Chronic Dietary Quercetin Enrichment and Cardiac Pathology in Mdx and Mdx-Utrn +/-Mice
Type of DegreeDissertation
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BACKGROUND: Duchenne Muscular Dystrophy causes declines in cardiac health resulting in mortality in up to 40% patients due to fibrosis and cardiopathology. Quercetin is a polyphenol possessing inherent anti-inflammatory and antioxidant effects and also potently activates SIRT1/PGC-1α increasing mitochondrial biogenesis, antioxidant enzymes, and attenuates cardiopathology. METHODS: Our experiments tested whether life-long 0.2% dietary quercetin enrichment attenuates dystrophic cardiopathology in mdx and mdx-utrn +/- mice. Dystrophic animals were fed quercetin enriched or control diet for 14 or 10 months respectively. C57BL10 animals were fed a control diet for age-matched time. Cardiac function was assessed via 7T MRI. Post mortem, hearts were collected for histology and Western blotting. RESULTS: Findings reveal quercetin preserved overall cardiac function when compared to control mdx and mdx-utrn +/- mice. Histological analysis revealed increased expression of utrophin, α-sarcoglycan, utrophin/α-sarcoglycan co-localization, decreased fibronectin, and decreased markers of cardiac damage versus control mdx and mdx-utrn +/-mice. Western blot analysis revealed quercetin increased cardiac PGC-1α, cytochrome-c, ETC complexes I-V, citrate synthase, SOD2, and GPX versus control mdx and mdx-utrn +/- control mice. Western blot targets for inflammation revealed that quercetin decreased NFκB, P- NFκBp65, P-IKBα, while preserving IKBα versus control mdx mice. Quercetin enrichment had a lower anti-inflammatory effect in mdx-utrn +/- mice. However, quercetin decreased TGF-β1 and F4/80 versus control mdx and mdx-utrn +/- mice. CONCLUSION: Data suggest that long term quercetin enrichment attenuates cardiac dysfunction, increases mitochondrial biogenesis markers, antioxidant enzymes, decreases inflammation, and may partially reassemble the DGC in the dystrophic heart.