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

基本信息

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
项目类别：
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

项目摘要

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我们最近报道了激活的骨骼肌干释放的外泌体。细胞在肌肉肥大期间通过骨骼运输调节细胞外基质重塑肌肉特异性 miR-206 对成纤维细胞的这种新作用的发现激发了我们的灵感。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，它们的根据初步数据，我们合作增强肾上腺素信号传导。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型。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：确定是否源自人类骨骼肌纤维外泌体通过增强的 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促进 miR-1 介导的脂肪细胞脂肪分解。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在脂肪组织代谢中的作用。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

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

细胞外囊泡在骨骼肌适应调节中的新作用。

DOI：
10.1152/japplphysiol.00914.2018
发表时间：
2019-08-01
期刊：
Journal of applied physiology
影响因子：
3.3
作者：
I. Vechetti
通讯作者：
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。

DOI：
发表时间：
2022-05
期刊：
影响因子：
0
作者：
Wen, Yuan;Valentino, Taylor;Depa, Lauren;Goh, Jensen;Alimov, Alexander;Vechetti, Ivan;Peterson, Charlotte A;McCarthy, John J
通讯作者：
McCarthy, John J

The role of extracellular vesicles in skeletal muscle and systematic adaptation to exercise.

细胞外囊泡在骨骼肌和系统运动适应中的作用。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Vechetti Jr, Ivan J;Valentino, Taylor;Mobley, C Brooks;McCarthy, John J
通讯作者：
McCarthy, John J

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

机械过载诱导的肌肉源性细胞外囊泡促进脂肪组织脂解。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Vechetti Jr, Ivan J;Peck, Bailey D;Wen, Yuan;Walton, R Grace;Valentino, Taylor R;Alimov, Alexander P;Dungan, Cory M;Van Pelt, Douglas W;von Walden, Ferdinand;Alkner, Björn;Peterson, Charlotte A;McCarthy, John J
通讯作者：
McCarthy, John J