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