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Glucose transporters and cellular antioxidant potential

葡萄糖转运蛋白和细胞抗氧化潜力

基本信息

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
项目类别：
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&apos -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

项目摘要

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)：活性氧物种(ROS)具有导致胰岛素抵抗和氧化损伤的能力。一些特殊类型的细胞具有细胞外抗坏血酸循环的能力。在这个过程中，抗坏血酸作为抗氧化剂输出，在它被氧化成脱氢抗坏血酸(DHA)后，DHA被吸收并在细胞内还原为抗坏血酸，用于另一轮抗氧化剂外流。我们已经获得的初步数据表明，小鼠骨骼肌具有减少细胞外电子受体的能力，这一过程依赖于抗坏血酸的释放。因此，该项目的目的是阐明骨骼肌细胞外抗坏血酸循环的机制、调节和生理后果。目的1是确定骨骼肌细胞外抗坏血酸循环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，电子由抗坏血酸携带，过氧化氢在这一过程中起到抵消作用。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动和抗坏血酸外流。目的2确定骨骼肌细胞外还原和抗坏血酸循环是否受胰岛素和AMP活化蛋白激酶(AMPK)激活的调节。特别是，目的是确定胰岛素是否协同增加DHA转运、葡萄糖6-磷酸脱氢酶(G6PD)活性和抗坏血酸外流，并确定AMPK是否刺激DHA转运而不是G6PD活性或抗坏血酸外流。目的3是确定抗坏血酸循环的功能作用，如预防氧化损伤和维持胰岛素的作用。以前，抗坏血酸循环被描述为专门的组织，相对于骨骼肌来说很小，骨骼肌含有40%的全身抗坏血酸。该项目将使骨骼肌成为细胞外抗氧化剂的主要生成者，从而成为全身抗氧化剂状态的重要组织。此外，它可以确定抗坏血酸循环的重要性，特别是肌肉DHA摄取在控制ROS从而维持正常的胰岛素作用方面的重要性。如果成功，该项目将引入骨骼肌抗坏血酸循环的操作，作为解决胰岛素抵抗的一种新方法。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

DOI：
10.3390/antiox6040089
发表时间：
2017-11-09
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
0
作者：
Eccardt AM;Bell TP;Mattathil L;Prasad R;Kelly SC;Fisher JS
通讯作者：
Fisher JS

Myoglobin as a versatile peroxidase: Implications for a more important role for vertebrate striated muscle in antioxidant defense.

DOI：
10.1016/j.cbpb.2019.04.005
发表时间：
2019-08
期刊：
Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology
影响因子：
0
作者：
Mark H. Mannino;Rishi S Patel;Amanda M. Eccardt;Rodrigo A Perez Magnelli;Chiron L C Robinson;Blythe E. Janowiak;Daniel E. Warren;J. Fisher
通讯作者：
Mark H. Mannino;Rishi S Patel;Amanda M. Eccardt;Rodrigo A Perez Magnelli;Chiron L C Robinson;Blythe E. Janowiak;Daniel E. Warren;J. Fisher

Measuring Trans-Plasma Membrane Electron Transport by C2C12 Myotubes.

通过 C2C12 肌管测量跨质膜电子传输。