Lifelong quercetin enrichment and cardioprotection in Mdx/Utrn+/- mice

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 312; no. 1; pp. H128 - H140
• Main Authors: Ballmann, Christopher, Denney, Thomas S, Beyers, Ronald J, Quindry, Tiffany, Romero, Matthew, Amin, Rajesh, Selsby, Joshua T, Quindry, John C
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.01.2017
• Subjects: Animals; Antigens, Differentiation - drug effects; Antigens, Differentiation - metabolism; Antioxidants - pharmacology; Blotting, Western; Citrate (si)-Synthase - drug effects; Citrate (si)-Synthase - metabolism; Cyclooxygenase 2 - drug effects; Cyclooxygenase 2 - metabolism; Cytochromes c - drug effects; Cytochromes c - metabolism; Disease Models, Animal; Electron Transport Chain Complex Proteins - drug effects; Electron Transport Chain Complex Proteins - metabolism; Fibronectins - metabolism; Food, Fortified; Glycoproteins; Heart - diagnostic imaging; Heart - drug effects; Heart - physiopathology; Magnetic Resonance Imaging; Matrix Metalloproteinase 9 - metabolism; Medical treatment; Mice; Mice, Inbred mdx; Mitochondria, Muscle - drug effects; Mitochondria, Muscle - metabolism; Motor Activity; Muscular Dystrophy, Animal - metabolism; Muscular Dystrophy, Animal - physiopathology; Muscular Dystrophy, Duchenne; Myocardium - metabolism; Myocardium - pathology; NF-kappa B - drug effects; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha - drug effects; NF-KappaB Inhibitor alpha - metabolism; NMR; Nuclear magnetic resonance; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - drug effects; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Phosphorylation; Quercetin - pharmacology; Receptors, IgG - drug effects; Receptors, IgG - metabolism; Rodents; Sarcoglycans - metabolism; Superoxide Dismutase - drug effects; Superoxide Dismutase - metabolism; Transforming Growth Factor beta1 - drug effects; Transforming Growth Factor beta1 - metabolism; Utrophin - genetics; Utrophin - metabolism; polyphenol; utrophin; Duchenne muscular dystrophy
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00552.2016

Duchenne Muscular Dystrophy (DMD) is associated with progressive cardiac pathology; however, the SIRT1/PGC1-α activator quercetin may cardioprotect dystrophic hearts. We tested the extent to which long-term 0.2% dietary quercetin enrichment attenuates dystrophic cardiopathology in Mdx/Utrn mice. At 2 mo, Mdx/Utrn mice were fed quercetin-enriched (Mdx/Utrn -Q) or control diet (Mdx/Utrn ) for 8 mo. Control C57BL/10 (C57) animals were fed a control diet for 10 mo. Cardiac function was quantified by MRI at 2 and 10 mo. Spontaneous physical activity was quantified during the last week of treatment. At 10 mo hearts were excised for histological and biochemical analysis. Quercetin feeding improved various physiological indexes of cardiac function in diseased animals. Mdx/Utrn -Q also engaged in more high-intensity physical activity than controls. Histological analyses of heart tissues revealed higher expression and colocalization of utrophin and α-sarcoglycan. Lower abundance of fibronectin, cardiac damage (Hematoxylin Eosin-Y), and MMP9 were observed in quercetin-fed vs. control Mdx/Utrn mice. Quercetin evoked higher protein abundance of PGC-1α, cytochrome c, ETC complexes I-V, citrate synthase, SOD2, and GPX compared with control-fed Mdx/Utrn Quercetin decreased abundance of inflammatory markers including NFκB, TGF-β1, and F4/80 compared with Mdx/Utrn ; however, P-NFκB, P-IKBα, IKBα, CD64, and COX2 were similar between groups. Dietary quercetin enrichment improves cardiac function in aged Mdx/Utrn mice and increases mitochondrial protein content and dystrophin glycoprotein complex formation. Histological analyses indicate a marked attenuation in pathological cardiac remodeling and indicate that long-term quercetin consumption benefits the dystrophic heart. The current investigation provides first-time evidence that quercetin provides physiological cardioprotection against dystrophic pathology and is associated with improved spontaneous physical activity. Secondary findings suggest that quercetin-dependent outcomes are in part due to PGC-1α pathway activation.