Regulation of Protein Synthesis by Glucose

葡萄糖对蛋白质合成的调节

基本信息

批准号：
10685894
负责人：
Paul A Roberson
金额：
$ 6.98万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10685894
关键词：
5&apos -AMP-activated protein kinase Adenosine Monophosphate Aging Amino Acids Animal Husbandry Binding Biological Models Branched-Chain Amino Acids Carbohydrates Cell Culture Techniques Cell Fractionation Cells Chronic Co-Immunoprecipitations Complement Complex Consumption Cyclic AMP-Dependent Protein Kinases Data Disease Dissociation Electroporation FRAP1 gene Family Fasting Fluorescence Resonance Energy Transfer Future Glucose Glycogen Growth Hexokinase 2 Immunoprecipitation Knowledge Leucine Mediating Metabolism Methods Microscopy Molecular Molecular Biology Techniques Morbidity - disease rate Muscle Muscle Proteins Nutrient Nutrient Depletion Oral Administration Pharmacologic Substance Plasmids Play Protein Biosynthesis Protein Family Protein Kinase Proteins Rattus Regulation Research Rodent Model Role Scientist Signal Pathway Signal Transduction Skeletal Muscle Techniques Testing base cell growth deprivation experience experimental study gain of function glucose metabolism glycogenolysis improved in vivo knock-down loss of function mitochondrial membrane molecular marker muscle form novel overexpression protein complex protein expression sensor skeletal muscle metabolism skeletal muscle wasting stable cell line training opportunity

项目摘要

PROJECT SUMMARY/ABSTRACT Skeletal muscle loss is associated with aging and various disease states. The mechanistic Target of Rapamycin in Complex 1 (mTORC1) is a protein kinase that acts to upregulate skeletal muscle protein synthesis and thereby promote muscle growth. Adenosine monophosphate-activated protein kinase (AMPK), a nutrient sensor, inhibits mTORC1 during nutrient depletion and thereby inhibits cellular growth. Similarly, the Sestrin family of proteins (Sestrins1-3) are leucine sensors that act to suppress mTORC1 by binding to and inhibiting the mTORC1 activating complex referred to as GAP activity toward Rags (GATOR2). Interestingly, the Sestrins bind not only to GATOR2 but also AMPK, suggesting that they may mediate leucine-induced activation of mTORC1 through multiple mechanisms. In novel preliminary studies presented herein, I show that the Sestrins mediate not only leucine, but also glucose signaling to mTORC1. However, which of the three Sestrins mediates glucose-induced regulation of mTORC1 is unknown. Moreover, whether glucose-induced activation of mTORC1 is mediated through the Sestrin-GATOR2 complex and/or the Sestrin-AMPK complex is unexplored. Previous studies have shown that AMPK is not only regulated by glucose but that it also regulates glucose metabolism, e.g. it upregulates hexokinase 2 (HKII) expression, suppresses glycogen synthesis, and promotes glycogenolysis. In novel preliminary studies presented herein, I show a specific interaction of Sestrin3 with AMPK and also show that Sestrin3 associates with HKII. Based on these findings, I propose to test the hypothesis that glucose acts through Sestrin3 and HKII to both stimulate mTORC1 activity and promote glycogenolysis. By using knockdown and overexpression cell culture and rodent models as well as advanced microscopy techniques I will elucidate the mechanisms through which glucose acts to modulate skeletal muscle protein synthesis and glucose metabolism. It is anticipated that delineation of the molecular markers associated with glucose-mediated stimulation of skeletal muscle metabolism will provide novel targets for future studies as well as targets for pharmaceutical manipulation.

项目摘要/摘要骨骼肌损失与衰老和各种疾病状态有关。雷帕霉素的机械目标在复合物1中（MTORC1）是一种蛋白激酶，可用于上调骨骼肌蛋白质合成，从而促进肌肉生长。营养传感器腺苷单磷酸激活的蛋白激酶（AMPK）抑制养分耗竭期间的MTORC1，从而抑制细胞生长。同样，Sestrin蛋白质家族（Sestrins1-3）是亮氨酸传感器，可通过结合并抑制MTORC1来抑制MTORC1 激活称为缝隙活动的复合物（Gator2）。有趣的是，sestrins不仅结合了到gator2但也向AMPK进行多种机制。在本文介绍的新型初步研究中，我表明sestrins不仅介导亮氨酸，但也向MTORC1发出葡萄糖信号。但是，三个sestrins中的哪个介导了葡萄糖诱导的 MTORC1的调节尚不清楚。此外，葡萄糖诱导的MTORC1激活是否介导通过Sestrin-Gator2复合物和/或Sestrin-Ampk复合物未探索。先前的研究已有表明AMPK不仅受葡萄糖调节，而且还调节葡萄糖代谢，例如它上调己糖酶2（HKII）表达，抑制糖原合成并促进糖原分解。在本文介绍的新型初步研究，我显示了Sestrin3与AMPK的特定相互作用，也显示了 Sestrin3与HKII相关。基于这些发现，我建议测试葡萄糖作用的假设通过Sestrin3和HKII均刺激MTORC1活性并促进糖原分解。通过使用敲低和过表达的细胞培养和啮齿动物模型以及高级显微镜技术我将阐明葡萄糖作用于调节骨骼肌的机制蛋白质合成和葡萄糖代谢。预计分子标记的描述与葡萄糖介导的骨骼肌代谢相关的刺激将为未来提供新的目标研究以及药物操纵的目标。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tissue-specific expression differences in Ras-related GTP-binding proteins in male rats.

DOI：
10.14814/phy2.15928
发表时间：
2024-02
期刊：
Physiological reports
影响因子：
2.5
作者：
通讯作者：

LAT1 Protein Content Increases Following 12 Weeks of Resistance Exercise Training in Human Skeletal Muscle.

DOI：
10.3389/fnut.2020.628405
发表时间：
2020
期刊：
Frontiers in nutrition
影响因子：
5
作者：
Roberson PA;Mobley CB;Romero MA;Haun CT;Osburn SC;Mumford PW;Vann CG;Greer RA;Ferrando AA;Roberts MD
通讯作者：
Roberts MD

An intron variant of the GLI family zinc finger 3 (GLI3) gene differentiates resistance training-induced muscle fiber hypertrophy in younger men.

DOI：
10.1096/fj.202100113rr
发表时间：
2021-05
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Vann CG;Morton RW;Mobley CB;Vechetti IJ;Ferguson BK;Haun CT;Osburn SC;Sexton CL;Fox CD;Romero MA;Roberson PA;Oikawa SY;McGlory C;Young KC;McCarthy JJ;Phillips SM;Roberts MD
通讯作者：
Roberts MD