Sin Thomas K, Yung Benjamin Y, Siu Parco M
Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
Cell Physiol Biochem. 2015;35(2):541-52. doi: 10.1159/000369718. Epub 2015 Jan 27.
Aging individuals and diabetic patients often exhibit concomitant reductions of skeletal muscle mass/strength and insulin sensitivity, suggesting an intimate link between muscle aging and insulin resistance. Foxo1, a member of the FOXO transcription factor family, is an important player in insulin signaling due to its inhibitory role in glucose uptake and utilization in skeletal muscle. Phosphorylation of Foxo1 is thought to mitigate the transactivation of pyruvate dehydrogenase lipoamide kinase 4 (PDK4), which is a negative regulator of the glycolytic enzyme pyruvate dehydrogenase (PDH). In contrast, how aging would regulate acetylation/deacetylation machineries and glucose utilization in skeletal muscle through the Foxo1/PDH axis remains largely undetermined. Accumulating body of evidence have shown that resveratrol, a natural polyphenol in grapes and red wine, activates the longevity-related protein sirtuin 1 (SIRT1) and augments insulin sensitivity in addition to its well-documented effects on mitochondrial energetics. The present review summarizes the role of Foxo1/SIRT1 in insulin signaling in skeletal muscle and proposes the insight that activation of SIRT1 deacetylase activity to deacetylate and suppress the Foxo1-induced transactivation of PDK4 may represent an anti-hyperglycemic mechanism of resveratrol in aging skeletal muscle.
衰老个体和糖尿病患者常同时出现骨骼肌质量/力量和胰岛素敏感性下降，提示肌肉衰老与胰岛素抵抗之间存在密切联系。Foxo1是FOXO转录因子家族的成员，由于其对骨骼肌葡萄糖摄取和利用具有抑制作用，因而在胰岛素信号传导中发挥重要作用。Foxo1的磷酸化被认为可减轻丙酮酸脱氢酶硫辛酰胺激酶4（PDK4）的反式激活，而PDK4是糖酵解酶丙酮酸脱氢酶（PDH）的负调节因子。相比之下，衰老如何通过Foxo1/PDH轴调节骨骼肌中的乙酰化/去乙酰化机制及葡萄糖利用，在很大程度上仍不明确。越来越多的证据表明，白藜芦醇作为葡萄和红酒中的一种天然多酚，除了对线粒体能量代谢有充分记载的作用外，还能激活与长寿相关的蛋白沉默调节蛋白1（SIRT1）并增强胰岛素敏感性。本综述总结了Foxo1/SIRT1在骨骼肌胰岛素信号传导中的作用，并提出如下观点：激活SIRT1脱乙酰酶活性以去乙酰化并抑制Foxo1诱导的PDK4反式激活，可能是白藜芦醇在衰老骨骼肌中发挥抗高血糖作用的机制。
