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：
10522769
负责人：
Congcong He
金额：
$ 46.15万
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/10522769
关键词：
1-Phosphatidylinositol 3-Kinase Acute Address Affect Antidiabetic Drugs Automobile Driving Autophagocytosis Autophagosome Binding Biochemical Biological Biology Blood Circulation Cells Cellular biology Communication Complex Contracts Cultured Cells Data Degradation Pathway Disease Exercise Extracellular Matrix Proteins Fasting Fibronectin Receptors Fibronectins Genetic Glycoproteins High Fat Diet Impairment 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 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 Wild Type Mouse base feeding glucose metabolism glucose tolerance insulin sensitizing drugs 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的续订，用于对2型糖尿病（T2D）的锻炼效果的作用和机制对T2D进行了反对，锻炼者Syst emic代谢有益的机制，其中损坏或不必要的cargos被运送到溶酶体中。仅在肌肉组织中，但在非收缩组织（例如肝脏）中，我们的初步数据可能会通过运动和循环蛋白研究来介导自噬激活。急性运动后正常（静止）下的蛋白质在循环中增加。分泌的纤连蛋白是CTIN受体的特别重新调节蛋白。通过纤连蛋白-IKK-JNK1途径对T2D的益处。并通过非取包组织中的纤连蛋白-α5β1整合素-JNK途径的瞄准，介导运动运动的锻炼 - 总体上对T2D的代谢益处，我们的研究将在非合同组织中建立运动性，并将证明，并将证明在调节肝道和整个体体代谢中，纤连蛋白 - 整合素信号通路的功能和机制。