Muscle and Bone Growth in Aging

衰老过程中的肌肉和骨骼生长

基本信息

批准号：
10688232
负责人：
Hui Jean Kok
金额：
$ 8.56万
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：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10688232
关键词：
Ablation Acceleration Affect Afibrinogenemia Age Aging Attenuated Beds Beta Cell Biochemical Biological Assay Biology Bone Density Bone Growth Bone Matrix Bone Regeneration Bone Resorption Bone remodeling Cell Proliferation Cells Communities Coupling Disease Elderly Extracellular Matrix Failure Fellowship Fibroblast Growth Factor Florida Foundations Fracture Goals Growth Growth Factor Health Heparan Sulfate Proteoglycan Hindlimb Suspension Impairment In Vitro Indiana Insulin-Like Growth Factor I Intervention Light Liver Mature Bone Mechanical Stimulation Mechanics Mediating Mediator Mentors Muscle Muscle Contraction Muscle Fibers Muscle Weakness Muscle function Muscle satellite cell Muscular Atrophy Musculoskeletal Musculoskeletal System Natural regeneration Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteoporosis Phase Physical activity Physiology Population Population Decreases Postdoctoral Fellow Process Production Proliferating Quality of life Regenerative capacity Regulation Research Resources Risk Scientist Skeletal Muscle Skeletal bone Skeleton Source Testing Training Universities Work aging population bone bone cell bone loss bone mass bone strength career fracture risk improved in vivo insight mechanical force mechanical load mechanical stimulus mechanotransduction mouse model multimodality muscle form muscle physiology muscle regeneration novel perlecan physical inactivity post-doctoral training pre-doctoral regenerative repaired response sarcopenia satellite cell skeletal therapeutically effective

项目摘要

PROJECT SUMMARY/ABSTRACT Skeletal muscle and bone integrity progressively declines as we age, largely due to decreased levels of growth factors and physical activity. Insulin-like Growth Factor-I (IGF-I) is a major mediator of muscle growth and regeneration, specifically through the regulation of muscle stem cells (satellite cells) in order to repair damaged muscle fibers. During aging, the gradual decrease in IGF-I levels contributes to the failure of the muscle growth and regenerative capacity further causing loss of muscle mass and function; however, which cell in the muscle provides the critical source of IGF-I have yet to be established. Thus, Aim 1 of this fellowship is to determine the critical source of IGF-I in the muscle milieu that promotes muscle growth and regeneration, with novel mouse models that ablate cell-specific IGF-I production, developed by the PI. The hypertrophic response of the muscle beds from IGF-I has the potential to provide the benefits of mechanical loading to the bone. Indeed, muscular contraction facilitates mechanical stimulation to the bone; however, physical inactivity in the aging population decreases the ability of bones to sense and respond to mechanical forces, which contributes to the decline in bone density and strength. Osteocytes are mature bone cells that sense and respond to mechanical stimuli from the muscle, further directing the activity of osteoclasts (bone resorption) and osteoblasts (bone formation) for bone remodeling. Perlecan (PLN) is essential for osteocyte mechanotransduction; however, PLN availability decreases with age due to decreased mechanotransduction. Nonetheless, the effects of bone remodeling due to decreased PLN expression in the osteocytic matrix remains unknown. Additionally, PLN is known to sequester numerous growth factors; however, whether PLN serves as a growth factor reservoir to induce bone formation is entirely unexplored. Therefore, Aim 2 of this proposal is to determine if PLN plays a role as a growth factor reservoir in the ECM surrounding osteocytes that further enhances bone remodeling. This proposal will investigate the mechanism of growth factors necessary to increase muscle and bone mass, in order to strengthen the musculoskeletal system in the aging community. In the F99 phase of this proposed research, the PI will be trained and mentored on muscle physiology to test the hypothesis that IGF-I ablation in satellite cells slows the proliferation rate and impairs muscle growth and regeneration. Her work will be performed at the University of Florida, which houses the Myology Institute providing rich resources from extensive muscle expertise. During the K00 phase, the PI will perform her work with bone experts at the Indiana Center for Musculoskeletal Health to test the hypothesis that PLN serves as a reservoir for growth factors in the osteocytic matrix for bone remodeling. The completion of this work will provide mechanistic insight into the growth factors necessary to increase muscle and bone mass, and will shed light to potential factors that interact in the muscle-bone unit. This fellowship will aid in a successful transition from pre-doctoral to post-doctoral training, and develop a well-trained junior scientist poised to independently investigate the muscle-bone interactions in aging and disease.

项目摘要/摘要随着年龄的增长，骨骼肌和骨骼完整性逐渐下降，主要是由于生长水平降低因素和体育锻炼。胰岛素样生长因子I（IGF-I）是肌肉生长和再生，特别是通过调节肌肉干细胞（卫星细胞）来修复受损的肌肉纤维。在衰老期间，IGF-I水平的逐渐下降有助于肌肉生长的失败再生能力进一步导致肌肉质量和功能丧失；但是，肌肉中哪个细胞提供IGF-I的关键来源尚未确定。因此，该奖学金的目标1是确定新型小鼠促进肌肉生长和再生的肌肉环境中IGF-1的关键来源由PI开发的消融细胞特异性IGF-I产生的模型。肌肉的肥厚反应 IGF-I的床有可能为骨骼提供机械负荷的好处。确实，肌肉收缩促进机械刺激到骨头；但是，人口老龄化的身体不活动降低了骨骼感知和响应机械力的能力，这有助于下降骨密度和强度。骨细胞是成熟的骨细胞，感知并响应于机械刺激肌肉进一步指导破骨细胞的活性（骨吸收）和成骨细胞（骨形成）骨骼重塑。 perlecan（PLN）对于骨细胞机械转导至关重要。但是，PLN可用性由于机械转导减少而随着年龄的增长而减小。但是，骨骼重塑的影响在骨细胞基质中降低PLN表达仍然未知。另外，已知PLN隔离许多增长因素；但是，PLN是否是诱导骨形成的生长因子库完全没有探索。因此，该提案的目标2是确定PLN是否扮演着生长因素在骨细胞周围的ECM中的储层，进一步增强了骨重塑。该提议将研究增加肌肉和骨骼所需的生长因子的机制，以增强衰老社区的肌肉骨骼系统。在这项拟议研究的F99阶段，PI将是经过培训和指导肌肉生理学，以检验以下假设增殖率并损害肌肉的生长和再生。她的工作将在大学的大学佛罗里达州，该佛罗里达州的肌科学院从广泛的肌肉专业知识中提供丰富的资源。期间 K00阶段，PI将与印第安纳州肌肉骨骼健康中心的骨骼专家一起工作为了检验PLN作为骨细胞基质生长因子的储层的假设重塑。这项工作的完成将提供对生长因素的机械洞察增加肌肉和骨骼量，并将光吹向肌肉骨单位相互作用的潜在因素。这奖学金将有助于成功从博士前培训过渡到博士后培训，并开发训练有素的初级科学家准备独立研究衰老和疾病中的肌肉骨相互作用。