Resveratrol induces expression of the slow, oxidative phenotype in mdx mouse muscle together with enhanced activity of the SIRT1-PGC-1α axis.
Slower, more oxidative muscle fibers are more resistant to the dystrophic pathology in Duchenne muscular dystrophy (DMD) patients as well as in the preclinical mdx mouse model of DMD. Therefore, one therapeutic strategy for DMD focuses on promoting expression of the slow, oxidative myogenic program. In the current study, we explored the therapeutic potential of stimulating the slow, oxidative phenotype in mdx mice by feeding 6-wk-old animals with the natural phenol resveratrol (RSV; ~100 mg·kg(-1)·day(-1)) for 6 wk. Sirtuin 1 (SIRT1) activity and protein levels increased significantly, as well as peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) activity, in the absence of alterations in AMPK signaling. These adaptations occurred concomitant with evidence of a fast, glycolytic, to slower, more oxidative fiber type conversion, including mitochondrial biogenesis and increased expression of slower myosin heavy chain isoforms. These positive findings raised the question of whether increased exposure to RSV would result in greater therapeutic benefits. We discovered that an elevated RSV dose of ~500 mg·kg(-1)·day(-1) across a duration of 12 wk was clearly less effective at muscle remodeling in mdx mice. This treatment protocol failed to influence SIRT1 or AMPK signaling and did not result in a shift towards a slower, more oxidative phenotype. Taken together, this study demonstrates that RSV can stimulate SIRT1 and PGC-1α activation, which in turn may promote expression of the slow, oxidative myogenic program in mdx mouse muscle. The data also highlight the importance of selecting an appropriate dosage regimen of RSV to maximize its potential therapeutic effectiveness for future application in DMD patients.
Department of Cellular and Molecular Medicine, Faculty of Medicine, and Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada.
Vladimir
V
Ljubicic
Department of Cellular and Molecular Medicine, Faculty of Medicine, and Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada.
Matthew
M
Burt
Department of Cellular and Molecular Medicine, Faculty of Medicine, and Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada.
John A
JA
Lunde
Department of Cellular and Molecular Medicine, Faculty of Medicine, and Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada jasmin@uottawa.ca.
Bernard J
BJ
Jasmin
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D004195:Disease Models, Animal; D006019:Glycolysis / Q000187:drug effects; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D024510:Muscle Development / Q000187:drug effects; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010641:Phenotype; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*
D000975:Antioxidants; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D013267:Stilbenes; D014157:Transcription Factors; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol
AMPK; DMD; PGC-1α; SIRT1; utrophin A