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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.

修改项目摘要/摘要部分这是R 01 DK 113170的更新申请，旨在研究自噬激活在调节运动诱导的代谢益处对抗2型糖尿病（T2 D）中的作用和机制。T2 D是一种影响葡萄糖代谢的久坐症相关疾病，也是其他疾病的风险因素。体育锻炼已被广泛认为对T2 D发挥有益作用。然而，运动增强全身代谢益处的机制尚不清楚，这限制了治疗干预的发展。自噬是细胞内一种重要的降解途径，将损伤的或不必要的物质转运到溶酶体中并在其中分解。在正常情况下，它发生在低基础水平，并且可以由应激源（如禁食）诱导。我们发现，运动是一种有效的自噬诱导剂，不仅在收缩的肌肉组织中，而且在非收缩组织如肝脏中也是如此。运动对非收缩性组织中自噬激活的机制和代谢重要性从未得到解决。我们的初步数据显示，系统性自噬激活可能是由运动诱导的循环因子介导的。通过蛋白质组学研究，我们发现纤连蛋白（Fn 1），通常被认为是在正常（休息）条件下的细胞外基质蛋白，在急性运动后的循环中显着增加。重要的是，肌肉特异性纤连蛋白耗竭（FN 1 [delta]肌肉小鼠）消除了运动诱导的循环纤连蛋白水平、肝脏中的自噬激活和全身胰岛素敏化，表明肌肉分泌的纤连蛋白是运动诱导的全身自噬和代谢益处的重要调节剂。此外，纤连蛋白受体α5β1整联蛋白的敲低消除了运动小鼠血清激活培养细胞中自噬的能力，进一步支持了纤连蛋白-α5β1整联蛋白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，即非收缩组织中的自噬激活通过纤连蛋白-α5β1整合素-IKK-JNK 1途径驱动运动诱导的代谢益处对抗T2 D。使用遗传、代谢、生物化学和细胞生物学方法的组合，我们提出了两个目的：目的1是确定运动是否通过纤连蛋白-α5β1整联蛋白-IKK-JNK 1途径在非收缩性组织中全身性激活自噬;目的2是确定在非收缩性组织中通过纤连蛋白-α5β1整联蛋白-JNK途径的自噬激活是否介导运动诱导的针对T2 D的代谢益处。总的来说，我们的研究将建立运动激活的自噬在非收缩组织中预防T2 D的生理重要性，并将证明纤连蛋白-整合素信号通路在调节肌肉-肝脏通讯和全身代谢中的先前未表征的功能和机制。