Department of Cellular and Molecular Medicine, Faculty of Medicine, and Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada.
Department of Cellular and Molecular Medicine, Faculty of Medicine, and Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada
Am J Physiol Cell Physiol. 2014 Jul 1;307(1):C66-82. doi: 10.1152/ajpcell.00357.2013. Epub 2014 Apr 23.
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.
较慢、更氧化的肌肉纤维对杜氏肌营养不良症（DMD）患者以及 DMD 的临床前 mdx 小鼠模型中的营养不良病理更具抗性。因此，DMD 的一种治疗策略集中于促进缓慢、氧化的肌生成程序的表达。在当前的研究中，我们通过用天然酚类白藜芦醇（RSV；~100mg·kg(-1)·day(-1)）喂养 6 周龄动物 6 周，探索了在 mdx 小鼠中刺激缓慢、氧化表型的治疗潜力。Sirtuin 1（SIRT1）活性和蛋白水平显著增加，过氧化物酶体增殖物激活受体-γ共激活物-1α（PGC-1α）活性也增加，而 AMPK 信号没有改变。这些适应伴随着快速、糖酵解到较慢、更氧化的纤维类型转换的证据，包括线粒体生物发生和较慢肌球蛋白重链同工型的表达增加。这些积极的发现提出了一个问题，即增加 RSV 的暴露是否会带来更大的治疗益处。我们发现，在 mdx 小鼠中，持续 12 周、约 500mg·kg(-1)·day(-1)的 RSV 升高剂量在肌肉重塑方面的效果明显较差。这种治疗方案未能影响 SIRT1 或 AMPK 信号，也没有导致向较慢、更氧化的表型转变。总之，这项研究表明，RSV 可以刺激 SIRT1 和 PGC-1α 的激活，这反过来可能促进 mdx 小鼠肌肉中缓慢、氧化的肌生成程序的表达。该数据还强调了选择适当的 RSV 剂量方案以最大限度地发挥其在未来 DMD 患者中的潜在治疗效果的重要性。
