Mechanism of autophagy activation in exercise-induced anti-diabetic benefits

自噬激活在运动引起的抗糖尿病益处中的机制

基本信息

批准号：
10704114
负责人：
Congcong He
金额：
$ 40.2万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-12 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10704114
关键词：
Acute Address Affect Antidiabetic Drugs Automobile Driving Autophagocytosis Autophagosome Binding Biochemical Biological Biology Cells Cellular biology Circulation Communication Complex Contracts Cultured Cells Data Degradation Pathway Disease Exercise Extracellular Matrix Proteins Fasting Fibronectin Receptors Fibronectins Genetic Glycoproteins High Fat Diet Impairment Insulin Integrin Signaling Pathway Integrin alpha5beta1 Integrins Knock-in Knock-in Mouse Liver Lysosomes MAPK8 gene Mediating Metabolic Metabolism Modeling Mus Muscle Muscle Cells Muscle Contraction Muscle Fibers Myoblasts Non-Insulin-Dependent Diabetes Mellitus PIK3CG gene Pathway interactions Physical Exercise Physiological Play Prevention Proteins Proteomics Regulation Rest Risk Factors Role Serum Signal Pathway Signaling Molecule Skeletal Muscle Stress Structure Therapeutic Intervention Tissues Undifferentiated Vps34 Phosphatidylinositol 3 Kinase Wild Type Mouse feeding glucose metabolism glucose tolerance improved knock-down mouse model mutant prevent receptor stressor therapeutic development tumorigenesis

项目摘要

Modified Project Summary / Abstract Section This is a renewal application for R01 DK113170 to investigate the role and mechanism of autophagy activation in the regulation of exercise-induced metabolic benefits against type 2 diabetes (T2D). T2D is a sedentarism-associated disease affecting glucose metabolism and a risk factor for other disorders. Physical exercise has been widely recognized to exert beneficial effects against T2D. However, the mechanisms by which exercise elicits systemic metabolic benefits are unclear, which limits the development of therapeutic interventions. Autophagy is an essential intracellular degradation pathway, in which damaged or unnecessary cargos are transported to and broken down in lysosomes. It occurs at a low basal level under normal conditions, and can be induced by stressors such as fasting. We found that exercise is a potent inducer of autophagy, not only in contracting muscle tissues but also systemically in non-contractile tissues such as the liver. The mechanism and metabolic importance of autophagy activation by exercise in non-contractile tissues have never been addressed. Our preliminary data reveal that systemic autophagy activation may be mediated by exercise-induced circulating factors. By proteomic studies we discovered that fibronectin (Fn1), generally considered as an extracellular matrix protein under normal (resting) conditions, is significantly increased in the circulation after acute exercise. Importantly, muscle-specific depletion of fibronectin (FN1[delta]muscle mice) abolishes exercise-induced circulating fibronectin levels, autophagy activation in the liver, and systemic insulin sensitization, suggesting that muscle-secreted fibronectin is an essential regulator of exercise-induced systemic autophagy and metabolic benefits. In addition, knockdown of the fibronectin receptor, α5β1 integrin, abolishes the ability of exercised mouse serum in activating autophagy in cultured cells, further supporting the key role of the fibronectin-α5β1 integrin pathway in exercise-induced autophagy. Based on these data, we propose our overall hypothesis that autophagy activation in non-contractile tissues drives exercise-induced metabolic benefits against T2D, through a fibronectin-α5β1 integrin-IKK-JNK1 pathway. Using a combination of genetic, metabolic, biochemical, and cell biology approaches, we propose two aims: Aim 1 is to determine whether exercise activates autophagy systemically in non-contractile tissues via the fibronectin-α5β1 integrin-IKK-JNK1 pathway; and Aim 2 is to determine whether autophagy activation by the fibronectin-α5β1 integrin-JNK pathway in non-contractile tissues mediates exercise-induced metabolic benefits against T2D. Overall, our studies will establish the physiological importance of exercise-activated autophagy in non-contractile tissues in the prevention of T2D, and will demonstrate the previously uncharacterized function and mechanism of the fibronectin-integrin signaling pathway in regulating muscle-liver communication and whole-body metabolism.

修改的项目摘要 /摘要部分这是R01 DK113170的续签应用，以研究自噬激活在调节运动诱导的2型糖尿病（T2D）的代谢益处中的作用和机制。 T2D是一种与导糖代谢相关的相关疾病，是葡萄糖代谢和其他疾病的危险因素。体育锻炼已被广泛认识到对T2D发挥有益的作用。但是，锻炼引起系统性代谢益处的机制尚不清楚，这限制了理论干预的发展。自噬是一种必不可少的细胞内降解途径，其中损伤或不必要的肉在溶酶体中转运并分解。它发生在正常条件下的基本水平低，并且可以由禁食等压力诱导。我们发现，运动是自噬的潜在诱导剂，不仅在收缩肌肉时机方面，而且在非收缩时机（例如肝脏）中有系统地诱导。从未解决过在非收缩时间内进行自噬激活的机制和代谢重要性。我们的初步数据表明，全身自噬激活可能是通过运动引起的循环因子介导的。通过蛋白质组学研究，我们发现纤连蛋白（FN1）在正常（静止）条件下通常被认为是细胞外基质蛋白，在急性运动后循环中显着增加。重要的是，纤连蛋白（FN1 [Delta]肌肉小鼠）的肌肉特异性部署消除了运动诱导的循环纤连蛋白水平，肝脏中的自噬激活以及全身性胰岛素敏感性，表明肌肉分泌的肌肉固定蛋白是运动诱导的肌肉诱导的，是一种运动诱导的自动型自动型。此外，敲低纤连蛋白受体α5β1整联蛋白，废除了运动小鼠血清激活培养细胞自噬的能力，进一步支持纤连蛋白蛋白 - α5β1整合素途径在运动诱导的自噬中的关键作用。基于这些数据，我们提出了我们的总体假设，即非取消时序中的自噬激活通过纤连蛋白-α5β1整合素-IKK-JNK1途径驱动运动引起的T2D的代谢益处。使用遗传，代谢，生化和细胞生物学方法的结合，我们提出了两个目的：目标1是通过纤连蛋白-α5β1整合素-IKK-JNK1途径在非收缩时间内确定运动是否在非收缩时间内进行自噬；目标2是确定在非收缩时序中纤连蛋白-α5β1整合素-JNK途径的自噬激活是否会介导运动诱导的T2D代谢益处。总体而言，我们的研究将确定在预防T2D中运动激活自噬的身体重要性，并将证明在调节性肌肉肝脏通信和全体体内代谢中，纤连蛋白胶质素 - 整合素信号通路的先前未表征的功能和机制。