The role of ATM in glucose transport and insulin signaling in skeletal muscle

ATM 在骨骼肌葡萄糖转运和胰岛素信号传导中的作用

• 批准号: 8006746
• 负责人: JONATHAN S. FISHER
• 金额: $ 4.5万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8006746
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Address; Adipocytes; Animals; Antibodies; Blood Circulation; Blood Glucose; Cells; Data; Diabetes Mellitus; Exercise; GLUT4 gene; Goals; Hormones; Human; Hyperglycemia; Insulin; Insulin Resistance; Insulin Signaling Pathway; Mus; Muscle; Muscle Fibers; Phosphorylation; Play; Prevention approach; Proteins; Regulation; Role; Site; Skeletal Muscle; Testing; Tissues; Transgenic Mice; ataxia telangiectasia mutated protein; cell type; glucose disposal; glucose transport; glucose uptake; impaired glucose tolerance; inhibitor/antagonist; insulin mediators; insulin signaling; member; novel strategies; phosphoinositide-dependent kinase 1; prevent; public health relevance; response; sugar; tool

DESCRIPTION (provided by applicant): Humans and animals with deficient ataxia telangiectasia mutated (ATM) are insulin-resistant or hyperglycemic. ATM reportedly indirectly influences insulin signaling, including phosphorylation of Akt, in various cell types. There is also evidence that ATM is an activating kinase for the AMP-activated protein kinase (AMPK), a mediator of insulin-independent stimulation of glucose transport. However, the potential roles of ATM in AMPK- and insulin-stimulated glucose transport have not previously been addressed in skeletal muscle, the predominant tissue in insulin-stimulated glucose disposal. Preliminary data from cultured myotubes demonstrate that a specific ATM inhibitor prevents stimulation of glucose transport by insulin and the AMPK activator AICAR. The specific aims are: 1) to test the hypothesis that ATM plays a role in insulin-independent stimulation of glucose transport by AMPK-activating treatments (e.g. exercise and/or the AMPK activator AICAR) in skeletal muscle, 2) to test the hypothesis that ATM plays a role in insulin-stimulated glucose transport and insulin signaling in skeletal muscle, and 3) to test the hypothesis that ATM directly phosphorylates and/or alters activity of components of the insulin signaling pathway in skeletal muscle. Experimental tools will include ATM deficient transgenic mice, a specific inhibitor of ATM, and an antibody specific for proteins that have been phosphorylated by ATM. Elucidating the possible role of a factor like ATM that might play a role in regulation of glucose transport stimulated by either AMPK or insulin--or both--is potentially valuable to describing new approaches to prevention or treatment of diabetes. PUBLIC HEALTH RELEVANCE STATEMENT: The project will examine the potential role of a protein called ATM in regulation of sugar transport into muscle in response to exercise and insulin, a hormone that enters the bloodstream when blood sugar levels increase. Understanding the factors that cause muscles to clear sugar from the bloodstream is vital to developing strategies to treat or prevent the high blood sugar concentrations that are the hallmark of diabetes.

描述（由申请人提供）：患有共济失调毛细血管扩张突变（ATM）缺陷的人类和动物具有胰岛素抵抗或高血糖。据报道，ATM 间接影响各种细胞类型中的胰岛素信号传导，包括 Akt 的磷酸化。还有证据表明，ATM 是 AMP 激活蛋白激酶 (AMPK) 的激活激酶，AMPK 是不依赖胰岛素​​的葡萄糖转运刺激的介质。然而，ATM 在 AMPK 和胰岛素刺激的葡萄糖转运中的潜在作用此前尚未在骨骼肌中得到解决，骨骼肌是胰岛素刺激的葡萄糖处理的主要组织。来自培养肌管的初步数据表明，特定的 ATM 抑制剂可防止胰岛素和 AMPK 激活剂 AICAR 对葡萄糖转运的刺激。具体目标是：1) 检验 ATM 在骨骼肌中 AMPK 激活治疗（例如运动和/或 AMPK 激活剂 AICAR）对葡萄糖转运的非胰岛素依赖性刺激中发挥作用的假设，2) 检验该假设ATM 在骨骼肌中胰岛素刺激的葡萄糖转运和胰岛素信号传导中发挥作用，以及 3) 检验 ATM 直接磷酸化和/或改变胰岛素信号传导途径成分的活性的假设在骨骼肌中。实验工具将包括ATM缺陷的转基因小鼠、ATM的特异性抑制剂以及针对已被ATM磷酸化的蛋白质的特异性抗体。阐明 ATM 等因子可能在调节 AMPK 或胰岛素（或两者）刺激的葡萄糖转运中发挥作用，对于描述预防或治疗糖尿病的新方法具有潜在价值。 公共卫生相关声明：该项目将研究一种名为 ATM 的蛋白质在调节糖转运到肌肉中的潜在作用，以响应运动和胰岛素，胰岛素是一种当血糖水平升高时进入血液的激素。了解导致肌肉从血液中清除糖的因素对于制定治疗或预防糖尿病标志的高血糖浓度的策略至关重要。

项目成果

Ataxia telangiectasia mutated impacts insulin-like growth factor 1 signalling in skeletal muscle.

共济失调毛细血管扩张突变会影响骨骼肌中胰岛素样生长因子 1 信号传导。

• 发表时间: 2013-02
• 影响因子: 2.7
• 作者: Ching, James Kain;Luebbert, Stephen H;Collins 4th, Roy L;Zhang, Zhihong;Marupudi, Nandhini;Banerjee, Sankha;Hurd, Robin D;Ralston, Lyle;Fisher, Jonathan S
• 通讯作者: Fisher, Jonathan S

ATM and GLUT1-S490 phosphorylation regulate GLUT1 mediated transport in skeletal muscle.

ATM 和 GLUT1-S490 磷酸化调节骨骼肌中 GLUT1 介导的运输。

• 发表时间: 2013
• 影响因子: 3.7
• 作者: Andrisse, Stanley;Patel, Gaytri D;Chen, Joseph E;Webber, Andrea M;Spears, Larry D;Koehler, Rikki M;Robinson;Ching, James K;Jeong, Imju;Fisher, Jonathan S
• 通讯作者: Fisher, Jonathan S

Ataxia telangiectasia mutated influences cytochrome c oxidase activity.

共济失调毛细血管扩张突变影响细胞色素 C 氧化酶活性。

• 发表时间: 2011-02-25
• 影响因子: 3.1
• 作者: Patel, Akshar Y;McDonald, Todd M;Spears, Larry D;Ching, James Kain;Fisher, Jonathan S
• 通讯作者: Fisher, Jonathan S

Chloroquine increases phosphorylation of AMPK and Akt in myotubes.

氯喹增加肌管中 AMPK 和 Akt 的磷酸化。

• 发表时间: 2016-03
• 影响因子: 4
• 作者: Spears, Larry D;Tran, Andrew V;Qin, Charles Y;Hobbs, Supriya B;Burns, Cheryl A Liang;Royer, Nathaniel K;Zhang, Zhihong;Ralston, Lyle;Fisher, Jonathan S
• 通讯作者: Fisher, Jonathan S

A role for ataxia telangiectasia mutated in insulin-independent stimulation of glucose transport.

共济失调毛细血管扩张症在不依赖胰岛素​​的葡萄糖转运刺激中的作用发生突变。

• 发表时间: 2017
• 作者: Spears, Larry D;Renth, Allyson L;McKuin, Michael R;Kennedy, Anne R;Andrisse, Stanley;Briggs, Nell E;Fisher, Jonathan S
• 通讯作者: Fisher, Jonathan S