Exercise-induced skeletal muscle exosomes promote adipocyte lipolysis

运动诱导的骨骼肌外泌体促进脂肪细胞脂肪分解

• 批准号: 10458636
• 负责人: JOHN Joseph MCCARTHY
• 金额: $ 37.23万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458636
• 关键词: AR gene; Acute; Address; Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic Receptor; Aerobic Exercise; Biological Assay; Biological Models; Biopsy; Blood Circulation; Blood specimen; Catecholamines; Colon Carcinoma; Coronary heart disease; Data; Development; Disease; Electric Stimulation; Exercise; Extracellular Matrix; Fatty Acids; Fatty acid glycerol esters; Female; Fibroblasts; Gene Expression; Genes; Glycerol; Heart failure; High Fat Diet; Human; Isoproterenol; Knowledge; Lipolysis; Mediating; Mediator of activation protein; Metabolism; Modeling; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle satellite cell; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Participant; Pathway interactions; Public Health; Reporter Genes; Reporting; Repression; Role; Serum; Signal Transduction; Skeletal Muscle; Source; Stimulus; Testing; Thinness; Tissues; Untranslated Regions; base; enhancer binding protein; exosome; experimental study; extracellular vesicles; fat burning; gain of function; gene repression; in vitro Model; intercellular communication; male; malignant breast neoplasm; mimetics; muscle hypertrophy; novel; novel therapeutic intervention; obesity development; prevent; resistance exercise; response; subcutaneous; transcription factor; vastus lateralis; young adult

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.

概括 外泌体是一种小型细胞外囊泡，在过去几年中作为新的介质出现 细胞间通讯。我们最近报道，激活的骨骼肌干释放外泌体 细胞通过骨骼肌的运输调节肌肉肥大期间的细胞外基质重塑 肌肉特异性 miR-206 作用于成纤维细胞。肌肉干细胞这一新作用的发现激励我们 进一步探讨外泌体是否因抵抗运动而从肌肉细胞中释放出来，如果是这样，它们的 对靶组织的影响。根据初步数据，我们假设增强的肾上腺素信号传导 脂肪组织对抗阻运动的反应部分是由外泌体肌肉特异性 miR-1 介导的 β3-肾上腺素能受体（β3-AR）表达的激活。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 的外泌体 将 miR-1 转运至脂肪细胞。结果，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，从而增强儿茶酚胺敏感性 脂肪细胞并促进脂肪酸和甘油释放到循环中，因为脂肪细胞增加 脂肪分解。拟议研究的目的是通过追求以下目标来测试我们的工作模式： 小鼠和人类：目标 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 通过激活 β3-AR 表达来发出信号；目标 2：确定人类骨骼肌纤维是否源自 外泌体通过增强β-肾上腺素信号传导直接促进脂肪细胞脂肪分解；目标 3：确定是否 人类的急性阻力运动会促进 miR-1 介导的脂肪细胞脂肪分解。我们的初步 数据提供了第一个证据，表明抗阻运动诱导的外泌体介导 运动对脂肪组织代谢的有益作用。更好地了解外泌体的作用 响应阻力运动而发生的系统适应预计将提供 使用外泌体作为传递运动模拟物的平台来治疗疾病所需的基础知识 肥胖。

项目成果

Emerging role of extracellular vesicles in the regulation of skeletal muscle adaptation.

• DOI: 10.1152/japplphysiol.00914.2018
• 发表时间: 2019-08
• 期刊: Journal of applied physiology
• 影响因子: 3.3
• 作者: I. Vechetti

Impact of Obesity on Exercise-Induced Skeletal Muscle Exosomes.

肥胖对运动引起的骨骼肌外泌体的影响。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Wen,Yuan;Valentino,Taylor;Depa,Lauren;Goh,Jensen;Alimov,Alexander;Vechetti,Ivan;Peterson,CharlotteA;McCarthy,JohnJ
• 通讯作者: McCarthy,JohnJ

Mechanical overload-induced muscle-derived extracellular vesicles promote adipose tissue lipolysis.

机械超载引起的肌肉衍生的细胞外囊泡促进脂肪组织脂解。

• DOI: 10.1096/fj.202100242r
• 发表时间: 2021-06
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Vechetti IJ Jr;Peck BD;Wen Y;Walton RG;Valentino TR;Alimov AP;Dungan CM;Van Pelt DW;von Walden F;Alkner B;Peterson CA;McCarthy JJ
• 通讯作者: McCarthy JJ