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

• 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
• 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

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，旨在研究自噬激活在调节运动诱导的代谢益处中对 2 型糖尿病 (T2D) 的作用和机制。T2D 是一种影响葡萄糖代谢的久坐相关疾病，也是其他疾病的危险因素。人们普遍认为体育锻炼对 T2D 具有有益作用，但运动引起全身代谢益处的机制尚不清楚，这限制了细胞内治疗干预措施的发展。降解途径，其中受损或不必要的货物被运输到溶酶体并在正常条件下以较低的基础水平分解，并且可以由禁食等压力源诱导。不仅在收缩的肌肉组织中，而且在非收缩组织（例如肝脏）中，非收缩组织中运动激活自噬的机制和代谢重要性从未得到解决。我们的初步数据表明，全身自噬可能被激活。通过蛋白质组学研究，我们发现纤连蛋白（Fn1）通常被认为是正常（休息）条件下的细胞外基质蛋白，但在急性运动后循环中显着增加。纤连蛋白（FN1δ肌肉小鼠）消除了运动诱导的循环纤连蛋白水平、肝脏自噬激活和全身胰岛素敏化，这表明肌肉分泌的纤连蛋白纤连蛋白是运动引起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整合素的敲低会消除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的关键作用。运动诱发的自噬中的 α5β1 整合素通路 基于这些数据，我们提出了我们的总体假设：非收缩组织中的自噬激活驱动了运动诱发的自噬。通过纤连蛋白-α5β1 整合素-IKK-JNK1 途径，我们提出了两个目标：目标 1 是确定运动是否在非糖尿病患者中系统性地激活自噬。通过纤连蛋白-α5β1 整合素-IKK-JNK1 途径收缩组织；目标 2 是确定自噬是否通过非收缩组织中的纤连蛋白-α5β1 整合素-JNK 通路介导运动诱导的针对 T2D 的代谢益处总体而言，我们的研究将确定非收缩组织中运动激活的自噬在预防 T2D 中的生理重要性，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功能和机制此前尚未表征。