Regulation of Muscle Mitochondrial Protein Homeostasis by Insulin/IGF-1/FoxO Signaling

胰岛素/IGF-1/FoxO 信号传导对肌肉线粒体蛋白稳态的调节

基本信息

批准号：
10436783
负责人：
Brian Timothy O'Neill
金额：
--
依托单位：
IOWA CITY VA MEDICAL CENTER
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：
2020-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10436783
关键词：
Acute Atrophic Autophagocytosis Bioenergetics Biosensor Cell Nucleus Chronic Complex Complications of Diabetes Mellitus Defect Degradation Pathway Diabetes Mellitus Disease Eating Exclusion FOXO1A gene FRAP1 gene Gel Gene Expression Genes Genetic Transcription Goals Impairment Insulin Insulin Receptor Insulin Resistance Insulin deficiency Insulin-Dependent Diabetes Mellitus Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor Knock-out Knockout Mice Lead Link Liver Lysosomes Measurement Measures Mediating Messenger RNA Metabolic Mitochondria Mitochondrial Proteins Modeling Morbidity - disease rate Mus Muscle Muscle Mitochondria Muscle Proteins Muscle Weakness Muscular Atrophy NADH dehydrogenase (ubiquinone)Nuclear Operative Surgical Procedures Oxidative Phosphorylation Parkin Pathologic Patients Production Proteins Proteome Reactive Oxygen Species Receptor Signaling Recovery Regulation Repression Role Signal Transduction Source Specific qualifier value Streptozocin Streptozocin Diabetes Tamoxifen Testing Transcriptional Regulation Veterans Withdrawal Work design diabetes mellitus therapy diabetic disability fluorophore gene repression genetic corepressor improved innovation insight knock-down lysosomal proteins military veteran mitochondrial autophagy mitochondrial dysfunction mitochondrial metabolism mortality muscle form muscle strength non-diabetic oxidation prevent protein degradation proteostasis reduced muscle strength response transcription factor transcriptome sequencing

项目摘要

Insulin resistance and uncontrolled diabetes are very common among Veterans and lead to decreased muscle strength, contributing to impaired recovery from illness and other disease-related morbidity. Indeed, patients with diabetes recover strength slower after major surgery than non-diabetic patients. These changes are associated with decreased muscle mitochondrial energy production, but the signals that control mitochondrial metabolism in muscle during diabetes remain incompletely understood. We recently showed that insulin receptors (IR) and IGF-1 receptors (IGF1R) display overlapping roles in the control of muscle protein turnover through cellular autophagy, or “self-eating”, to maintain muscle mass, and that this control is dependent on FoxO transcription factors. Furthermore, our preliminary studies show that knockout of IR/IGF1R both chronically and acutely lead to mitochondrial abnormalities that can be prevented by deletion of FoxOs in muscle. The goal of this proposal is to investigate whether FoxO proteins control muscle mitochondrial metabolism and mitochondrial-specific autophagy, or “mitophagy”, in the context of decreased IR and IGF1R signaling. To accomplish the goals of this project we propose 2 aims: Aim 1 will quantify mitophagy using mitoTIMER/LAMP1-YFP and Parkin-YFP mitophagy biosensors in muscle from muscle-specific inducible IR knockout, both IR/IGF1R knockout, or IR/IGF1R with FoxO1/3/4 quintuple knockout mice in concert with measurements of mitochondrial bioenergetics; Aim 2 will determine the regulation of transcriptional and protein homeostatic mechanisms by which loss of IR/IGF1R and/or FoxOs signaling in muscle leads to impairment of mitochondrial Complex I. Our long-term goals are to understand the impact of diabetes and insulin resistance on mitochondrial protein turnover in muscle to gain insights into the metabolic and mitochondrial changes that can contribute to decreased strength and other complications of diabetes, which are a significant source of morbidity and disability in our Veteran population.

胰岛素抵抗和不受控制的糖尿病在退伍军人中非常常见，并导致肌肉力量，导致疾病恢复受损和其他疾病相关的发病率。糖尿病患者在大手术后恢复体力的速度比非糖尿病患者慢。与肌肉线粒体能量产生减少有关，但控制信号我们最近表明，糖尿病期间肌肉中的线粒体代谢仍不完全清楚。胰岛素受体 (IR) 和 IGF-1 受体 (IGF1R) 在肌肉控制中表现出重叠的作用通过细胞自噬或“自食”进行蛋白质周转，以维持肌肉质量，并且这种控制是此外，我们的初步研究表明，FoxO 转录因子的敲除。 IR/IGF1R 会长期和急性导致线粒体异常，可以通过删除肌肉中的 FoxO 该提案的目的是研究 FoxO 蛋白是否控制肌肉。 IR 降低背景下的线粒体代谢和线粒体特异性自噬，或“线粒体自噬” 为了实现该项目的目标，我们提出了 2 个目标：目标 1 将量化线粒体自噬。在肌肉中使用 mitoTIMER/LAMP1-YFP 和 Parkin-YFP 线粒体自噬生物传感器进行肌肉特异性诱导 IR敲除，IR/IGF1R敲除，或IR/IGF1R与FoxO1/3/4五重敲除小鼠协同线粒体生物能量学的测量；目标 2 将确定转录和转录的调节；肌肉中 IR/IGF1R 和/或 FoxOs 信号传导丧失导致的蛋白质稳态机制线粒体复合物 I 的损伤。我们的长期目标是了解糖尿病和胰岛素抵抗对肌肉中线粒体蛋白质周转的影响，以深入了解代谢和线粒体变化可能导致力量下降和其他糖尿病并发症，是我们退伍军人群体发病和残疾的重要来源。