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Skeletal Muscle Glucose Uptake: Exercise and Insulin

骨骼肌葡萄糖摄取：运动和胰岛素

基本信息

批准号：
9921359
负责人：
Gregory D. Cartee
金额：
$ 52.15万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2022-04-30
项目状态：
已结题

项目摘要

Increased post-exercise insulin sensitivity in skeletal muscle is a well-known health benefit of acute exercise, but the underlying mechanisms remain uncertain. The long-range goal is to fully understand the cellular events responsible for this major health benefit. Skeletal muscle is a heterogenous tissue comprised of multiple fiber types with diverse metabolic phenotypes. Conventional tissue analysis cannot discern cellular mechanisms, but a recently developed and validated method enables determination of glucose uptake (GU) and fiber type in single muscle fibers. Recent research using this approach has uncovered striking and unexpected fiber type- selective exercise effects in normal and insulin resistant muscle that were not attributable to lack of recruitment of the fiber types that failed to attain exercise-induced improvement in insulin sensitivity. Akt Substrate of 160 kDa (AS160) is a key insulin signaling protein that regulates GLUT4 glucose transporter translocation. Greater AS160 phosphorylation is consistently linked to greater insulin-mediated GU in whole muscles from normal and insulin-resistant rats. In addition to determination of single fiber GU, this project will use novel methods to measure, for the first time, exercise effects on cellular insulin signaling (including AS160 phosphorylation) and cell surface GLUT4 levels in specific fiber types, thereby advancing understanding from the level of whole muscles to the cellular level of specific fiber types. Newly created AS160-null rats with AAV vector-mediated wildtype or phosphomutated AS160 expression will be used to reveal if AS160 expression or phosphorylation is essential for greater insulin-mediated GU post-exercise in whole muscles and specific fiber types of normal and insulin resistant rats. These unique approaches will make possible unprecedented evaluation of cellular events responsible for the post-exercise increase in insulin sensitivity. The Specific Aims are: 1) To elucidate mechanisms for the exercise-induced improvement in insulin-stimulated GU of whole muscles and specific fiber types from normal rats; 2) To test the mechanisms for high fat diet (HFD)-induced insulin resistance in whole muscles and specific fiber types; and 3) To test the mechanisms for exercise-induced improvement in insulin-stimulated GU of whole muscles and specific fiber types from high fat diet-induced insulin resistant rats. The predicted results are that in whole muscles and fiber types with enhanced insulin-mediated GU after exercise by normal and insulin resistant rats of both sexes, γ3-AMP-activated protein kinase (AMPK) stimulation immediately post-exercise is a trigger that catalyzes greater phosphorylation of AS160 Ser704 (AMPK phosphosite) which acts as a memory element favoring greater insulin-induced AS160 phosphorylation on Thr642 and Ser588, mediators for greater cell surface GLUT4, the end-effector enabling greater insulin- mediated GU post-exercise. We also predict AS160 expression and site-selective phosphorylation are essential for exercise effects on insulin-mediated GU in normal and insulin resistant muscle. This research will provide groundbreaking insights into cellular mechanisms underlying improved insulin sensitivity post-exercise.

运动后骨骼肌中胰岛素敏感性的增加是急性运动的众所周知的健康益处，但其潜在机制仍不确定。长期目标是完全理解细胞活动为这一重大健康效益负责。骨骼肌是由多种纤维组成的异质性组织具有不同代谢表型的类型。传统的组织分析不能辨别细胞机制，但最近开发和验证的方法能够确定葡萄糖摄取（GU）和纤维类型，单根肌纤维最近使用这种方法的研究发现了惊人的和意想不到的纤维类型- 在正常和胰岛素抵抗肌肉中的选择性运动效应不是由于缺乏募集的纤维类型，未能达到运动引起的胰岛素敏感性的改善。Akt底物160 kDa（AS 160）是调节GLUT 4葡萄糖转运蛋白转位的关键胰岛素信号蛋白。更大 AS 160磷酸化始终与正常人和正常人的整个肌肉中更高的胰岛素介导的GU相关，胰岛素抵抗大鼠。除了测定单根纤维的GU外，该项目还将使用新的方法，首次测量运动对细胞胰岛素信号传导（包括AS 160磷酸化）的影响，细胞表面GLUT 4水平在特定的纤维类型，从而推进从整体水平的理解，肌肉到特定纤维类型的细胞水平。新创建的具有AAV载体介导的AS 160-null大鼠野生型或磷酸突变的AS 160表达将用于揭示AS 160表达或磷酸化是必不可少的更大的胰岛素介导的GU运动后，在整个肌肉和特定的纤维类型的正常和胰岛素抵抗大鼠。这些独特的方法将使前所未有的细胞评估成为可能。运动后胰岛素敏感性增加的事件。具体目的是：（1）阐明运动诱导的胰岛素刺激的整个肌肉和特定GU的改善机制 2）探讨高脂饮食（HFD）诱导胰岛素抵抗的机制。整个肌肉和特定的纤维类型;和3）测试运动引起的改善的机制，高脂饮食诱导的胰岛素抵抗大鼠的胰岛素刺激的整个肌肉和特定纤维类型的GU。预测的结果是，在胰岛素介导的GU增强的整个肌肉和纤维类型中，正常和胰岛素抵抗大鼠运动后，γ3-AMP活化蛋白激酶（AMPK）运动后立即刺激是催化AS 160 Ser 704更大磷酸化的触发因素 (AMPK磷酸化位点），其作为有利于更大的胰岛素诱导的AS 160磷酸化的记忆元件在Thr 642和Ser 588上，更大细胞表面GLUT 4的介导剂，末端效应器使更大的胰岛素- 介导的运动后GU。我们还预测AS 160的表达和位点选择性磷酸化是运动对正常和胰岛素抵抗肌肉中胰岛素介导的GU的影响至关重要。这项研究将为运动后胰岛素敏感性改善的细胞机制提供了突破性的见解。