Skeletal Muscle Glucose Uptake: Exercise and Insulin

骨骼肌葡萄糖摄取：运动和胰岛素

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/9921359
• 关键词: 5' -AMP-activated protein kinase; Acute; Beta Cell; Blood Glucose; Cell surface; Defect; Diet; Elements; Evaluation; Event; Exercise; Fiber; GLUT4 gene; Glucose Transporter; Goals; Health Benefit; High Fat Diet; Insulin; Insulin Resistance; Knowledge; Link; Measures; Mediating; Mediator of activation protein; Memory; Metabolic; Methods; Muscle; Muscle Cells; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Phosphorylation; Process; Protein Kinase; Protocols documentation; Public Health; Rattus; Research; Role; Secondary to; Signaling Protein; Site; Skeletal Muscle; Testing; Time; Tissues; adeno-associated viral vector; glucose disposal; glucose uptake; improved; insight; insulin sensitivity; insulin signaling; metabolic phenotype; mutant; novel; novel therapeutics; recruit; sedentary; sex

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.

运动后胰岛素敏感性提高在骨骼肌中是急性运动的众所周知的健康益处， 但是潜在的机制仍然不确定。远程目标是充分了解蜂窝事件 负责这一主要健康益处。骨骼肌是多个纤维的异质组织 具有潜水代谢表型的类型。常规的组织分析无法辨别细胞机制， 但是最近开发和验证的方法可以确定葡萄糖摄取（GU）和纤维类型 单肌纤维。最近使用这种方法的研究发现了罢工和意外的纤维类型 - 在正常和胰岛素抵抗肌肉中的选择性运动作用，这些肌肉不足 在未能达到运动引起的胰岛素敏感性改善的纤维类型中。 AKT基板为160 KDA（AS160）是调节Glut4葡萄​​糖转运蛋白转运的关键胰岛素信号蛋白。更大 AS160磷酸化一直与正常和 耐胰岛素的大鼠。除了确定单光纤GU之外，该项目还将使用新颖的方法 测量首次对细胞胰岛素信号传导（包括AS160磷酸化）和 特定纤维类型中的细胞表面GLUT4水平，从而从整体水平中提高理解 肌肉达到特定纤维类型的细胞水平。与AAV矢量介导的新创建的AS160-NULL大鼠 野生型或磷酸化的AS160表达将用于揭示AS160表达或磷酸化是 对于整个肌肉和特定纤维类型的正常纤维类型，对于更大的胰岛素介导的GU运动至关重要 和抗胰岛素的大鼠。这些独特的方法将使细胞的前所未有的评估可能 导致运动后胰岛素敏感性增加的事件。具体目的是：1）阐明 运动引起的整个肌肉胰岛素刺激的GU的改善和特定的机制 正常大鼠的纤维类型； 2）测试高脂饮食（HFD）诱导的胰岛素抵抗的机制 全肌肉和特定的纤维类型； 3）测试运动引起的改善的机制 胰岛素刺激的全肌肉和高脂饮食诱导的胰岛素耐药大鼠的特定纤维类型的GU。 预测的结果是，在整个肌肉和纤维类型中，胰岛素介导的GU在 通过两性的正常和胰岛素耐药大鼠运动，γ3AMP激活的蛋白激酶（AMPK）运动 运动后立即刺激是一种触发，可催化AS160 Ser704的更大磷酸化 （AMPK磷材料）充当有利于胰岛素诱导的AS160磷酸化的记忆元件 在Thr642和Ser588上，用于更大细胞表面GLUT4的介体，最终效应器可实现更大的胰岛素 - 调解后运动。我们还预测AS160表达和现场选择性磷酸化是 对胰岛素介导的GU在正常和胰岛素耐药性肌肉中的锻炼至关重要。这项研究会 对运动后改善胰岛素敏感性的基础机制提供开创性的见解。

项目成果

Protein Phosphatase 1-α Regulates AS160 Ser588 and Thr642 Dephosphorylation in Skeletal Muscle.

• DOI: 10.2337/db15-0867
• 发表时间: 2016-09
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Sharma P;Arias EB;Cartee GD
• 通讯作者: Cartee GD

A novel genetic model provides a unique perspective on the relationship between postexercise glycogen concentration and increases in the abundance of key metabolic proteins after acute exercise.

• DOI: 10.1371/journal.pone.0295964
• 发表时间: 2024
• 期刊: PloS one
• 影响因子: 3.7

Akt substrate of 160 kDa dephosphorylation rate is reduced in insulin-stimulated rat skeletal muscle after acute exercise.

急性运动后，胰岛素刺激的大鼠骨骼肌中 160 kDa 去磷酸化率的 Akt 底物降低。

• DOI: 10.33549/physiolres.933591
• 发表时间: 2018
• 期刊: Physiological research
• 影响因子: 2.1
• 作者: Arias,EB;Wang,H;Cartee,GD
• 通讯作者: Cartee,GD

Fiber type-selective exercise effects on AS160 phosphorylation.

纤维类型选择性运动对 AS160 磷酸化的影响。

• DOI: 10.1152/ajpendo.00528.2018
• 发表时间: 2019
• 期刊: American journal of physiology. Endocrinology and metabolism
• 作者: Wang,Haiyan;Arias,EdwardB;Oki,Kentaro;Pataky,MarkW;Almallouhi,JalalA;Cartee,GregoryD
• 通讯作者: Cartee,GregoryD

AMPK-TBC1D4-dependent mechanism for increasing insulin sensitivity of skeletal muscle.

AMPK-TBC1D4 依赖性机制可增加骨骼肌的胰岛素敏感性。

• DOI: 10.2337/db15-0010
• 发表时间: 2015
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Cartee,GregoryD