Muscle and Bone Growth in Aging

衰老过程中的肌肉和骨骼生长

• 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
• 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

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.

项目概要/摘要 随着年龄的增长，骨骼肌和骨骼完整性逐渐下降，这主要是由于生长水平下降 因素和体力活动。胰岛素样生长因子-I (IGF-I) 是肌肉生长和生长的主要介质。 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。在衰老过程中，IGF-I 水平逐渐下降，导致肌肉生长失败 再生能力进一步导致肌肉质量和功能丧失；然而，肌肉中的哪个细胞 IGF-I 的关键来源尚未确定。因此，本次研究金的目标 1 是确定 肌肉环境中 IGF-I 的重要来源，可促进肌肉生长和再生，新型小鼠 PI 开发的消除细胞特异性 IGF-I 产生的模型。肌肉的肥大反应 IGF-I 床有可能为骨骼提供机械负荷的好处。确实肌肉发达 收缩有利于对骨骼的机械刺激；然而，老龄化人口中缺乏身体活动 降低骨骼感知和响应机械力的能力，从而导致 骨密度和强度。骨细胞是成熟的骨细胞，可以感知并响应机械刺激 肌肉，进一步指导破骨细胞（骨吸收）和成骨细胞（骨形成）的活动 骨骼重塑。基底膜蛋白 (PLN) 对于骨细胞机械传导至关重要；然而，PLN 可用性 由于机械转导减少，随着年龄的增长而减少。尽管如此，由于骨重塑的影响 骨细胞基质中 PLN 表达减少的原因仍不清楚。此外，众所周知，PLN 可以隔离 多种生长因子；然而，PLN 是否作为生长因子库来诱导骨形成 完全是未经探索的。因此，该提案的目标 2 是确定 PLN 是否发挥生长因子的作用 骨细胞周围 ECM 中的储库进一步增强骨重塑。该提案将 研究增加肌肉和骨量所需的生长因子的机制，以加强 老龄化社会的肌肉骨骼系统。在本拟议研究的 F99 阶段，PI 将是 在肌肉生理学方面接受过培训和指导，以检验卫星细胞中 IGF-I 消融会减慢肌肉生长速度的假设 增殖率并损害肌肉生长和再生。她的作品将在大学进行 佛罗里达州设有肌肉研究所，提供丰富的肌肉专业知识资源。期间 K00 阶段，PI 将与印第安纳肌肉骨骼健康中心的骨骼专家一起开展工作 检验 PLN 作为骨骨细胞基质中生长因子的储存库的假设 重塑。这项工作的完成将为我们提供对必要的生长因子的机械洞察。 增加肌肉和骨骼质量，并将揭示肌肉-骨骼单元中相互作用的潜在因素。这 奖学金将有助于从博士前培训到博士后培训的成功过渡，并培养训练有素的 年轻科学家准备独立研究衰老和疾病中肌肉与骨骼的相互作用。