Muscle regulatory T cells in exercise and aging

运动和衰老中的肌肉调节 T 细胞

基本信息

批准号：
10615721
负责人：
Paul Kent Langston
金额：
$ 7.38万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10615721
关键词：
Acute Adult Age Aging Animals Antiinflammatory Effect Biochemical Cardiovascular Diseases Cell Count Cell physiology Cells Chronic Coupled Data Disease Elderly Enrollment Exercise Female Flow Cytometry Gene Expression Profile Goals Health Homeostasis Human Immunologics Immunophenotyping Impairment Individual Inflammaging Inflammation Inflammatory Injections Injury Intervention Life Life Expectancy Longevity Maintenance Malignant Neoplasms Measurement Measures Mediating Molecular Morbidity - disease rate Mus Muscle Muscle function Natural regeneration Nerve Degeneration Obesity Organism Performance Phase Physical activity Play Population Process Regenerative capacity Regulatory T-Lymphocyte Research Role Skeletal Muscle Stress T cell response Testing Time Tissues Translations Work age effect age related age-related muscle loss aged biological adaptation to stress cytokine design endurance exercise exercise intervention exercise regimen experimental study follow-up frailty gain of function healthspan human old age (65+)immune system function improved loss of function male middle age model organism mortality mouse model muscle aging muscle regeneration new therapeutic target preconditioning prophylactic repaired response sarcopenia tissue injury transcriptome sequencing

项目摘要

PROJECT SUMMARY An increase in human life expectancy without a proportional extension of time spent in good health, or “health span,” has led to expansion of the global population of aged and frail individuals carrying multiple morbidities. Chronic exercise improves health span in multiple model organisms. Such health span extension may be underpinned by the anti-inflammatory effects of chronic exercise, which have been primarily identified through measurements of changes in circulating cells and cytokines; however, tissue-resident immunocytes also play a critical role in maintaining homeostasis and supporting stress responses; yet little is known about how tissue immunophenotypes change with age or exercise. Recently, we have established mouse models of endurance exercise that elicit rapid accumulation of immunocytes in skeletal muscle. This response shares many features with the response to severe tissue injury, including accumulation of regulatory T cells (Tregs), which orchestrate the transition from pro-inflammatory to repair processes. In an aged setting, function of tissue Tregs after injury is reduced, contributing to the impaired muscle regeneration seen in old vis-à-vis young mice. A deeper characterization of the relationship between exercise and muscle Treg activities is needed to improve our understanding of the benefits of chronic exercise on muscle function and regenerative capacity. Thus, in the current research plan, the overall goal is to understand the effects of exercise intervention in different phases of life on age-associated changes in muscle function and immunocyte profiles. Aim 1 is designed to deepen our characterization of immunocyte profiles and the functional importance of Tregs in acutely exercised muscle. We postulate that acute exercise promotes muscle-specific accumulation of Tregs with unique transcriptional profiles and that such accumulation supports maintenance of homeostasis in exercised muscle. In Aim 2, we will elucidate and compare acute exercise-inducible changes in muscle biochemical and immunocyte profiles across the mouse lifespan. We postulate that exercise-induced changes in muscle immunocyte profiles are sensitive to age and that such age-associated changes in immunophenotype and function underpin impaired biochemical adaptations of myofibers to exercise, worse control of inflammation, and increased muscle damage in old age. Finally, in Aim 3, we will investigate the effects of chronic endurance exercise on age-related changes in muscle function and biochemical and immunocyte profiles in mice. We postulate that chronic exercise protects against age-related decline in muscle function and maintains “young” biochemical and immunocyte profiles in muscle. Furthermore, we hypothesize that exercise preconditioning is prophylactic against subsequent muscular injury and that such protection is mediated by augmented Treg function. If completed, this work will be the first characterization of changes in exercise-induced muscle immunocyte profiles over a time-course of aging. An understanding of how exercise modulates tissue immunophenotype may illuminate new therapeutic targets for the management of age-related decline in muscle function.

项目摘要预期寿命的增加而没有成比例的延长时间，或者“健康” SPAN，“导致了全球携带多种病因的年龄和脆弱人群的扩大。慢性运动可以改善多种模型生物的健康跨度。这样的健康跨度可能是受慢性运动的抗炎作用的基础，主要是通过测量循环细胞和细胞因子的变化；但是，组织居住的免疫细胞也会发挥在维持稳态和支持压力反应方面的关键作用；然而，关于如何组织知之甚少免疫表型随着年龄或运动而变化。最近，我们建立了耐力的鼠标模型运动引起骨骼肌中免疫细胞的快速积累。此响应分享了许多功能随着对严重组织损伤的反应，包括调节性T细胞（Treg）的积累从促炎症到修复过程的过渡。在衰老的环境中，受伤后组织Treg的功能它减少了，导致旧小鼠旧的肌肉再生受损。需要表征运动与肌肉Treg活动之间的关系以改善我们的了解慢性运动对肌肉功能和再生能力的好处。那在当前的研究计划，总体目标是了解运动干预的影响与年龄相关的肌肉功能变化和免疫细胞谱的寿命。 AIM 1旨在加深我们免疫细胞谱的表征和Treg在急性执行肌肉中的功能重要性。我们假设急性运动可以促进具有独特的转录曲线的Treg的肌肉特异性积累而且这种积累支持在运动肌肉中维持体内平衡。在AIM 2中，我们将阐明并比较跨肌肉生化和免疫细胞概况的急性运动诱导变化鼠标寿命。我们假设运动引起的肌肉免疫细胞轮廓变化对年龄以及这种与年龄相关的免疫表型和功能的变化是生化受损的适应肌纤维的运动，对感染的控制较差以及老年肌肉损害增加。最后，在AIM 3中，我们将研究慢性耐力运动对与年龄相关的肌肉变化的影响小鼠的功能以及生化和免疫细胞谱。我们假设长期运动可以预防与年龄相关的肌肉功能下降，并保持肌肉中的“年轻”生化和免疫细胞特征。此外，我们假设运动预处理是预防性的，以防止随后的肌肉损伤并且这种保护是通过增强的Treg功能介导的。如果完成，这项工作将是第一个在衰老的时间过程中，运动引起的肌肉免疫细胞谱的变化表征。一个了解运动如何调节组织免疫表型可能会阐明新的治疗靶标与年龄相关的肌肉功能下降的管理。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A discrete 'early-responder' stromal-cell subtype orchestrates immunocyte recruitment to injured tissue.

一种离散的“早期反应者”基质细胞亚型协调免疫细胞向受损组织的募集。

DOI：
10.1038/s41590-023-01669-w
发表时间：
2023
期刊：
Nature immunology
影响因子：
30.5
作者：
Yaghi,OmarK;Hanna,BolaS;Langston,PKent;Michelson,DanielA;Jayewickreme,Teshika;Marin-Rodero,Miguel;Benoist,Christophe;Mathis,Diane
通讯作者：
Mathis,Diane

The potential for Treg-enhancing therapies in tissue, in particular skeletal muscle, regeneration.

Treg 增强疗法在组织（特别是骨骼肌）再生中的潜力。