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

项目摘要/摘要 保持行动能力是老年人最关心的健康问题之一，与 衰老。确定可保持老年人独立性和活动能力的经济有效的疗法 将是重要的，并影响许多其他方面的心理和身体健康。即使是耐力 锻炼是最有效的干预措施，可以重复延长人类和动物的活动健康寿命， 运动益处背后的分子机制一直难以捉摸。我建议调查一名 潜在的运动调节剂Sestrins，可能导致治疗或预防方法的发展 这可以在没有实际身体运动的情况下利用锻炼的好处，这在 这个现代社会。Sestrins是一种压力诱导蛋白家族，可以抑制两种活性氧 物种(ROS)和mTOR复合体1(MTORC1)信号通路。ROS积聚过多与慢性 MTORC1的激活被认为是组织衰老和退化的促进剂。对蠕虫、苍蝇、 小鼠的研究表明，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，包括心功能不全、胰岛素抵抗和肌肉变性 积聚和过度活跃的mTORC1.有趣的是，尽管Sestrins下调了ROS和mTORC1的表达，但他们 诱导自噬并强烈增强mTORC2/AKT信号对胰岛素的激活。 Sestrins潜在的抗衰老特性促使我研究我们是否能够延缓 通过转基因补充Sestrins活性实现组织衰老。在果蝇身上的初步实验表明 肌肉组织中Sestrin的过度表达可以显著增加老年果蝇的活动能力：增加一倍以上 在Sestrin过度表达的果蝇中观察到攀爬速度和耐力都比 对照组。苍蝇和小鼠的运动训练都可以增加Sestrin的表达。果蝇体内Sestrin的丢失 和Sestrin1在小鼠身上抵消了运动训练在延长它们的耐力和 改善他们的新陈代谢。基于这些发现，我们建议(目标1)表征骨骼、心脏和 Sestrins缺陷小鼠不同年龄段的横隔肌表型，(目标2)表征肌肉表型 肌肉特异性Sestrins调节的小鼠，以及(目标3)检查Sestrins如何改善的机制 肌肉功能。我们的中心假设是，和苍蝇一样，哺乳动物的Sestrin也是重要的运动 调停者，并能在以后的生活中开展活动。因此，拟议的研究可能会揭示 七叶皂苷的抗衰老及与衰老相关的功能和结构的有益作用 骨骼肌和心肌的变性。这可能会导致创新的Sestrins仿制的发展 在晚年保持机动性和提高生活质量的方法。

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.