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

Sestrins介导的亮氨酸整合和运动对线粒体稳态的益处

• 批准号: 10734830
• 负责人: Myungjin Kim
• 金额: $ 53.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734830
• 关键词: Age; Aging; Anabolism; Animal Model; Attenuated; Autophagocytosis; Binding; Biochemical; Biogenesis; Biological Assay; Branched-Chain Amino Acids; Communities; Complex; Cyclic AMP-Dependent Protein Kinases; Data; Diet; Disease; Elderly; Elements; Exercise; Family; Funding; Generations; Genetic; Genetic study; Health; Homeostasis; In Vitro; Intervention; Leucine; Lipids; Mediating; Medical; Mental Health; Metabolic; Metabolic Pathway; Metabolism; Methodology; Methods; Mitochondria; Modeling; Molecular Target; Mus; Muscle; Muscle Fibers; Muscle Mitochondria; Muscle Proteins; Muscle function; Muscular Atrophy; Names; Nutrient; Outcome; Output; Oxidation-Reduction; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Physiological; Play; Population; Preventive; Protein Kinase; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Quality of life; Regulation; Research; Role; STK11 gene; Series; Signal Transduction; Stress; System; Technology; Testing; Therapeutic; Up-Regulation; Work; cost effective treatment; dietary; experimental study; fly; improved; in vivo; inhibitor; innovation; metabolomics; muscle aging; muscle degeneration; muscle form; muscle physiology; muscle strength; muscular structure; novel; physical conditioning; preservation; protein complex; protein purification; transcriptomics; ultra high resolution

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.

概括： 保存流动性是老年人口最重要的健康问题之一。运动是 最好的干预措施可以在以后的年龄保持肌肉质量和力量。了解如何 运动在肌肉中产生代谢益处非常重要。除运动外，饮食是另一个关键 肌肉健康的决定因素。在各种饮食元素中，尤氨酸被认为特别是 重要的是因为它在肌肉中积极代谢，并且可以抵抗肌肉变性。之前， 人们认为亮氨酸通过激活MTORC1（一种上调一般的蛋白激酶）来维持肌肉质量 蛋白质和脂质合物。但是，正如我们最近的工作和他人的工作所证明的那样，mtorc1 上调相当产生的退化表型和肌肉质量的浪费，而MTORC1则适度 发现抑制作用有益于在衰老过程中维持肌肉稳态。因此，亮氨酸 在制备肌肉结构和功能中的作用可能独立于MTORC1激活和需求 要澄清。在过去的资金期间，我们的研究小组一直专注于Sestrins，这是一个家庭 高度保守的蛋白质是在各种应力​​输入下诱导的。使用生化和遗传 方法，我们已经表明sestrins是控制许多新陈代谢的多功能蛋白 控制包括氧化还原信号，蛋白激酶信号传导（AMPK，MTORC1，MTORC2和AKT）的途径， 和自噬。通过在小鼠和苍蝇中的遗传研究，我们表明sestrins具有关键 生理作用在调解运动益处。此外，其他实验表明sestrins 可以绑定并感知亮氨酸。尽管有充分的证据表明Sestrin在运动之间处于十字路口，但 亮氨酸和肌肉稳态，这些组件如何相互连接的机制是 不清楚。例如，抑制MTORC1（肌肉合成代谢激酶）的sestrins可保持肌肉 衰老和废弃期间的功能和质量。建议亮氨酸与Sestrin的MTORC1-对抗 抑制活动，激活mTORC1。然而，亮氨酸和sestrin都对肌肉健康有益 尽管在MTORC1信号传导中扮演着相反的角色。我们建议解决复杂的关系 通过结合纯化蛋白质复合物的创新方法运动，亮氨酸和sestrin 肌管，体内动物模型和Seq-Scope的培养，最先进的超高分辨率空间 转录组技术由我们自己的团队开发。关于预期的结果，工作 这里提出的可以阐明sestrins在整合亮氨酸的代谢益处的关键功能 运动以肌肉稳态运动。这样的结果将产生重要的积极影响，因为它们将提供 我们清楚地了解了亮氨酸和运动如何改善肌肉体内平衡并提供更好 预防和治疗理由，以保留衰老期间的肌肉力量和功能 通过控制Sestrin活动。