Glucose transporters and cellular antioxidant potential

葡萄糖转运蛋白和细胞抗氧化潜力

• 批准号: 8879635
• 负责人: JONATHAN S. FISHER
• 金额: $ 44.93万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-16 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8879635
• 关键词: 5' -AMP-activated protein kinase; Address; Adipocytes; Animal Feed; Anions; Antioxidants; Ascorbic Acid; Astrocytes; Back; Cells; Data; Dehydroascorbic Acid; Diabetes Mellitus; Diet; Electron Transport; Electrons; Exercise; Fatty acid glycerol esters; Functional disorder; Glucose Transporter; Glucosephosphate Dehydrogenase; Hydrogen Peroxide; Insulin; Insulin Resistance; L-Ascorbate oxidase; Liquid substance; Maintenance; Mediating; Mental Depression; Metabolism; Modeling; Mus; Muscle; Muscle Cells; Natural regeneration; Oxidants; Oxidation-Reduction; Physiological; Play; Prevention; Process; Reactive Oxygen Species; Recycling; Regulation; Relative (related person); Reporting; Role; SLC2A1 gene; Skeletal Muscle; Superoxide Dismutase; Tissues; ascorbate; catalase; cell type; extracellular; glucose uptake; insulin sensitivity; meetings; novel; overexpression; oxidation; oxidative damage; prevent; public health relevance; sugar; uptake

 DESCRIPTION (provided by applicant): Reactive oxygen species (ROS) have the capacity to cause insulin resistance and oxidative damage. A few specialized cell types have the capacity for extracellular ascorbate cycling. In this process, ascorbate is exported as an antioxidant, and after it is oxidized to dehydroascorbic acid (DHA), the DHA is taken up and reduced intracellularly to ascorbate for another round of antioxidant efflux. We have obtained preliminary data showing that mouse skeletal muscle has the ability to reduce extracellular electron acceptors in a process that is dependent on ascorbate release. Accordingly, the aims of the project are to elucidate the mechanism for, the regulation of, and the physiological consequences of extracellular ascorbate recycling by skeletal muscle. Aim 1 is to determine whether extracellular ascorbate recycling by skeletal muscle provides extracellular antioxidants. The hypotheses for Aim 1 are that muscle cells can reduce extracellular electron acceptors, that the electrons are carried by ascorbate, and that H2O2 plays a countervailing role in this process. Additional hypotheses are that GLUT1-mediated DHA transport supports ascorbate recycling and that anion channels are responsible for extracellular reduction activity and ascorbate efflux. Aim 2 is to determine whether extracellular reduction and ascorbate recycling by skeletal muscle are regulated by insulin and activation of the AMP-activated protein kinase (AMPK). In particular, the aim is to determine whether insulin produces a synergistic increase in DHA transport, glucose 6-phosphate dehydrogenase (G6PD) activity, and ascorbate efflux and to determine whether AMPK stimulates DHA transport but not G6PD activity or ascorbate efflux. Aim 3 is to determine functional roles of ascorbate recycling such as prevention of oxidative damage and maintenance of insulin action. Previously, ascorbate cycling was described for specialized tissues that are small relative to skeletal muscle, which contains 40% of whole-body ascorbate. This project will establish skeletal muscle as a primary generator of extracellular antioxidant and thus an important tissue in whole-body antioxidant status. Further, it could establish the importance of ascorbate cycling and in particular muscle DHA uptake in controlling ROS, thus maintaining normal insulin action. If successful, the project will introduce manipulation of skeletal muscle ascorbate cycling as a novel means for addressing insulin resistance.

 描述（由申请人提供）：活性氧（ROS）能够引起胰岛素抵抗和氧化损伤。一些特殊的细胞类型具有细胞外抗坏血酸循环的能力，在此过程中，抗坏血酸作为抗氧化剂被输出。它被氧化为脱氢抗坏血酸 (DHA)，DHA 在细胞内被吸收并还原为抗坏血酸，以进行另一轮抗氧化剂流出。小鼠骨骼肌具有在依赖于抗坏血酸释放的过程中减少细胞外电子受体的能力，因此，该项目的目的是阐明骨骼肌细胞外抗坏血酸回收的机制、调节和生理后果。目标 1 是确定骨骼肌的细胞外抗坏血酸回收是否提供细胞外抗氧化剂。目标 1 的假设是肌肉细胞可以减少细胞外电子受体，即电子。其他假设是 GLUT1 介导的 DHA 转运支持抗坏血酸循环，阴离子通道负责细胞外还原活性和抗坏血酸流出。骨骼肌的抗坏血酸循环受到胰岛素和 AMP 激活蛋白激酶 (AMPK) 的激活的调节。特别是，目的是确定胰岛素是否产生抗坏血酸。 DHA 转运、葡萄糖 6-磷酸脱氢酶 (G6PD) 活性和抗坏血酸流出的协同增加，并确定 AMPK 是否刺激 DHA 转运而不刺激 G6PD 活性或抗坏血酸流出 目的 3 是确定抗坏血酸循环的功能作用，例如防止氧化。此前，抗坏血酸循环被描述为相对于骨骼肌较小的特殊组织，骨骼肌含有 40% 的胰岛素。该项目将确立骨骼肌作为细胞外抗氧化剂的主要产生者，从而成为全身抗坏血酸状态的重要组织。此外，它还可以确定抗坏血酸循环，特别是肌肉 DHA 摄取在控制 ROS 方面的重要性。因此，如果成功，该项目将引入控制骨骼肌抗坏血酸循环作为解决胰岛素抵抗的新方法，从而维持正常的胰岛素作用。

项目成果

Measuring Trans-Plasma Membrane Electron Transport by C2C12 Myotubes.

通过 C2C12 肌管测量跨质膜电子传输。

• 发表时间: 2018-05-04
• 作者: Kelly, Shannon C;Eccardt, Amanda M;Fisher, Jonathan S
• 通讯作者: Fisher, Jonathan S

A peroxidase mimetic protects skeletal muscle cells from peroxide challenge and stimulates insulin signaling.

过氧化物酶模拟物可保护骨骼肌细胞免受过氧化物挑战并刺激胰岛素信号传导。

• 发表时间: 2020
• 作者: Eccardt, Amanda M;Pelzel, Ross J;Mattathil, Lyn;Moon, Yerin A;Mannino, Mark H;Janowiak, Blythe E;Fisher, Jonathan S
• 通讯作者: Fisher, Jonathan S

Glucose-dependent trans-plasma membrane electron transport and p70S6k phosphorylation in skeletal muscle cells.

骨骼肌细胞中葡萄糖依赖性跨质膜电子传递和 p70S6k 磷酸化。

• 发表时间: 2019
• 影响因子: 11.4
• 作者: Kelly, Shannon C;Patel, Neej N;Eccardt, Amanda M;Fisher, Jonathan S
• 通讯作者: Fisher, Jonathan S

Stimulation of Akt Phosphorylation and Glucose Transport by Metalloporphyrins with Peroxynitrite Decomposition Catalytic Activity.

具有过氧亚硝酸盐分解催化活性的金属卟啉刺激 Akt 磷酸化和葡萄糖转运。

• 发表时间: 2022-08
• 作者: Eccardt, Amanda M;Pelzel, Ross J;Bell, Thomas P;Fisher, Jonathan S
• 通讯作者: Fisher, Jonathan S

Trans-Plasma Membrane Electron Transport and Ascorbate Efflux by Skeletal Muscle.

骨骼肌的跨质膜电子传输和抗坏血酸流出。

• 发表时间: 2017-11-09
• 作者: Eccardt, Amanda M;Bell, Thomas P;Mattathil, Lyn;Prasad, Rohan;Kelly, Shannon C;Fisher, Jonathan S
• 通讯作者: Fisher, Jonathan S