Molecular Underpinnings of Enduring Exercise Benefits

持久运动益处的分子基础

基本信息

批准号：
10388673
负责人：
MONICA A. DRISCOLL
金额：
$ 23.55万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10388673
关键词：
Address Adult Affect Age Aging Animals Area Automobile Driving Biology Biology of Aging 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 Mediating Medicine Membrane Memory Modeling Modification Molecular Muscle Neurodegenerative Disorders Neurons Organism Outcome Oxidation-Reduction Phase Physiological Physiology Property Proteins RNA Interference Regimen Rodent Rodent Model Role Series Signal Transduction Skeletal Muscle Stress Superoxide Dismutase Swimming System Testing Time Tissues Training Transcript Translating Work base chromatin modification design effective therapy epigenome exercise program exercise regimen experience extracellular fascinate gene function genetic approach genetic manipulation healthy aging human model improved in vivo insight knock-down mutant novel pharynx muscle resilience spatiotemporal young adult

项目摘要

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.

定期运动对成人健康产生深远的积极影响，但我们对分子的理解建立和维持系统性锻炼益处的机制仍然令人惊讶地不完整。在特别，对于定期运动后保持有益运动结果的分子知之甚少结束。我们建议根据基于运动模型在简单的动物秀丽隐杆线虫。年轻的成年秀丽隐杆线虫的定期游泳运动将动物设置在与年龄匹配的对照相比，具有更好肌肉，肠道和神经元功能的健康衰老不运动的动物。这些健康的组织结局中有许多持续运动期结束后成人生活的显着比例已经结束。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第一个见解解密生理机制的基础，通过这些机制，它们产生了这些迷人的结果。目的1是破译分子机制，SOD-4介导维持运动益处。细胞外ecsod促进了人类和啮齿动物模型的健康弹性，而ecsod的表达为通过运动提升。我们发现秀丽隐杆线虫细胞外SOD-4是长期维护所必需的锻炼后的运动戒断后，不需要建立这些运动培训结果。我们将定义不同的膜跨膜和分泌形式的SOD-4的作用保持肌肉，肠道和神经元功能的运动益处，确定时空SOD-4 在单个细胞级别的分布，解决SOD-4的过表达以获取利益，并测试秀丽隐杆线虫中先前详细阐述的SOD-4分子信号传导电路是否类似地参与保持运动益处。 AIM 2是确定持久运动益处所需的表观遗传因素，这是迈向的第一步了解可能触发可能影响持久健康促进健康生理的分子开关。我们将检验以下假设，即运动信号诱导表观遗传修饰以赋予全身性和持久性通过破坏编码秀丽隐杆线虫表皮的76个已知修饰符的基因，包括一些先前与氧化还原生物学，应力信号和寿命有关的涉及。我们希望我们的工作能为运动生物学，衰老，表观遗传学， ROS信号传导和老年健康维护同时我们为未来建立基础机械解剖。鉴于明确的证据表明锻炼是最有效的亲保健，反疾病在医学中已知的干预措施，在本地环境中及以上的遗传剖析时间，应产生新的见解，以指导改善人类健康和衰老质量的策略。