Role of Extracellular Vesicles in Bone-Muscle Crosstalk with Aging

细胞外囊泡在衰老过程中骨-肌肉串扰中的作用

基本信息

批准号：
10166745
负责人：
SARAH L DALLAS
金额：
$ 34.09万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10166745
关键词：
Age-Related Bone Loss Age-Related Osteoporosis Aging Blood Circulation Blood Vessels Bone Marrow Bone Surface Cell Communication Cell Line Cell model Cell physiology Cells Communication Data Dendrites Diagnosis Disease Distant Docking Elderly Exercise Harvest Hindlimb Hormones Image Impairment In Vitro Kinetics Label Laboratories Lead Marrow Mediating Mediator of activation protein Membrane Mesenchymal Stem Cells Messenger RNA MicroRNAs Molecular Monitor Mus Muscle Muscle Cells Muscle Fibers Muscle function Muscular Atrophy Myoblasts Osteoblasts Osteocytes Osteoporosis Phenotype Population Proteins Proteome Quality of life Regulation Reporter Role Running Signal Transduction Site Skeletal Muscle Testing Tissues Transgenic Organisms Undifferentiated Work age effect age related aged beta catenin bone bone cell bone circulation cell age cell type circulating biomarkers exosome extracellular vesicles in vivo insight intravital imaging live cell imaging microCT microvesicles mouse model muscle regeneration novel novel therapeutics paracrine particle sarcopenia uptake vesicular release

项目摘要

ABSTRACT Osteoporosis and sarcopenia are diseases of aging that frequently occur together and reduce quality of life in the elderly population. Evidence is emerging for signaling crosstalk between bone and muscle via circulating and local mediators, leading to the concept that muscle-bone crosstalk may coordinate age- related degenerative changes. An exciting new paradigm in cell-cell communication is that extracellular vesicles (EV) (exosomes and microvesicles) may provide a novel mechanism for communication between cells. It has also been proposed that circulating muscle-derived exosomes (termed “exersomes”) may mediate some of the beneficial effects of exercise in the body. EV are membrane-bound particles shed from cells with a cargo of proteins, mRNAs and microRNAs (miRNAs). The EV dock with a target cell, delivering their cargo and altering its function. We have shown that young and aged osteocytes shed EV, which may provide a novel mechanism for regulation of osteoblast function. Live cell imaging suggests osteocytes shed EV from their cell body and dendrites and may shed them into the circulation. Osteocyte EV are taken up by osteoblasts and myoblasts and have potent effects on osteoblasts to promote differentiation towards an early osteocyte phenotype. EV from myoblasts and myotubes are taken up by osteocytes and induce β-catenin signaling. These findings lead to our overall hypothesis that extracellular vesicles (EV) are important regulators of bone and muscle cell function and provide a novel mechanism for crosstalk between muscle and bone that may regulate age-related osteoporosis and sarcopenia. This hypothesis will be tested using complimentary in vitro and in vivo approaches and using intravital imaging in young and aged mouse models with fluorescent reporters to tag bone and muscle cells. Aim 1 will determine the role of EV in regulating osteocyte-osteoblast reciprocal interactions in vitro and in vivo and how this is altered by aging and exercise. This will be done using EV from osteoblast and osteocyte cell lines and primary cells to determine EV effects on the differentiated function of the reciprocal cell type. Aim 2 will determine the role of EV in regulating muscle-bone crosstalk and how it is altered by aging and exercise. This will be done using EV from myoblast, osteoblast and osteocyte cell lines and primary cells to determine EV effects on the differentiated function of the reciprocal cell types. In both aims, live cell and intravital imaging will determine the kinetics of EV release and uptake in muscle and bone cells in vitro and in vivo. Young and aged mouse models will be used with and without wheel running exercise to determine in vitro and in vivo the effect of aging and exercise on EV release, composition and function. These studies may result in paradigm shifting insight into the mechanisms of molecular crosstalk between bone and muscle and will pave the way for exploiting the potential of muscle and bone derived EVs as circulating biomarkers and as novel therapeutics for age related bone and muscle loss.

抽象的骨质疏松症和肌肉减少症是经常一起发生并降低生活质量的衰老疾病越来越多的证据表明骨骼和肌肉之间通过信号传递串扰。循环和局部介质，导致肌肉骨骼串扰可能协调年龄的概念相关的退行性变化是细胞间通讯的一个令人兴奋的新范例。囊泡（EV）（外泌体和微囊泡）可能为细胞之间的通讯提供一种新的机制也有人提出，循环肌肉来源的外泌体（称为“exersomes”）可能 EV 调节体内运动的一些有益效果是膜结合颗粒脱落。来自含有蛋白质、mRNA 和 microRNA (miRNA) 的细胞 EV 与靶细胞对接，我们已经证明，年轻和衰老的骨细胞会脱落 EV，这可能为成骨细胞功能的调节提供一种新的机制。骨细胞从细胞体和树突中脱落 EV，并可能将其流入循环系统。 EV 被成骨细胞和成肌细胞吸收，对成骨细胞具有有效的促进作用 EV从成肌细胞和肌管分化为早期骨细胞表型。这些发现导致我们的总体假设是细胞外。囊泡（EV）是骨和肌肉细胞功能的重要调节剂，并提供了一种新的肌肉和骨骼之间的串扰机制可能调节与年龄相关的骨质疏松症该假设将使用互补的体外和体内方法进行测试。在年轻和老年小鼠模型中使用活体成像，并使用荧光发生器来标记骨骼和肌肉目标 1 将确定 EV 在体外调节骨细胞-成骨细胞相互作用中的作用。以及体内的情况以及衰老和运动如何改变这一点，这将使用来自成骨细胞和运动的 EV 来完成。骨细胞系和原代细胞以确定 EV 对分化功能倒数的影响目标 2 将确定 EV 在调节肌肉-骨骼串扰中的作用以及它如何被改变。这将使用来自成肌细胞、成骨细胞和骨细胞系的 EV 来完成。原代细胞以确定 EV 对相互细胞类型的分化功能的影响在这两个目标中，活细胞和活体成像将确定肌肉和骨细胞中 EV 释放和摄取的动力学体外和体内的年轻和老年小鼠模型将在有或没有轮跑运动的情况下使用。确定体外和体内衰老和运动对 EV 释放、组成和功能的影响。这些研究可能会导致对分子间相互作用机制的范式转变。骨骼和肌肉，将为开发肌肉和骨骼衍生电动汽车的潜力铺平道路循环生物标志物以及作为与年龄相关的骨和肌肉损失的新疗法。