Thesis (Ph. D.)--University of Wisconsin, 1996. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--Drexel University, 2007. / Includes abstract and vita. Includes bibliographical references (leaves 94-110).

Thesis (Ph. D.)--University of Nevada, Reno, 2008. / "December, 2008." Includes bibliographical references (leaves 257-286). Online version available on the World Wide Web.

Dissertation (MSc (Human Genetics))--University of Pretoria, 2005. / Genetics / unrestricted

The radioactive isotope K⁴² was used to measure the rate of potassium exchange in muscle from 129 strain mice. The results followed an unique course if plotted as K⁴² uptake versus (external potassium concentration ∙ time) [superscript ½], and corresponded to the result predicted for K⁴² uptake mediated by an ion-exchange compartment in the muscle. Variations in external potassium concentration did not affect the uptake rate if plotted this way, but sodium ion exerted some effect on the rate. Dystrophic mouse tissue accumulated K⁴² more rapidly than did normal tissue, and the effect of varying the external potassium concentration did not alter this rate. The effects of sodium variation were more pronounced than in normal tissue. Inulin space of muscle was measured in vivo as well as in vitro, to enable a correction for K⁴² in the extracellular space to be made. The inulin space was found to decrease with increasing muscle size, and this was thought to be related to the development of the muscle. Dystrophic muscle exhibited more of a dependance of inulin space on muscle size than did normal muscle. The suggestion was made that the dystrophic muscle membrane might be abnormally permeable to inulin. Muscles were excised and assayed by flame photometry for sodium and potassium content. They were assayed when freshly excised, and also following incubation in a variant of Locke’s solution. The muscle cations were stable for the first two hours of incubation, but after this time, intracellular sodium rose and potassium fell. Fresh dystrophic mouse muscle had lower potassium and higher sodium content than normal fresh muscle. The cation changes following incubation resembled those found for normal muscle. The changes in intracellular cations were correlated with the K⁴² uptake results, and discussed in some detail. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

Duchenne Muscular Dystrophy (DMD) results from the absence of a functional dystrophin protein. Among its possible therapeutic options is the upregulation of dystrophin’s autosomal analogue, utrophin A. This can be achieved by a pharmacologically induced shift towards a slower, more oxidative skeletal muscle phenotype, which has been shown to confer morphological and functional improvements on models of DMD. Whether these improvements are a result of the utrophin A upregulation or other beneficial adaptations associated with the slow, oxidative phenotype, such as improved autophagy, has not been determined. To understand the importance of utrophin A to the therapeutic value of the slow, oxidative phenotype, we used the utrophin/dystrophin double knockout (dKO) model of DMD. We found the dKO mouse to have a similar skeletal muscle signaling capacity and phenotype to mdx mice. When treated with the adenosine monophosphate activated protein kinase (AMPK) agonist 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), both dKO and mdx mice expressed a shift towards a slower, more oxidative phenotype. In the mdx mice, this shift caused improvements in muscle fiber central nucleation, IgM penetration, damage from eccentric contractions, and forelimb grip strength. These morphological and functional benefits were not seen in the AICAR treated dKO mice. This study highlights the importance of utrophin A upregulation to the benefits of the slow, oxidative myogenic program to dystrophic mice. It confirms utrophin A as a therapeutic target in DMD and the slow, oxidative myogenic program as clinically relevant avenue towards treatment of the disease.

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive neuromuscular disorder caused by mutations or deletions in the dystrophin gene. Utrophin up-regulation therapy is among the various therapeutic strategies that are being investigated to treat DMD. In this strategy utrophin, a dystrophin homologue, is up-regulated along the entire length of the sarcolemma to replace the absent dystrophin protein. Previous studies have revealed that utrophin A expression can be controlled by various transcriptional, post-transcriptional and translational mechanisms and pharmacological modulation of these pathways can stimulate its expression in muscle. In the present study we screened several FDA approved and natural pharmacological compounds that can potentially activate utrophin A expression in muscle. We found that AICAR (AMPK activator) and heparin (p38 activator) were most effective in stimulating utrophin A expression in our C2C12 muscle cell system. Next, we analyzed the effect of combining these activators on utrophin A expression in muscle cells and preclinical mdx mouse model of DMD. Our findings revealed that combinatorial treatment of AICAR and heparin instigated an additive effect on utrophin A expression both in C2C12 muscle cells and mdx mice. Further characterization of treated mdx mice revealed that combinatorial treatment of AICAR and heparin caused improvements in the dystrophic phenotype as indicated by decreased central nucleation, decreased fiber size variability and improved sarcolemmal integrity in dystrophic muscle. Together these findings established that combinatorial treatment of AICAR and heparin ameliorates the dystrophic phenotype in mdx mice and may serve as an effective therapeutic strategy for DMD.

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