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

• 批准号: 10553640
• 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
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553640
• 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; receptor; reduced muscle strength; response; transcription factor; transcriptome sequencing

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很常见， 肌肉力量，有助于从疾病和其他疾病相关的发病率中恢复受损。的确， 糖尿病患者在大手术后恢复力量比非糖尿病患者慢。这些变化 与肌肉线粒体能量产生减少有关，但控制线粒体能量产生的信号 糖尿病期间肌肉中的线粒体代谢仍不完全清楚。我们最近展示了 胰岛素受体（IR）和IGF-1受体（IGF 1 R）在肌肉的控制中显示重叠的作用， 蛋白质周转通过细胞自噬，或“自食”，以维持肌肉质量，这种控制是 依赖于FoxO转录因子。此外，我们的初步研究表明，敲除 IR/IGF 1 R慢性和急性均可导致线粒体异常，可通过缺失 肌肉中的FoxO该提案的目标是调查FoxO蛋白是否控制肌肉 线粒体代谢和线粒体特异性自噬，或“线粒体自噬”，在IR降低的背景下 IGF 1 R信号为了实现这个项目的目标，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/LAMP 1-YFP和Parkin-YFP线粒体自噬生物传感器 IR敲除、IR/IGF 1 R敲除或IR/IGF 1 R与FoxO 1/3/4五重敲除小鼠， 线粒体生物能量学的测量;目标2将确定转录和 蛋白质稳态机制，通过该机制，肌肉中IR/IGF 1 R和/或FoxOs信号传导的丧失导致 线粒体复合物I的损伤。我们的长期目标是了解糖尿病的影响， 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 线粒体的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中发病和残疾的重要来源。

项目成果

Loss of FoxOs in muscle increases strength and mitochondrial function during aging.

• DOI: 10.1002/jcsm.13124
• 发表时间: 2023-02
• 期刊: Journal of cachexia, sarcopenia and muscle

Elamipretide treatment during pregnancy ameliorates the progression of polycystic kidney disease in maternal and neonatal mice with PKD1 mutations.

• DOI: 10.1016/j.kint.2021.12.006
• 发表时间: 2022-05
• 期刊: KIDNEY INTERNATIONAL
• 影响因子: 19.6
• 作者: Daneshgar, Nastaran;Liang, Peir-In;Lan, Renny S.;Horstmann, McKenna M.;Pack, Lindsay;Bhardwaj, Gourav;Penniman, Christie M.;O'Neill, Brian T.;Dai, Dao-Fu
• 通讯作者: Dai, Dao-Fu

Immediate preoperative hyperglycemia correlates with complications in non-cardiac surgical cases.

• DOI: 10.1016/j.jclinane.2021.110375
• 发表时间: 2021-11
• 期刊: Journal of clinical anesthesia
• 影响因子: 6.7
• 作者: Dougherty SM;Schommer J;Salinas JL;Zilles B;Belding-Schmitt M;Rogers WK;Shibli-Rahhal A;O'Neill BT
• 通讯作者: O'Neill BT