Molecular Underpinnings of Enduring Exercise Benefits

有规律的锻炼对成年人的健康有深远的积极影响，但我们对 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……里面 特别是，人们对经常锻炼后维持有益锻炼结果的分子知之甚少。 结束了。 我们建议从一个新的和可处理的角度来解决这一知识鸿沟，该模型基于 简单的动物线虫。年轻的成年线虫经常进行游泳运动，使它们的运动轨迹 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衰老 在年轻的成年生活中不锻炼的动物。这些健康的组织结果中的许多可以持续一年 在运动期结束后，成年人的生活中有相当大一部分已经结束。在这里，我们提出了基于发现的工作 这将为持久运动效果所需的分子提供一些初步的见解，为 为破译这些令人着迷的结果的生理机制奠定了基础。 目的1是破译超氧化物歧化酶-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弹性，EcSOD的表达是 因运动而升高的。我们发现线虫胞外的超氧化物歧化酶-4是维持人体健康所必需的。 运动停止后运动诱导的运动改善，但不是必须的 培训结果。我们将定义不同的跨膜和分泌形式的SOD-4在 维持运动对肌肉、肠道和神经功能的益处，确定时空SOD-4 在单个细胞水平上的分布，解决SOD-4过度表达的好处，并进行测试 先前阐述的线虫中的SOD-4分子信号通路是否类似于参与 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，作为迈向 了解可能被触发的分子开关，以影响持久的促进健康的生理。 我们将测试运动信号诱导表观遗传修饰以赋予系统和持久的假说 运动通过扰乱线虫表观基因组的76个已知修饰物的编码基因而受益，包括 一些之前与氧化还原生物学、压力信号和长寿有关。 我们期待我们的工作将为运动生物学、衰老、表观遗传学、 ROS信令和老年健康维护的同时，我们为未来奠定了基础 机械解剖。鉴于明确的证据表明锻炼是最有效的有利于健康、抗击疾病的 医学上已知的干预措施，在本土背景下对运动维持生物学的遗传剖析，以及其他 随着时间的推移，应该会产生新的见解，指导改善人类健康和老龄化质量的战略。

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.