Skeletal Muscle Nrf2: Exercise-Induced Cardiovascular Protection

项目总结 本研究的目的是阐明运动训练(EXT)诱导交感神经传导的新机制。 慢性心力衰竭(CHF)的抑制(目标1)与急性冠脉病变后的心脏保护 缺血/再灌注(I/R)(目标2)，基于抗氧化剂器官间转移的创新概念 酵素。众所周知，运动产生的肌肉衍生的活性氧物种(ROS)可以 激活核因子(红系衍生的2)样2(NRF2)，导致一组抗氧化剂上调 骨骼肌本身中的酶。我们假设这些抗氧化剂可以从骨骼 通过循环细胞外小泡(EVS)将肌肉传递到远程组织，为受体细胞提供 第二，增强抗氧化防御线。小鼠延髓头端腹外侧区(RVLM) CHF，这些抗氧化剂恢复交感前神经元的氧化还原动态平衡，有助于外部交感神经- 抑制力。此外，在冠状动脉I/R的小鼠心脏中，这些抗氧化剂可以减少自由基 损伤和挽救缺血心肌，从而在体外心脏保护中发挥关键作用。致信地址 在这些假设下，我们建立了三个骨骼肌特异性转基因小鼠品系。MS-MG系列是一种 报告模型，它允许我们跟踪、捕获和分析专门从骨骼肌释放的电动汽车。 该模型将用于检测骨骼肌源性EV的货运蛋白及其在脑中的分布。 心跟随着EXT。IMS-Nrf2FLOX/FLOX和IMS-Keap1FLOX/FLOX将使我们能够删除骨骼肌 Nrf2(即Nrf2缺乏)和Keap1(即Nrf2过表达)。这两个模型将用于 在AIM 1中证明NRF2/抗氧化剂系统和外交感抑制之间的因果关系 和体外心脏保护的目标2。肠道病毒生物学，蛋白质组学，生物信息学， 电生理学和心血管生理学将被用来表征骨骼肌源性电动汽车 在EXT后，确定EXT-EVS对中枢神经元放电和周围交感神经的影响 并探讨EXT-EVS抗冠状动脉I/R损伤的机制。 在这个项目完成后，我们希望为体外心血管疾病提供新的机制见解 保护，铺平了一条将定期体力活动的有益效果转化为临床的新途径 实践预防和治疗急慢性缺血性心脏病。

PROJECT SUMMARY The goal of this study is to elucidate novel mechanisms underlying exercise training (ExT)-induced sympatho- inhibition in chronic heart failure (CHF) (Aim 1) and cardioprotection following acute coronary ischemia/reperfusion (I/R) (Aim 2), based on an innovative concept of inter-organ transfer of antioxidant enzymes. It is well established that exercise generates muscle-derived reactive oxygen species (ROS) which activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2), resulting in upregulation of a panel of antioxidant enzymes in skeletal muscle per se. We hypothesize that these antioxidants can be transported from skeletal muscle to remote tissues through circulating extracellular vesicles (EVs), providing recipient cells with a second and enhanced line of antioxidant defense. In the rostral ventrolateral medulla (RVLM) of mice with CHF, these antioxidants restore redox homeostasis of pre-sympathetic neurons, contributing to ExT-sympatho- inhibition. Furthermore, in the heart of mice subjected to coronary I/R, these antioxidants reduce free radical damage and salvage ischemic myocardium, thus playing a critical role in ExT-cardioprotection. To address these hypotheses, we developed three skeletal muscle-specific transgenic mouse lines. The MS-mG line is a reporter model, which allows us to track, capture, and analyze EVs released specifically from skeletal muscle. This model will be used to assay cargo proteins of skeletal muscle-derived EVs and their distribution in brain and heart following ExT. The iMS-Nrf2flox/flox and iMS-Keap1flox/flox lines will enable us to delete skeletal muscle Nrf2 (i.e. Nrf2 deficiency) and Keap1 (i.e. Nrf2 overexpression), respectively. These two models will be used to demonstrate a causal relationship between the Nrf2/antioxidant system and ExT-sympatho-inhibition in Aim 1 and ExT-cardioprotection in Aim 2. Interdisciplinary methods of EV biology, proteomics, bioinformatics, electrophysiology, and cardiovascular physiology will be utilized to characterize skeletal muscle-derived EVs following ExT, determine the effects of ExT-EVs on central neuron discharge and peripheral sympathetic nerve activity, and explore the mechanisms underpinning cardioprotection of ExT-EVs against coronary I/R injury. Upon completion of this project, we expect to provide novel mechanistic insights on ExT-cardiovascular protection, paving a new avenue to translate the beneficial effects of regular physical activity into clinical practice to prevent and treat acute and chronic ischemic heart diseases.