Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine in St. Louis, Missouri, United States of America.
PLoS Biol. 2013 Jul;11(7):e1001603. doi: 10.1371/journal.pbio.1001603. Epub 2013 Jul 9.
It has been reported that feeding mice resveratrol activates AMPK and SIRT1 in skeletal muscle leading to deacetylation and activation of PGC-1α, increased mitochondrial biogenesis, and improved running endurance. This study was done to further evaluate the effects of resveratrol, SIRT1, and PGC-1α deacetylation on mitochondrial biogenesis in muscle. Feeding rats or mice a diet containing 4 g resveratrol/kg diet had no effect on mitochondrial protein levels in muscle. High concentrations of resveratrol lowered ATP concentration and activated AMPK in C₂C₁₂ myotubes, resulting in an increase in mitochondrial proteins. Knockdown of SIRT1, or suppression of SIRT1 activity with a dominant-negative (DN) SIRT1 construct, increased PGC-1α acetylation, PGC-1α coactivator activity, and mitochondrial proteins in C₂C₁₂ cells. Expression of a DN SIRT1 in rat triceps muscle also induced an increase in mitochondrial proteins. Overexpression of SIRT1 decreased PGC-1α acetylation, PGC-1α coactivator activity, and mitochondrial proteins in C₂C₁₂ myotubes. Overexpression of SIRT1 also resulted in a decrease in mitochondrial proteins in rat triceps muscle. We conclude that, contrary to some previous reports, the mechanism by which SIRT1 regulates mitochondrial biogenesis is by inhibiting PGC-1α coactivator activity, resulting in a decrease in mitochondria. We also conclude that feeding rodents resveratrol has no effect on mitochondrial biogenesis in muscle.
据报道，给老鼠喂食白藜芦醇会激活骨骼肌中的 AMPK 和 SIRT1，导致 PGC-1α 去乙酰化和激活，增加线粒体生物发生，并提高跑步耐力。本研究旨在进一步评估白藜芦醇、SIRT1 和 PGC-1α 去乙酰化对肌肉中线粒体生物发生的影响。给大鼠或小鼠喂食含 4 g 白藜芦醇/公斤饮食的饮食对肌肉中线粒体蛋白水平没有影响。高浓度的白藜芦醇降低了 C₂C₁₂肌管中的 ATP 浓度并激活了 AMPK，导致线粒体蛋白增加。SIRT1 的敲低，或用显性负（DN）SIRT1 构建体抑制 SIRT1 活性，增加了 C₂C₁₂ 细胞中的 PGC-1α 乙酰化、PGC-1α 共激活剂活性和线粒体蛋白。DN SIRT1 在大鼠三头肌中的表达也诱导了线粒体蛋白的增加。SIRT1 的过表达降低了 C₂C₁₂ 肌管中的 PGC-1α 乙酰化、PGC-1α 共激活剂活性和线粒体蛋白。SIRT1 的过表达也导致大鼠三头肌中的线粒体蛋白减少。我们得出的结论是，与一些先前的报告相反，SIRT1 调节线粒体生物发生的机制是通过抑制 PGC-1α 共激活剂活性，导致线粒体减少。我们还得出结论，给啮齿动物喂食白藜芦醇对肌肉中线粒体生物发生没有影响。
