Project 2 - Role of bone-derived exosomes in musculoskeletal aging

衰老与骨骼减少、骨量和密度的丧失有关。 以骨质疏松的形式出现。随着年龄的增长，肌肉和骨量的减少是潜在的因素 老年人跌倒和骨折，这些骨折在经济负担和医疗费用方面都非常昂贵 生活质量。在纠正随年龄增长的肌肉和骨骼流失问题方面取得进展的一个关键障碍是 对与年龄相关的肌肉骨骼潜在的分子和细胞机制认识不足 功能障碍。我们的目标是通过提供关于分子和分子的关键的新信息来解决这个问题 控制这些过程的细胞机制，从而提高科学知识、技术 能力，以及最终的临床实践。我们的中心假设是细胞外小泡(EV)，包括 骨髓干细胞分泌的外切体和微囊随着年龄的增长而显著改变， 这种改变的电动汽车通过运输特定的microRNAs(MiRNAs)导致肌肉和骨骼的损失。这 假设是基于我们的初步数据，表明EV在骨髓中携带的miRNAs是 随着年龄的增长发生了显著的变化。此外，EVS对年轻的骨髓基质细胞(BMSCs)的治疗 从老年动物骨髓中提取抑制这些细胞的成骨分化，并治疗 带有这些EVS的年轻成肌细胞抑制生肌基因的表达。我们的初步结果也 提示EV来源的miRNAs的这些与年龄相关的变化可以通过长期的卡路里来逆转 限制。我们的目标是1)确定衰老如何改变骨源性电动汽车的分泌和运输 干细胞，以及2)确定这些EV如何调节骨骼丢失和肌肉萎缩中的关键细胞事件。 预期结果包括1)鉴定EV来源的由骨髓活跃分泌的miRNAs 干细胞和随年龄变化，以及2)这些小分子如何影响关键细胞 随着年龄的增长，骨骼和肌肉的流失直接相关的过程。这个项目的影响将是新的发现 关于EVS和miRNAs在年龄相关疾病和终末器官损伤发展中的作用。在 未来，这一知识可能在诊断、治疗和管理脆弱患者方面起到至关重要的作用 因大量的年龄引起的病理而衰弱的人群。目标1将检验这样的假设：骨骼- 衍生的EV及其miRNAs是由特定的年龄相关刺激诱导的。目标2将检验这一假设 EV及其miRNAs随年龄变化直接影响肌肉萎缩和骨骼中的关键细胞事件 在体外形成。目标3将测试EV及其miRNAs随年龄变化直接影响的假设 活体肌肉萎缩和骨形成中的关键细胞事件。

Aging is associated with a loss of muscle mass in the form of sarcopenia and a loss of bone mass and density in the form of osteoporosis. Loss of muscle and bone mass with age are in turn underlying factors contributing to falls and fractures in the elderly, and these fractures are very costly both in terms of financial burden and quality of life. A critical barrier to progress in correcting the problem of muscle and bone loss with aging is a poor understanding of the molecular and cellular mechanisms underlying age-related musculoskeletal dysfunction. Our goal is to address this problem by providing critical, new information on the molecular and cellular mechanisms that control these processes, and thereby improve scientific knowledge, technical capability, and eventually clinical practice. Our central hypothesis is that extracellular vesicles (EVs), including exosomes and microvesicles, secreted by stem cells in bone marrow are significantly altered with aging, and that altered EVs contribute to muscle and bone loss by transporting specific microRNAs (miRNAs). This hypothesis is based on our preliminary data indicating that the miRNAs carried by EVs in bone marrow are significantly altered with age. Moreover, treatment of young bone marrow stromal cells (BMSCs) with EVs from bone marrow of aged animals suppresses the osteogenic differentiation of these cells, and treatment of young myoblasts with these EVs suppresses the expression of myogenic genes. Our preliminary results also suggest that these age-related changes in EV-derived miRNAs can be reversed with long-term caloric restriction. Our objectives are to 1) define how aging alters the secretion and cargo of EVs from bone-derived stem cells, and 2) determine how these EVs regulate key cellular events in bone loss and muscle atrophy. Our expected outcomes include 1) identification of EV-derived miRNAs that are actively secreted by bone marrow stem cells and are altered with age, and 2) determination of how these small molecules affect key cellular processes directly related to bone and muscle loss with aging. The impact of this project will be new findings on the role of EVs and miRNAs in the development of age-related diseases and end-organ injuries. In the future this knowledge may be critical in the diagnosis, treatment and management of vulnerable patient populations debilitated by the vast array of age-induced pathologies. Aim 1 will test the hypothesis that bone- derived EVs, and their miRNAs, are induced by specific age-related stimuli. Aim 2 will test the hypothesis that EVs, and their miRNAs, altered with aging directly impact key cellular events in muscle atrophy and bone formation in vitro. Aim 3 will test the hypothesis that EVs, and their miRNAs, altered with aging directly impact key cellular events in muscle atrophy and bone formation in vivo.