title: Resveratrol ameliorates muscular pathology in the dystrophic mdx mouse, a model for Duchenne muscular dystrophy.
abstract: Muscular dystrophies are inherited myogenic disorders accompanied by progressive skeletal muscle weakness and degeneration. We previously showed that resveratrol (3,5,4'-trihydroxy-trans-stilbene), an antioxidant and activator of the NAD(+)-dependent protein deacetylase SIRT1, delays the progression of heart failure and prolongs the lifespan of δ-sarcoglycan-deficient hamsters. Because a defect of dystroglycan complex causes muscular dystrophies, and δ-sarcoglycan is a component of this complex, we hypothesized that resveratrol might be a new therapeutic tool for muscular dystrophies. Here, we examined resveratrol's effect in mdx mice, an animal model of Duchenne muscular dystrophy. mdx mice that received resveratrol in the diet for 32 weeks (4 g/kg diet) showed significantly less muscle mass loss and nonmuscle interstitial tissue in the biceps femoris compared with mdx mice fed a control diet. In the muscles of these mice, resveratrol significantly decreased oxidative damage shown by the immunostaining of nitrotyrosine and 8-hydroxy-2'-deoxyguanosine and suppressed the up-regulation of NADPH oxidase subunits Nox4, Duox1, and p47(phox). Resveratrol also reduced the number of α-smooth muscle actin (α-SMA)(+) myofibroblast cells and endomysial fibrosis in the biceps femoris, although the infiltration of CD45(+) inflammatory cells and increase in transforming growth factor-β1 (TGF-β1) were still observed. In C2C12 myoblast cells, resveratrol pretreatment suppressed the TGF-β1-induced increase in reactive oxygen species, fibronectin production, and expression of α-SMA, and SIRT1 knockdown blocked these inhibitory effects. SIRT1 small interfering RNA also increased the expression of Nox4, p47(phox), and α-SMA in C2C12 cells. Taken together, these findings indicate that SIRT1 activation may be a useful strategy for treating muscular dystrophies.
authors.affiliation: Department of Pharmacology, School of Medicine, Sapporo Medical University, Sapporo, Japan.
authors.forename: Yusuke S
authors.initials: YS
authors.lastname: Hori
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kuno
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Hosoda
authors.forename: Masaya
authors.initials: M
authors.lastname: Tanno
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Miura
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shimamoto
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Horio
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D003402:Creatine Kinase / Q000378:metabolism; D018274:Electroporation; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis / Q000517:prevention & control; D006657:Histones / Q000378:metabolism; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000473:pathology*; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D006657:Histones; D007202:Indicators and Reagents; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013267:Stilbenes; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol