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

项目总结/摘要 保持活动能力是老年人最重要的健康问题之一， 衰老确定可保持老年人独立性和移动的能力的具有成本效益的疗法 这将是重要的，并影响许多其他方面的心理和身体健康。尽管耐力 锻炼是可以可重复地延长人类和动物的移动的健康寿命的最有效的干预， 运动益处背后的分子机制一直是难以捉摸的。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 它可以利用锻炼的好处，而不需要实际的身体运动，这在实践中是具有挑战性的。 这个现代社会。Sestrins是一个应激诱导蛋白家族，可以抑制活性氧， ROS和mTOR复合物1（mTORC 1）信号通路。过量的ROS积累和慢性 mTORC 1激活被认为是组织老化和退化的促进剂。对蠕虫，苍蝇， 小鼠证明，Sestrins的丢失会加速各种与年龄和肥胖相关的代谢， 与ROS相关的病理学，包括心功能障碍、胰岛素抵抗和肌肉变性 积累和过度活跃的mTORC 1。有趣的是，虽然Sestrin下调ROS和mTORC 1，但它们 诱导自噬并强烈增强mTORC 2/AKT信号传导激活。 Sestrin潜在的抗衰老特性促使我研究我们是否能够减弱 通过转基因补充Sestrins活性的组织老化。果蝇的初步实验表明 肌肉组织中Sestrin的过度表达可以显著增加老年果蝇的活动性： 在Sestrin过度表达的果蝇中观察到， 对照组果蝇和小鼠的运动训练可以增加Sestrin的表达。果蝇中Sestrin的丢失 和Sestrin 1的小鼠抵消了运动训练在增强耐力方面的益处， 改善他们的新陈代谢。基于这些发现，我们建议（目的1）表征骨骼，心脏和 不同年龄的Sestrins缺陷小鼠的膈肌表型，（目的2）表征肌肉表型 的小鼠肌肉特异性Sestrins调制，并（目的3）检查如何Sestrins改善机制 肌肉功能。我们的中心假设是，与苍蝇一样，哺乳动物的Sestrin也是重要的运动 调解人，并可以产生移动扩展活动在以后的生活。因此，拟议的研究可能会揭示 Sestrin激活在防止衰老和与年龄相关的功能和结构方面的有益作用 骨骼肌和心肌的退化。这可能会导致创新的Sestrins模仿的发展 保持活动能力和提高晚年生活质量的方法。

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.