Role of Extracellular Vesicles in Bone-Muscle Crosstalk with Aging

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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.