Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 312, Issue 1, Pages H128-H140Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00552.2016
Keywords
polyphenol; utrophin; Duchenne muscular dystrophy
Funding
- Duchenne Alliance
- Ryan's Quest
- Hope for Gus
- Michael's Cause
- Duchenne Now
- Zack Heger Foundation
- Pietro's Fight
- RaceMD
- JB's Keys
- Romito Foundation
- Harrison's Fund
- Alex'sWish
- Two Smiles One Hope Foundation [100065, 100071]
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Duchenne Muscular Dystrophy (DMD) is associated with progressive cardiac pathology; however, the SIRT1/PGC1-alpha 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 alpha -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-1 alpha, cytochrome c, ETC complexes I-V, citrate synthase, SOD2, and GPX compared with control-fed Mdx/Utrn(+/-). Quercetin decreased abundance of inflammatory markers including NF kappa B, TGF-beta 1, and F4/80 compared with Mdx/Utrn(+/-); however, P-NF kappa B, P-IKB alpha, IKB alpha, 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. NEW & NOTEWORTHY 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 quercetindependent outcomes are in part due to PGC-1 alpha pathway activation.
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