Molecular Underpinnings of Enduring Exercise Benefits

持久运动益处的分子基础

• 批准号: 10545757
• 负责人: MONICA A. DRISCOLL
• 金额: $ 19.63万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545757
• 关键词: Address; Adult; Affect; Age; Aging; Animals; Area; Automobile Driving; Biology; Caenorhabditis elegans; Cardiac; Cells; Complex; Control Animal; Data; Defect; Disease; Dissection; Environment; Epigenetic Process; Exercise; Exhibits; Foundations; Functional disorder; Future; Genes; Genetic; Genetic Transcription; Health; Health Benefit; Health Promotion; Human; Individual; Intervention; Intestines; Invertebrates; Knowledge; Life; Longevity; Maintenance; Maps; Mediating; Medicine; Membrane; Memory; Modeling; Modification; Molecular; Muscle; Neurodegenerative Disorders; Neurons; Organism; Outcome; Oxidation-Reduction; Phase; Physiological; Physiology; Property; Proteins; RNA Interference; Regimen; Reproducibility; Rodent; Rodent Model; Role; Series; Signal Induction; Signal Transduction; Skeletal Muscle; Stress; Superoxide Dismutase; Swimming; System; Testing; Time; Tissues; Training; Transcript; Translating; Work; chromatin modification; design; effective therapy; epigenome; exercise program; exercise regimen; experience; extracellular; fascinate; gene function; genetic approach; genetic manipulation; healthy aging; human model; human old age (65+); improved; in vivo; insight; knock-down; molecular resilience; mutant; novel; overexpression; pharynx muscle; resilience; spatiotemporal; young adult

Regular exercise exerts profound positive impacts on adult health, yet our understanding of the molecular mechanisms that establish and sustain systemic exercise benefits remains surprisingly incomplete. In particular, little is known of the molecules that maintain beneficial exercise outcomes after regular exercise is ended. We propose to address this knowledge gap from a new and tractable angle based on an exercise model in the simple animal C. elegans. Regular swim exercise in young adult C. elegans sets the animals on a trajectory of healthy aging that features better muscle, gut and neuronal functionality as compared to age-matched control animals that did not exercise in young adult life. Many of these healthy tissue outcomes endure for a remarkable proportion of adult life after the exercise period is over. Here we propose discovery-based work that will provide some of the first insights into the molecules required for lasting exercise effects, laying the foundation for deciphering the physiological mechanisms by which they exert these fascinating outcomes. Aim 1 is to decipher molecular mechanisms by which SOD-4 mediates maintained exercise benefits. Extracellular ecSOD promotes health resilience in humans and rodent models, and ecSOD expression is elevated by exercise. We found that C. elegans extracellular SOD-4 is required for long-lasting maintenance of exercise-induced locomotory improvements after exercise cessation, but is not required to establish these training outcomes. We will define roles of distinct membrane-spanning and secreted forms of SOD-4 in maintaining exercise benefits in muscle, gut and neuronal function, determine spatio-temporal SOD-4 distribution at the level of individual cells, address SOD-4 over-expression sufficiency for benefits, and test whether previously elaborated SOD-4 molecular signaling circuitry in C. elegans is analogously engaged to maintain exercise benefits. Aim 2 is to identify epigenetic factors required for enduring exercise benefits as a first step toward understanding molecular switches that might be triggered to affect long-lasting health-promoting physiology. We will test the hypothesis that exercise signals induce epigenetic modifications to confer systemic and lasting exercise benefits by disrupting genes encoding the 76 known modifiers of the C. elegans epigenome, including some previously implicated in redox biology, stress signaling and longevity. We expect our work to contribute a significant advance to the fields of exercise biology, aging, epigenetics, ROS signaling, and older-age health maintenance at the same time we establish the foundation for future mechanistic dissection. Given unequivocal evidence that exercise is the most effective pro-health, anti-disease intervention known in medicine, genetic dissection of exercise maintenance biology in native context, and over time, should yield new insights that guide strategies for improving human health and aging quality.

定期锻炼对成年人的健康产生深远的积极影响，但我们对分子生物学的理解 令人惊讶的是，建立和维持系统性锻炼益处的机制仍然不完善。在 特别是，很少有人知道的分子，保持有益的运动成果后，定期运动， 结束 我们建议从一个新的和易处理的角度来解决这个知识差距的基础上，在练习模型， 简单动物C.优美的青少年经常游泳锻炼。秀丽线虫让动物们沿着 与年龄匹配的对照组相比，具有更好的肌肉、肠道和神经元功能的健康老龄化 在年轻的成年生活中不锻炼的动物。许多这些健康组织的结果持续了一段时间。 在运动期结束后，成年人的生活比例很大。在这里，我们建议基于发现的工作 这将为持久运动效果所需的分子提供一些初步的见解， 这是破译它们发挥这些迷人结果的生理机制的基础。 目的1是阐明SOD-4介导维持运动益处的分子机制。 细胞外ecSOD促进人类和啮齿动物模型的健康恢复力， 通过锻炼提高。我们发现C. elegans胞外SOD-4是长期维持 运动停止后运动诱导的运动改善，但不需要建立这些 培训成果。我们将定义不同的跨膜和分泌形式的SOD-4的作用， 维持运动对肌肉、肠道和神经元功能的益处，确定时空SOD-4 在单个细胞水平上的分布，解决SOD-4过表达的益处，并测试 是否先前在C. elegans类似地致力于 保持锻炼的好处。 目标2是确定持久运动益处所需的表观遗传因素，作为实现以下目标的第一步： 了解可能被触发以影响持久健康促进生理的分子开关。 我们将测试这一假设，即运动信号诱导表观遗传修饰， 通过破坏编码76种已知的C.线虫表观基因组，包括 一些先前与氧化还原生物学、应激信号和寿命有关。 我们希望我们的工作能为运动生物学、衰老、表观遗传学、 ROS信号转导，同时为我们的老年健康维护奠定了基础， 机械解剖有明确的证据表明，运动是最有效的健康，抗病， 医学上已知的干预，在本土背景下运动维持生物学的遗传解剖，等等。 时间，应该产生新的见解，指导改善人类健康和老龄化质量的战略。