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Research ArticleCellular and Molecular

Resveratrol Ameliorates Muscular Pathology in the Dystrophic mdx Mouse, a Model for Duchenne Muscular Dystrophy

Yusuke S. Hori, Atsushi Kuno, Ryusuke Hosoda, Masaya Tanno, Tetsuji Miura, Kazuaki Shimamoto and Yoshiyuki Horio
Journal of Pharmacology and Experimental Therapeutics September 2011, 338 (3) 784-794; DOI: https://doi.org/10.1124/jpet.111.183210
Yusuke S. Hori
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Atsushi Kuno
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Ryusuke Hosoda
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Masaya Tanno
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Tetsuji Miura
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Kazuaki Shimamoto
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Yoshiyuki Horio
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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 p47phox. 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, p47phox, and α-SMA in C2C12 cells. Taken together, these findings indicate that SIRT1 activation may be a useful strategy for treating muscular dystrophies.

Footnotes

  • This work was supported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan [Grant-in-Aid 22590245]; a National Project of Knowledge Cluster Initiative of Second Stage; Sapporo Biocluster Bio-S; the Program for Developing the Supporting System for Upgrading the Education and Research; and the Akiyama Life Science Foundation.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.183210.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    DMD
    Duchenne muscular dystrophy
    α-SMA
    α-smooth muscle actin
    CK
    creatine kinase
    CM-H2DCFDA
    5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate acetyl ester
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    IL-1β
    interleukin-1β
    LDH
    lactate dehydrogenase
    Nox
    NADPH oxidase
    8-OHdG
    8-hydroxy-2′-deoxyguanosine
    PBS
    phosphate-buffered saline
    qRT-PCR
    quantitative reverse transcription-polymerase chain reaction
    PGC-1α
    peroxisome proliferator-activated receptor-γ coactivator 1α
    ROS
    reactive oxygen species
    siRNA
    small interfering RNA
    Sod
    superoxide dismutase
    TGF-β
    transforming growth factor-β
    TNF-α
    tumor necrosis factor-α
    MHC
    myosin heavy chain
    Hmox1
    heme oxygenase 1
    Nqo1
    NAD(P)H quinone oxidoreductase 1
    Gclm
    glutamylcysteine ligase modulator
    Gclc
    glutamylcysteine ligase catalytic subunit
    n.s
    not significant
    NF-κB
    nuclear factor κB
    RSV
    resveratrol
    Ctrl
    control.

  • Received April 21, 2011.
  • Accepted June 6, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 3
1 Sep 2011
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Research ArticleCellular and Molecular

Resveratrol Ameliorates Muscular Pathology in the Dystrophic mdx Mouse, a Model for Duchenne Muscular Dystrophy

Yusuke S. Hori, Atsushi Kuno, Ryusuke Hosoda, Masaya Tanno, Tetsuji Miura, Kazuaki Shimamoto and Yoshiyuki Horio
Journal of Pharmacology and Experimental Therapeutics September 1, 2011, 338 (3) 784-794; DOI: https://doi.org/10.1124/jpet.111.183210

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Research ArticleCellular and Molecular

Resveratrol Ameliorates Muscular Pathology in the Dystrophic mdx Mouse, a Model for Duchenne Muscular Dystrophy

Yusuke S. Hori, Atsushi Kuno, Ryusuke Hosoda, Masaya Tanno, Tetsuji Miura, Kazuaki Shimamoto and Yoshiyuki Horio
Journal of Pharmacology and Experimental Therapeutics September 1, 2011, 338 (3) 784-794; DOI: https://doi.org/10.1124/jpet.111.183210
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