Exercise-induced skeletal muscle exosomes promote adipocyte lipolysis

摘要 Exosome是一种小的细胞外小泡，在过去的几年里作为一种新的媒介出现。 细胞间通信。我们最近报道了从激活的骨骼肌干中释放的外切体 细胞通过骨骼运输调节肌肉肥大过程中细胞外基质重塑 肌肉特异性miR-206对成纤维细胞的作用。肌肉干细胞这一新角色的发现启发了我们 进一步探讨是否肌肉细胞释放外切体作为抵抗运动的反应，如果是的话，它们的 对目标组织的影响。根据初步数据，我们假设肾上腺素能信号增强在 脂肪组织对阻力运动的反应部分是由外体肌肉特异性miR-1介导的 激活β3-肾上腺素能受体(β3-AR)的表达。特别是，我们开发了一个工作模型， 哪种运动会导致骨骼肌细胞释放含有肌肉特异性miR-1的外体 将miR-1转运到脂肪细胞。因此，CAATT/增强子结合蛋白α(C/eBPα)激活β3-AR 通过miR-1介导的抑制AP-2α的基因表达，从而增强大鼠对儿茶酚胺的敏感性 脂肪细胞和促进脂肪酸和甘油的释放进入循环的结果是增加 脂肪分解。拟议研究的目的是通过实现以下目标来测试我们的工作模式： 小鼠和人：目标1：确定运动诱导的外体miR-1是否增强脂肪细胞的肾上腺素能 通过激活β3-AR表达来传递信号；目标2：确定人类骨骼肌纤维是否来源于 Exosome通过增强的β-肾上腺素能信号直接促进脂肪细胞脂解；目标3：确定 人类的一场急性阻力运动促进了miR-1介导的脂肪细胞脂肪分解。我们的预赛 数据首次提供证据表明，阻力运动诱导的外切体介导了 运动对脂肪组织代谢的有益作用。更好地理解外切体在人类免疫系统中的作用 对阻力运动的系统适应预计将提供 使用外切体作为提供运动模拟疗法的平台所需的基础知识 肥胖。

Summary Exosomes are small extracellular vesicles that have emerged over the past few years as novel mediators of intercellular communication. We recently reported that exosomes released from activated skeletal muscle stem cells regulate extracellular matrix remodeling during muscle hypertrophy through the transport of skeletal muscle-specific miR-206 to fibroblasts. The discovery of this novel role for muscle stem cells inspired us to further explore if exosomes are released from muscle cells in response to resistance exercise and, if so, their impact on target tissues. Based on preliminary data, we hypothesize that enhanced adrenergic signaling in adipose tissue in response to resistance exercise is mediated in part by exosomal muscle-specific miR-1 activation of β3-adrenergic receptor (β3-AR) expression. In particular, we have developed a working model in which exercise causes skeletal muscle cells to release exosomes containing muscle-specific miR-1 that transport miR-1 to adipocytes. As a result, CAATT/enhancer binding protein alpha (C/EBPα) activates β3-AR gene expression through miR-1-mediated repression of AP-2α, thereby enhancing catecholamine sensitivity of adipocytes and promoting the release of fatty acids and glycerol into the circulation as the result of increased lipolysis. The purpose of the proposed studies is to test our working model by pursuing the following aims in both mice and humans: Aim 1: Determine if exercise-induced exosomal miR-1 enhances adipocyte adrenergic signaling through activation of β3-AR expression; Aim 2: Determine if human skeletal muscle fiber-derived exosomes directly promote adipocyte lipolysis through enhanced β-adrenergic signaling; Aim 3: Determine if an acute bout of resistance exercise in humans promotes miR-1-mediated adipocyte lipolysis. Our preliminary data provide the first evidence demonstrating that resistance exercise-induced exosomes mediate the beneficial effect of exercise on adipose tissue metabolism. A better understanding of the role of exosomes in the systemic adaptations that occur in response to resistance exercise are expected to provide the fundamental knowledge necessary to use exosomes as a platform for the delivery of exercise mimetics to treat obesity.