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 anti-oxidant 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 dystrophin-associated protein 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 non-muscle 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 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 siRNA 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.
- cell injury
- drug discovery
- reactive oxygen species (ROS)
- redox regulation
- transcriptional regulation
- transforming growth factor (TGF)
- Received April 21, 2011.
- Revision received June 6, 2011.
- Accepted June 6, 2011.
- The American Society for Pharmacology and Experimental Therapeutics