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
基本信息
- 批准号:10734830
- 负责人:
- 金额:$ 53.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AgeAgingAnabolismAnimal ModelAttenuatedAutophagocytosisBindingBiochemicalBiogenesisBiological AssayBranched-Chain Amino AcidsCommunitiesComplexCyclic AMP-Dependent Protein KinasesDataDietDiseaseElderlyElementsExerciseFamilyFundingGenerationsGeneticGenetic studyHealthHomeostasisIn VitroInterventionLeucineLipidsMediatingMedicalMental HealthMetabolicMetabolic PathwayMetabolismMethodologyMethodsMitochondriaModelingMolecular TargetMusMuscleMuscle FibersMuscle MitochondriaMuscle ProteinsMuscle functionMuscular AtrophyNamesNutrientOutcomeOutputOxidation-ReductionPathway interactionsPharmaceutical PreparationsPhenotypePhosphotransferasesPhysiologicalPlayPopulationPreventiveProtein KinaseProteinsProto-Oncogene Proteins c-aktPublishingQuality of lifeRegulationResearchRoleSTK11 geneSeriesSignal TransductionStressSystemTechnologyTestingTherapeuticUp-RegulationWorkcost effective treatmentdietaryexperimental studyflyimprovedin vivoinhibitorinnovationmetabolomicsmuscle agingmuscle degenerationmuscle formmuscle physiologymuscle strengthmuscular structurenovelphysical conditioningpreservationprotein complexprotein purificationtranscriptomicsultra high resolution
项目摘要
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.
总结:
保持行动能力是老年人最重要的健康问题之一。演习是
最好的干预措施,可以保持肌肉质量和力量在以后的年龄。了解如何
运动对肌肉产生代谢益处是非常重要的。除了运动,饮食是另一个关键
肌肉健康的决定因素。在各种膳食元素中,亮氨酸被特别考虑
重要是因为它在肌肉中代谢活跃,可以对抗肌肉退化。在此以前,
亮氨酸被认为是通过激活mTORC 1来维持肌肉质量的,mTORC 1是一种蛋白激酶,
蛋白质和脂质的抗氧化剂。然而,正如我们最近的工作和其他人的工作所证明的那样,mTORC 1
上调,而不是产生退行性表型和肌肉质量的浪费,而适度的mTORC 1
发现抑制对于在老化期间维持肌肉稳态是有益的。因此,亮氨酸
在肌肉结构和功能的保存中的作用可能独立于mTORC 1的激活和需要。
待澄清。在上一个资助期间,我们的研究小组一直专注于Sestrins,一个家族,
高度保守的蛋白质,在各种压力输入时被诱导。利用生物化学和遗传学
方法,我们已经表明,Sestrin是多功能蛋白质,控制许多代谢-
控制途径包括氧化还原信号传导、蛋白激酶信号传导(AMPK、mTORC 1、mTORC 2和AKT),
和自噬。通过对小鼠和苍蝇的遗传研究,我们已经表明,Sestrin具有关键的
在调节运动益处中的生理作用。此外,其他人的实验表明,
可以结合和感知亮氨酸。虽然很明显,塞斯特林是在运动之间的十字路口,
亮氨酸和肌肉内稳态,这些成分如何相互连接的机制,
不清楚例如,抑制mTORC 1(肌肉合成代谢激酶)的Sestrin具有保护肌肉的功能
功能和质量在老化和废弃。亮氨酸被认为可以拮抗Sestrin的mTORC 1-
抑制活性激活mTORC 1然而,亮氨酸和Sestrin都对肌肉健康有益
尽管在mTORC 1信号传导中起相反的作用。我们建议解决
运动,亮氨酸和Sestrins通过创新的方法结合纯化的蛋白质复合物,离体
肌管的培养,体内动物模型,和Seq-Scope,最先进的超高分辨率空间
转录组学技术。关于预期成果,
本文提出的方法可以阐明Sestrin在整合亮氨酸和亮氨酸的代谢益处中的关键功能,
锻炼肌肉平衡。这些成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稳态,
在老化和废用过程中保持肌肉力量和功能的预防和治疗原理
通过控制塞斯特林的活动
项目成果
期刊论文数量(0)
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Myungjin Kim其他文献
Myungjin Kim的其他文献
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{{ truncateString('Myungjin Kim', 18)}}的其他基金
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:
9977109 - 财政年份:2019
- 资助金额:
$ 53.35万 - 项目类别:
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:
10609890 - 财政年份:2019
- 资助金额:
$ 53.35万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 53.35万 - 项目类别:
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:
10375365 - 财政年份:2019
- 资助金额:
$ 53.35万 - 项目类别:
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:
10113500 - 财政年份:2019
- 资助金额:
$ 53.35万 - 项目类别:
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