Lifelong quercetin enrichment and cardioprotection in Mdx/Utrn+/- mice.
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.
School of Kinesiology, Auburn University, Auburn, Alabama.
Christopher
C
Ballmann
MRI Research Center, Auburn University, Auburn, Alabama.
Thomas S
TS
Denney
MRI Research Center, Auburn University, Auburn, Alabama.
Ronald J
RJ
Beyers
School of Kinesiology, Auburn University, Auburn, Alabama.
Tiffany
T
Quindry
School of Kinesiology, Auburn University, Auburn, Alabama.
Matthew
M
Romero
Harrison School of Pharmacy, Auburn University, Auburn, Alabama; and.
Rajesh
R
Amin
Department of Animal Science, Iowa State University, Ames, Iowa.
Joshua T
JT
Selsby
School of Kinesiology, Auburn University, Auburn, Alabama; john.quindry@mso.umt.edu.
John C
JC
Quindry
D000818:Animals; D000943:Antigens, Differentiation / Q000187:drug effects / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D002950:Citrate (si)-Synthase / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D045304:Cytochromes c / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D045222:Electron Transport Chain Complex Proteins / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005527:Food, Fortified; D006321:Heart / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018101:Mice, Inbred mdx; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity; D009137:Muscular Dystrophy, Animal / Q000378:metabolism / Q000503:physiopathology*; D020388:Muscular Dystrophy, Duchenne; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011794:Quercetin / Q000494:pharmacology*; D017452:Receptors, IgG / Q000187:drug effects / Q000378:metabolism; D049031:Sarcoglycans / Q000378:metabolism; D013482:Superoxide Dismutase / Q000187:drug effects / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000187:drug effects / Q000378:metabolism; D049411:Utrophin / Q000235:genetics / Q000378:metabolism; D000099156:Superoxide Dismutase 2
D000943:Antigens, Differentiation; D000975:Antioxidants; D002950:Citrate (si)-Synthase; D051546:Cyclooxygenase 2; D045304:Cytochromes c; D045222:Electron Transport Chain Complex Proteins; D005353:Fibronectins; D020780:Matrix Metalloproteinase 9; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011794:Quercetin; D017452:Receptors, IgG; D049031:Sarcoglycans; D013482:Superoxide Dismutase; D053773:Transforming Growth Factor beta1; D049411:Utrophin; D000099156:Superoxide Dismutase 2; C485290:Ppargc1a protein, mouse; C508961:Tgfb1 protein, mouse; C483600:Utrn protein, mouse; C036763:monocyte-macrophage differentiation antigen; C077623:Ptgs2 protein, mouse; C501830:Mmp9 protein, mouse
Duchenne muscular dystrophy; polyphenol; utrophin