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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.

修改后的项目摘要/摘要部分这是R01 DK113170的更新应用，用于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(T2D)中的作用和机制。T2D是一种影响葡萄糖代谢的静坐相关疾病，也是其他疾病的危险因素。体育锻炼已被广泛认识到对T2D有好处。然而，运动产生全身代谢益处的机制尚不清楚，这限制了治疗干预措施的发展。自噬是一种重要的细胞内降解途径，在这个过程中，受损或不必要的货物被运输到溶酶体中并被分解。在正常情况下，它发生在较低的基础水平，并可由诸如禁食等应激源诱发。我们发现，运动是一种有效的自噬诱因，不仅在收缩的肌肉组织中，而且在肝脏等非收缩组织中也是如此。在非收缩组织中，运动激活自噬的机制和代谢重要性从未被讨论过。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，纤维连接蛋白(Fn1)，通常被认为是一种细胞外基质蛋白，在正常(安静)条件下，在急性运动后循环中显著增加。重要的是，肌肉特异性纤维连接蛋白(FN1[Delta]肌肉小鼠)的缺失可以消除运动诱导的循环纤维连接蛋白水平、肝脏自噬激活和全身性胰岛素敏化，这表明肌肉分泌的纤维连接蛋白是运动诱导的全身自噬和代谢益处的重要调节因子。此外，纤维连接蛋白受体α5β1整合素的敲除取消了运动小鼠血清激活培养细胞自噬的能力，进一步支持了FN-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，即非收缩组织中的自噬激活通过纤维连接蛋白-α5β1整合素-IKK-JNK1途径驱动运动诱导的代谢益处而不是T2D。结合遗传学、代谢、生化和细胞生物学的方法，我们提出了两个目的：目的1是确定运动是否通过纤维连接蛋白-α5β1整合素-IKK-JNK1途径系统性地激活非收缩组织中的自噬；目标2是确定非收缩组织中通过纤维连接蛋白-α5β1整合素-JNK途径激活的自噬是否介导了运动诱导的针对T2D的代谢益处。总之，我们的研究将确定运动激活的非收缩组织自噬在预防T2D中的生理学重要性，并将证明纤维连接蛋白-整合素信号通路在调节肌肉-肝脏通讯和全身代谢中先前未知的功能和机制。