Sestrins-mediated integration of leucine and exercise benefits for mitochondrial homeostasis

摘要： 保持行动能力是老年人最关心的健康问题之一。锻炼是最重要的 最成熟的干预措施，可以在晚年保持肌肉质量和力量。了解如何 运动对肌肉的新陈代谢有好处是非常重要的。除了锻炼，节食是另一个关键 肌肉健康的决定因素。在各种饮食元素中，亮氨酸被特别考虑 这一点很重要，因为它在肌肉中代谢活跃，可以防止肌肉退化。此前， 亮氨酸被认为通过激活mTORC1来维持肌肉质量，mTORC1是一种蛋白激酶上调的通用蛋白 蛋白质和脂肪合成代谢。然而，正如我们最近的工作和其他人的工作所表明的那样，mTORC1 相反，上调会导致退行性表型和肌肉质量的萎缩，而mTORC1. 抑制被发现有利于在衰老过程中保持肌肉的动态平衡。因此，亮氨酸的 保持肌肉结构和功能的作用可能不依赖于mTORC1的激活和需求 有待澄清。在之前的资助期间，我们的研究小组一直专注于Sestrins，一个 在不同的压力输入下诱导的高度保守的蛋白质。同时使用生化和遗传技术 方法学，我们已经证明Sestrins是控制许多新陈代谢的多功能蛋白质- 调控途径包括氧化还原信号、蛋白激酶信号(AMPK、mTORC1、mTORC2和AKT)、 和自噬。通过对小鼠和苍蝇的遗传学研究，我们已经表明Sestrins具有关键的 在调节运动益处方面的生理作用。此外，其他人的实验表明，Sestrins 可以结合和感觉亮氨酸。尽管很明显，塞斯特林处于运动和运动之间的十字路口， 亮氨酸和肌肉动态平衡，这些成分如何相互联系的机制是 不清楚。例如，Sestrins抑制mTORC1(肌肉合成代谢酶)，起到保护肌肉的作用 老化和废弃过程中的功能和质量。亮氨酸被认为可以拮抗Sestrin的mTORC1- 抑制活动，激活mTORC1。然而，亮氨酸和七叶皂苷都有益于肌肉健康。 尽管在mTORC1信号转导中扮演相反的角色。我们建议解决两者之间的复杂关系 运动，亮氨酸和七叶皂苷，通过创新的方法结合纯化的蛋白质复合体，体外 肌管培养、活体动物模型和最先进的超高分辨率空间序列显微镜 由我们自己的团队开发的转录技术。关于预期结果，工作 这里提出的可以阐明Sestrins在整合亮氨酸和亮氨酸的代谢益处方面的关键功能 锻炼保持肌肉的动态平衡。这样的结果将产生重要的积极影响，因为它们将提供 我们更清楚地了解亮氨酸和运动如何改善肌肉动态平衡并提供更好的 在衰老和废弃过程中保持肌肉力量和功能的预防和治疗原理 通过控制Sestrin的活动。

SUMMARY: Preservation of mobility is one of the most significant health concerns of the elderly population. Exercise is the best-established intervention that can preserve muscle mass and strength at later ages. Understanding how exercise produces metabolic benefits in muscle is very important. In addition to exercise, diet is another key determinant of muscle health. Among various dietary elements, leucine has been considered particularly important because it is actively metabolized in muscle and can function against muscle degeneration. Previously, leucine was thought to maintain muscle mass by activating mTORC1, a protein kinase upregulating general protein and lipid anabolism. However, as demonstrated by our recent work and the work of others, mTORC1 upregulation rather produced degenerative phenotypes and wasting of muscle mass, while modest mTORC1 suppression was found to be beneficial for maintaining muscle homeostasis during aging. Therefore, leucine’s role in the preservation of muscle structure and function may be independent of mTORC1 activation and needs to be clarified. Over the previous funding period, our research group has been focusing on Sestrins, a family of highly conserved proteins that are induced upon various stress inputs. Using both biochemical and genetic methodologies, we have shown that Sestrins are multifunctional proteins that control many metabolism- controlling pathways including redox signaling, protein kinase signaling (AMPK, mTORC1, mTORC2 and AKT), and autophagy. Through genetic studies in mice and flies, we have shown that Sestrins have a critical physiological role in mediating exercise benefits. Furthermore, experiments of others have shown that Sestrins can bind and sense leucine. Although it is quite evident that Sestrins are at the crossroads between exercise, leucine, and muscle homeostasis, mechanisms of how these components are connected to each other are unclear. For instance, Sestrins, which inhibit mTORC1 (muscle anabolic kinase), function to preserve muscle function and mass during aging and disuse. Leucine was suggested to antagonize Sestrin’s mTORC1- suppressing activities, activating mTORC1. Yet, both leucine and Sestrins are beneficial for muscle health despite playing opposite roles in mTORC1 signaling. We propose to solve the intricate relationships between exercise, leucine and Sestrins through innovative methodologies combining purified protein complexes, ex vivo culture of myotubes, in vivo animal models, and Seq-Scope, the state-of-the-art ultra-high-resolution spatial transcriptomic technology developed by our own team. With respect to the expected outcomes, the work proposed here could clarify the critical functions of Sestrins in integrating the metabolic benefits of leucine and exercise in muscle homeostasis. Such results would have an important positive impact, because they will provide us with a clearer picture of how leucine and exercise can improve muscle homeostasis and provide better preventive and therapeutic rationales for preserving muscle strength and functionality during aging and disuse by controlling Sestrin activities.