARBs; and 3) mosaic expression of dystrophin in the heart results in elevated vulnerability to injury that is modulated by factors besides dystrophin levels. This work suggests that angiotensin signaling plays an exaggerated role in dystrophic heart injury through mechanisms that may be sex-dependent, and that earlier and more consistent use of angiotensin-blocking therapies has the potential to limit dystrophic cardiomyopathy. Furthermore, it reveals that dystrophic hearts may continue to show significant vulnerability in the context of gene therapies that restore partial dystrophin expression.
University of Minnesota Ph.D. dissertation. August 2019. Major: Integrative Biology and Physiology. Advisors: DeWayne Townsend, John Osborn. 1 computer file (PDF); vii, 122 pages.
Preclinical Models of Dystrophic Cardiomyopathy and Therapies for the Dystrophic Heart.
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