Beneficial effects of Sestrin protein for muscle health during aging and exercise

Sestrin 蛋白在衰老和运动过程中对肌肉健康的有益作用

• 批准号: 9816442
• 负责人: Myungjin Kim
• 金额: $ 12.49万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816442
• 关键词: 5' -AMP-activated protein kinase; Age; Aging; Animals; Attenuated; Autophagocytosis; Biochemical; Cardiac; Cell Respiration; Chronic; Complex; Control Groups; Data; Defect; Development; Down-Regulation; Drosophila genus; Elderly; Exercise; Exhibits; FRAP1 gene; Family; Fatty acid glycerol esters; Genetic study; Health; Histologic; Homeostasis; Human; Hyperactive behavior; Insulin; Insulin Resistance; Knock-out; Knockout Mice; Lead; Mediating; Mediator of activation protein; Mental Health; Metabolic; Metabolism; Methods; Modeling; Modernization; Molecular; Movement; Mus; Muscle; Muscle Proteins; Muscle function; Myoblasts; Myocardial dysfunction; Myocardium; Obesity; Organism; Pathology; Pathway interactions; Phenotype; Population; Preventive; Property; Protein Family; Protein Kinase; Proteins; Proto-Oncogene Proteins c-akt; Quality of life; Reactive Oxygen Species; Research; Respiratory Diaphragm; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Societies; Speed; Stress; Structure; Supplementation; Therapeutic; Tissues; Transgenic Mice; Transgenic Organisms; aged; anti aging; base; cost effective; effective intervention; effective therapy; endurance exercise; exercise training; exhaust; experimental study; fly; healthspan; improved; innovation; mitochondrial dysfunction; muscle degeneration; muscle physiology; overexpression; physical conditioning; preservation; promoter; response; skeletal; small molecule; therapeutic development; tissue degeneration; 5' -AMP-activated protein kinase; Age; Aging; Animals; Attenuated; Autophagocytosis; Biochemical; Cardiac; Cell Respiration; Chronic; Complex; Control Groups; Data; Defect; Development; Down-Regulation; Drosophila genus; Elderly; Exercise; Exhibits; FRAP1 gene; Family; Fatty acid glycerol esters; Genetic study; Health; Histologic; Homeostasis; Human; Hyperactive behavior; Insulin; Insulin Resistance; Knock-out; Knockout Mice; Lead; Mediating; Mediator of activation protein; Mental Health; Metabolic; Metabolism; Methods; Modeling; Modernization; Molecular; Movement; Mus; Muscle; Muscle Proteins; Muscle function; Myoblasts; Myocardial dysfunction; Myocardium; Obesity; Organism; Pathology; Pathway interactions; Phenotype; Population; Preventive; Property; Protein Family; Protein Kinase; Proteins; Proto-Oncogene Proteins c-akt; Quality of life; Reactive Oxygen Species; Research; Respiratory Diaphragm; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Societies; Speed; Stress; Structure; Supplementation; Therapeutic; Tissues; Transgenic Mice; Transgenic Organisms; aged; anti aging; base; cost effective; effective intervention; effective therapy; endurance exercise; exercise training; exhaust; experimental study; fly; healthspan; improved; innovation; mitochondrial dysfunction; muscle degeneration; muscle physiology; overexpression; physical conditioning; preservation; promoter; response; skeletal; small molecule; therapeutic development; tissue degeneration

PROJECT SUMMARY/ABSTRACT Preservation of mobility is one of the most significant health concerns of the elderly population associated with aging. Identification of cost-effective therapies that can preserve independence and mobile capacity in the elderly would be important and influence many other aspects of mental and physical health. Even though endurance exercise is the most effective intervention that can reproducibly extend mobile healthspan in humans and animals, the molecular mechanism underlying exercise benefits has been elusive. I propose to investigate the role of a potential exercise mediator Sestrins, which may lead to the development of therapeutic or preventive methods that can harness the benefits of exercise without actual physical movement, which is practically challenging in this modern society. Sestrins are a family of stress-inducible proteins that can suppress both reactive oxygen species (ROS) and mTOR complex 1 (mTORC1) signaling pathways. Excessive ROS accumulation and chronic mTORC1 activation are known as promoters of tissue aging and degeneration. Genetic studies in worms, flies, and mice demonstrated that loss of Sestrins accelerates various age- and obesity-associated metabolic pathologies including cardiac dysfunction, insulin resistance and muscle degeneration, associated with ROS accumulation and hyperactive mTORC1. Interestingly, while Sestrins downregulate ROS and mTORC1, they induce autophagy and strongly potentiate mTORC2/AKT signaling activation in response to insulin. The potential anti-aging properties of Sestrins prompted me to investigate whether we are able to attenuate tissue aging by transgenic supplementation of Sestrins activity. Preliminary experiments in Drosophila indicated that Sestrin overexpression in muscle tissue can dramatically increase mobility in aged flies: a more than twofold increase in both climbing speed and endurance was observed in Sestrin-overexpressing flies compared to the control group. Exercise training in both flies and mice can increase Sestrin expression. Loss of Sestrin in flies and Sestrin1 in mice nullified the benefits received from exercise training in expanding their endurance and improving their metabolism. Based on these findings, we propose to (aim 1) characterize skeletal, cardiac and diaphragm muscle phenotypes of Sestrins-deficient mice across ages, (aim 2) characterize muscle phenotypes of mice with muscle-specific Sestrins modulation, and (aim 3) examine the mechanism of how Sestrins improve muscle functionality. Our central hypothesis is that, as in flies, mammalian Sestrins are also important exercise mediators and can produce mobility-extending activities in later life. Therefore, the proposed research may reveal the beneficial effects of Sestrin activation in protection against aging and age-associated functional and structural degeneration of skeletal and cardiac muscle. This may lead to the development of innovative Sestrins-mimicking methods for preserving mobility and improving quality of life in later ages.

项目摘要/摘要 保存流动性是与老年人相关的最重要的健康问题之一 老化。鉴定可以保留老年人独立性和移动能力的经济高效疗法 将很重要，并影响精神和身体健康的许多其他方面。即使耐力 运动是最有效的干预措施，可以可重复地扩展人类和动物中的移动健康状态， 锻炼益处的分子机制是难以捉摸的。我建议调查一个 潜在的运动介质sestrins，这可能导致治疗或预防方法的发展 在没有实际的身体运动的情况下，可以利用锻炼的好处，这实际上是具有挑战性的 这个现代社会。 sestrins是一个可抗应力诱导蛋白的家族，可以抑制两种活性氧 物种（ROS）和MTOR复合物1（MTORC1）信号通路。 ROS积累过多和慢性 MTORC1激活被称为组织老化和变性的启动子。蠕虫，苍蝇的遗传研究， 小鼠表明，sestrins的损失会加速各种年龄和肥胖相关的代谢 与ROS相关的病理学包括心脏功能障碍，胰岛素抵抗和肌肉变性 累积和多动MTORC1。有趣的是，sestrins下调了ROS和MTORC1时，它们 响应胰岛素诱导自噬和强烈的MTORC2/AKT信号传导激活。 Sestrins的潜在抗衰老特性促使我调查我们是否能够减弱 通过补充转基因活性的转基因衰老。果蝇的初步实验指示 肌肉组织中的Sestrin过表达可以显着增加老年苍蝇的迁移率：两倍以上 在过表达的果蝇中观察到攀爬速度和耐力的增加，与 对照组。蝇和小鼠的运动训练都可以增加sestrin的表达。苍蝇中的sestrin损失 小鼠中的sestrin1无效从运动训练中获得的好处，以扩大耐力和 改善他们的新陈代谢。根据这些发现，我们建议（AIM 1）表征骨骼，心脏和 跨年龄段的缺陷小鼠的隔膜肌肉表型（AIM 2）表征肌肉表型 具有肌肉特异性sestrins调制的小鼠的小鼠，（目标3）检查囊素如何改善的机制 肌肉功能。我们的中心假设是，与苍蝇一样，哺乳动物sestrin也是重要的运动 调解人并可以在以后的生活中进行流动性延伸活动。因此，拟议的研究可能会揭示 Sestrin激活在保护衰老和与年龄相关的功能和结构方面的有益作用 骨骼和心肌的变性。这可能会导致创新的Sestrins模仿 保存流动性和改善后来生活质量的方法。