Skeletal Muscle Molecular Drug Targets for Exercise-induced Cardiometabolic Health

运动诱导心脏代谢健康的骨骼肌分子药物靶点 运动训练对健康的益处是巨大的，体力活动指南总结了这一点。 咨询委员会报告，并纳入2008年美国人体力活动指南 和2018年。了解运动调节其影响的机制将有两个主要好处。 它将促进人们理解如何根据个人的特定临床需求量身定做锻炼计划- 个性化生活方式药物。此外，它还将为新疗法的发展提供关键信息。 对于无数的健康状况来说，锻炼是很好的治疗方法。很可能是锻炼--就像许多环境因素一样 身体暴露-诱导表观遗传修饰，指导基因表达，蛋白质表达和 靶器官的代谢反应，通过运动来调节其作用。骨骼肌中的适应 运动训练对运动的许多健康益处起到了中介作用。然而，这些有益的影响是如何 人们对调解的理解很少。这个项目的目的是在三个人身上理解这些过程 STRRIDE队列包含范围广泛的七种不同的运动暴露-和非活动对照- 广泛的临床、生理数据与血液和骨骼肌样本的生物库配对。这个 推动这项工作的假设是，骨骼肌中的表观遗传修饰-起中介作用，并 随着时间的推移，整合者--DNA染色质甲基化--推动了一个重要的生物程序，促进了改进 对正在进行运动训练的人的心脏代谢健康的影响。我们的工作将在三个方面具体进行 目标。1)确定运动训练和随后的解除训练对 人骨骼肌表基因组、转录组、蛋白质组和代谢组。我们将着手解决这一问题 通过经典的联想建模。尽管我们知道一些DNA甲基化靶点和 下游分子信号对单次运动有反应，我们不知道这些信号有多长时间 修改持续存在；它们可能如何整合单次练习回合的响应，以及它们如何与 其他下游分子靶点在表观基因组、转录组、蛋白质组和代谢组水平。2) 确定运动量(剂量)、强度和方式对 人骨骼肌甲基化组及其下游分子信号通路的重要研究进展 生理和临床结果。为了了解运动影响的传导途径， 人类健康，重要的是联系运动特征对分子决定因素的具体影响 运动反应性，重点是剂量-反应关系。这一目标将通过以下途径实现 一种团队科学方法，涉及因果建模和调节电路以及已知的调节网络-稳定 动态网络--与已知的文学世代保持一致。3)确定和测试假定的药物靶点 在体外系统中模拟运动效果。我们将通过操纵候选对象来测试监管节点 我们的肌肉器官芯片微生理系统中的调节通路。在这项工作结束时，我们将 更好地理解运动对人类健康的有益影响，以及如何利用这些知识 制定针对个人健康目标的个性化锻炼计划，并理解 在导致新的治疗药物靶点的水平上的细胞分子生理学。

Skeletal Muscle Molecular Drug Targets for Exercise-induced Cardiometabolic Health The health benefits of exercise training are substantial, summarized in the Physical Activity Guidelines Advisory Committee Report, and incorporated into the Physical Activity Guidelines for Americans in both 2008 and 2018. Understanding the mechanisms whereby exercise mediates its effects will have two major benefits. It will promote an understanding how to tailor exercise programs to an individual’s specific clinical needs— personalized lifestyle medicine. Also, it will provide critical information for the development of new therapeutics for the myriad of health conditions exercise treats so well. It is likely that exercise—like many environmental bodily exposures—induces epigenetic modifications directing gene expression, protein expression and metabolic responses in target organs whereby exercise mediates its effects. Adaptations in skeletal muscle to exercise training mediate many of the health benefits of exercise. However, how these beneficial effects are mediated are little understood. It is the purpose of this project to understand these processes in three human STRRIDE cohorts containing a broad range of seven different exercise exposures—and inactive control—with extensive clinical, physiologic data paired with a biorepository of blood and skeletal muscle samples. The hypothesis driving this work is that epigenetic modifications in skeletal muscle—serves a mediator and integrator over time— DNA chromatin methylation—drives a major biological program mediating improvement in cardiometabolic health in humans undergoing exercise training. Our work will be conducted in three specific aims. 1) Determine the time course of the effects of exercise training and subsequent detraining on the human skeletal muscle epigenome, transcriptome, proteome and metabolome. This will be approached through classical associative modeling. Although we know that some DNA methylation targets and downstream molecular signaling are responsive to a single bout of exercise, we do not know how long these modifications persist; how they might integrate responses of single exercise bouts, and how they are related to other downstream molecular targets at the epigenome, transcriptome, proteome and metabolome levels. 2) Determine the specific and differential effects of exercise amount (dose), intensity and mode on the human skeletal muscle methylome and downstream molecular signaling pathways on important physiologic and clinical outcomes. In order to understand the pathways mediating exercise effects on human health, it is important to relate the specific effects of exercise characteristics on molecular determinants of exercise responsiveness with a focus on dose-response relationships. This aim will be approached through a team-science approach involving causal modeling and regulatory circuits and known regulatory networks—stable dynamic networks—consistent with the known literature generation. 3) Determine and test putative drug targets mimicking exercise effects in an in vitro system. We will test regulatory nodes by manipulating candidate regulatory pathways in our muscle organ-on-chip microphysiological system. At the end of this work we will understand better how exercise has its salutary effects on human health and how this knowledge may be used to develop both individualized exercise programs targeting an individual’s health goals, and an understanding of the cellular molecular physiology at a level leading to new therapeutic drug targets.