Exercise-induced skeletal muscle exosomes promote adipocyte lipolysis

总结 外泌体是小的细胞外囊泡，在过去几年中作为新的介导剂出现。 细胞间通讯我们最近报道了从激活的骨骼肌干细胞释放的外泌体， 细胞通过骨骼肌基质的转运来调节肌肉肥大时细胞外基质的重塑 肌肉特异性miR-206对成纤维细胞的作用。发现肌肉干细胞的这种新作用启发了我们， 进一步探索外泌体是否在抵抗运动中从肌肉细胞中释放出来，如果是的话， 对靶组织的影响。基于初步的数据，我们假设增强的肾上腺素能信号传导， 脂肪组织对抗阻运动的反应部分由外泌体肌肉特异性miR-1介导 β3-肾上腺素能受体（β3-AR）表达的激活。特别是，我们已经开发了一个工作模型， 运动导致骨骼肌细胞释放含有肌肉特异性miR-1的外泌体， 将miR-1转运至脂肪细胞。因此，CAATT/增强子结合蛋白α（C/EBPα）激活β3-AR 通过miR-1介导的AP-2α抑制基因表达，从而增强 脂肪细胞和促进释放的脂肪酸和甘油进入循环的结果增加 脂肪分解拟议研究的目的是通过以下目标来测试我们的工作模式， 目的1：确定运动诱导的外泌体miR-1是否增强脂肪细胞肾上腺素能受体 通过激活β3-AR表达进行信号传导;目的2：确定人骨骼肌纤维是否来源于 外泌体通过增强的β-肾上腺素能信号直接促进脂肪细胞脂解;目的3：确定 人类急性抗阻运动促进miR-1介导的脂肪细胞脂解。我们的初步 数据提供了第一个证据，证明阻力运动诱导的外泌体介导了 运动对脂肪组织代谢的有益作用。更好地理解外泌体在 对抗性运动所产生的系统性适应， 使用外泌体作为递送运动模拟物以治疗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.