Estrogen Receptor Mediated Regulation of Bone - Muscle Crosstalk during Aging

衰老过程中雌激素受体介导的骨-肌肉串扰调节

基本信息

批准号：
10166746
负责人：
MARK Louis JOHNSON
金额：
$ 31.66万
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/10166746
关键词：
Affect Age Age-Months Aging Architecture Biological Models Botox C57BL/6 Mouse Cell Line Cells Cellular Metabolic Process Complement Contracts Coupling Cyclic AMP-Dependent Protein Kinases Data Dexamethasone Disease Environment Estrogen Receptor alpha Estrogen Receptors Estrogens Exercise FRAP1 gene Female Forearm Foundations Genetic Transcription Healthcare Impairment In Vitro Lead Life MAP Kinase Gene Mediating Mitochondria Modeling Molecular Mus Muscle Muscle Cells Muscle Fibers Muscle function Myoblasts Nuclear Receptors Organ Osteocytes Osteopenia Osteoporosis Paralysed Pathway interactions Performance Play Postmenopause Property Publishing Reagent Receptor Signaling Regulation Reporter Research Role Running Signal Pathway Signal Transduction Skeletal Muscle Tamoxifen Testing Tissues United States age related aged beta catenin bone bone cell bone loss bone mass care burden design enhancing factor female sex hormone fracture risk in vivo innovation male mechanical load mouse model muscle form novel prevent receptor receptor-mediated signaling reduced muscle mass response sarcopenia skeletal substantia spongiosa

项目摘要

ABSTRACT Bone is a dynamic organ that is known to adjust in mass, material and architectural properties with respect to the load environment. The progressive decline in muscle mass, strength/performance (sarcopenia) and bone loss (osteopenia/osteoporosis) that occurs with aging suggests a functional coupling between the diseases. As the osteocyte is thought to be the mechanosensory cell in bone, an age-related reduction in its ability to respond to load would have significant consequences on bone mass. We have shown that the Wnt/β-catenin signaling pathway is a critical component of bone responsiveness to mechanical loading and is rapidly activated in osteocytes following the in vivo application of load. Our Preliminary Data demonstrate an important role of estrogen in the response of osteocytes to load. We also found that ex vivo contracted EDL muscles from 6 month old C57BL/6 mice release a factor that enhances activation of β-catenin in osteocytes. This enhancement effect is lost in 22 month old muscles. Using our recently developed β-catenin signaling osteocyte reporter cell line (TOPflash MLO-Y4), we found that C2C12 myotube conditioned media (MTCM) synergistically enhances Wnt3a induced β-catenin signaling and this is partially regulated by mTOR. This project will test the hypothesis that loss of estrogen mediated signaling with aging impairs crosstalk signaling between bone and muscle. To test this hypothesis we propose two specific aims. In Aim 1 we will determine if loss of ER mediated signaling in osteocytes alters critical bone-muscle crosstalk signaling pathways. In Aim 2 we will determine if loss of ER mediated signaling in muscle will induce changes in muscle and bone function and properties with aging and if exercise will protect against these changes in young mice. These aims will be accomplished using young (5-6 mo old), mature (12 mo) and aged (22 mo) mouse models with targeted deletion of estrogen receptors in muscle and bone. In vitro studies using bone and muscle cell model systems and primary cells will be used to dissect the molecular basis for the changes we observe in vivo. The information obtained from these studies is foundational for our understanding of how bone and muscle age, the potential mitigating effects of exercise and the possible molecular linkage between osteoporosis and sarcopenia.

抽象的骨骼是一种动态器官，已知可以根据以下方面调整质量、材料和结构特性：负荷环境中肌肉质量、力量/性能（肌肉减少症）和骨骼的逐渐下降。随年龄增长而发生的骨质流失（骨质减少/骨质疏松）表明这些疾病之间存在功能性耦合。骨细胞被认为是骨骼中的机械感觉细胞，其反应能力随着年龄的增长而下降负载会对骨量产生重大影响我们已经证明 Wnt/β-连环蛋白信号传导。通路是骨对机械负荷反应的关键组成部分，并且在我们的初步数据证明了体内施加负载后的骨细胞的重要作用。我们还发现，雌激素在骨细胞对负荷的反应中从 6 个月起就开始收缩 EDL 肌肉。老C57BL/6小鼠释放一种增强骨细胞中β-连环蛋白活化的因子，这种增强作用。使用我们最近开发的 β-连环蛋白信号骨细胞报告细胞系，在 22 个月大的肌肉中丢失。 (TOPflash MLO-Y4)，我们发现 C2C12 肌管条件培养基 (MTCM) 协同增强 Wnt3a 诱导 β-连环蛋白信号传导，并且这部分受 mTOR 调节。该项目将检验丢失的假设。雌激素介导的信号随着年龄的增长会损害骨骼和肌肉之间的串扰信号来测试这一点。假设我们提出两个具体目标，在目标 1 中，我们将确定 ER 介导的信号传导是否丢失。骨细胞改变关键的骨-肌肉串扰信号通路在目标 2 中，我们将确定 ER 是否丢失。随着年龄的增长，肌肉中介导的信号传导将引起肌肉和骨骼功能和特性的变化，如果运动可以防止幼鼠发生这些变化。肌肉中雌激素受体有针对性删除的小鼠模型使用骨和肌肉细胞模型系统和原代细胞的体外研究将用于解剖。我们在体内观察到的变化的分子基础是从这些研究中获得的信息。为我们了解骨骼和肌肉如何老化、运动的潜在缓解作用以及骨质疏松症和肌肉减少症之间可能存在的分子联系。