Acetylation and contraction-mediated glucose uptake

项目总结 收缩刺激的葡萄糖摄取对维持运动过程中的ATP产生很重要， 尤其是高强度的运动。它也是临床治疗和预防的基石。 高血糖与2型糖尿病的发展。因此，理解收缩的调节-- 刺激的葡萄糖摄取对于制定优化骨骼肌葡萄糖的策略很重要 新陈代谢。这项研究的长期目标是阐明调节收缩的机制- 刺激葡萄糖摄取。这一应用的基本前提是GLUT4-的赖氨酸乙酰化 运输蛋白是收缩刺激的葡萄糖摄取所必需的。因此，在此应用程序中，我们的 主要目的是阐明乙酰转移酶，p300(E1a结合蛋白p300)和 CBP(cAMP反应元件结合蛋白结合蛋白)对收缩刺激的葡萄糖摄取，以及 以确定收缩反应中乙酰化的GLUT4运输蛋白。我们的中心假设 P300和CBP通过乙酰化GLUT4转运来调节收缩刺激的葡萄糖摄取 蛋白质，并且它们这样做是独立于它们作为转录调节器的共同角色。要解决这个问题 假设，我们将测量基础和收缩刺激的葡萄糖摄取量和质膜GLUT4 在小鼠骨骼肌中含量丰富，其中p300和CBP乙酰转移酶活性受到强烈调控。 具体地说，目标1将调查p300/CBP在收缩刺激的葡萄糖摄取和 质膜GLUT4易位，包括基因转录对其调控的重要性 效果。目标#2将定义响应收缩而乙酰化的GLUT4运输蛋白， 包括p300/CBP的贡献。总而言之，这些研究将为我们深入了解 P300/CBP和赖氨酸乙酰化可促进收缩刺激的葡萄糖摄取。总之，由于这项工作，一个 对调节骨骼肌葡萄糖摄取的信号的理解有望得到改善，这 推而广之，有望转化为对人类健康的实实在在的好处。

PROJECT SUMMARY Contraction-stimulated glucose uptake is important to the maintenance of ATP production during exercise, especially exercise of high-intensity. It is also a cornerstone for the treatment and prevention of clinical hyperglycemia and the development of type 2 diabetes. Thus, understanding the regulation of contraction- stimulated glucose uptake is important for the development of strategies to optimize skeletal muscle glucose metabolism. The long-term objective of this research is to elucidate the mechanisms that regulate contraction- stimulated glucose uptake. The fundamental premise of this application is that lysine acetylation of GLUT4- trafficking proteins is necessary for contraction-stimulated glucose uptake. Accordingly, in this application our primary objective is to elucidate the importance of the acetyltransferases, p300 (E1A binding protein p300) and CBP (cAMP response element-binding protein binding protein) to contraction-stimulated glucose uptake, and to identify the GLUT4 trafficking proteins that are acetylated in response to contraction. Our central hypothesis is that p300 and CBP regulate contraction-stimulated glucose uptake through acetylation of GLUT4-trafficking proteins, and that they do so independent of their common role as transcriptional regulators. To address this hypothesis, we will measure basal and contraction-stimulated glucose uptake and plasma membrane GLUT4 abundance in mouse skeletal muscle in which p300 and CBP acetyltransferase activity is acutely regulated. Specifically, Aim #1 will investigate the contributions of p300/CBP to contraction-stimulated glucose uptake and plasma membrane GLUT4 translocation, including the importance of gene transcription to their regulatory effects. Aim #2 will define the GLUT4 trafficking proteins that are acetylated in response to contraction, including the contributions of p300/CBP. Altogether, these studies will provide insight into the contribution of p300/CBP and lysine acetylation to contraction-stimulated glucose uptake. Altogether, because of this work, an improved understanding of the signalling that regulates glucose uptake by skeletal muscle is anticipated, which by extension is expected to translate into tangible benefits to human health.