Muscle and Bone Growth in Aging

项目摘要/摘要 骨骼肌和骨骼的完整性随着我们年龄的增长而逐渐下降，这主要是由于生长水平的下降。 因素和体力活动。胰岛素样生长因子-I(IGF-I)是肌肉生长和 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水平的逐渐下降导致肌肉生长的失败。 和再生能力进一步导致肌肉质量和功能的丧失；然而，肌肉中的哪个细胞 提供了IGF-I的关键来源，但尚未确定。因此，这一奖学金的目标1是确定 新小鼠肌肉环境中促进肌肉生长和再生的IGF-I的关键来源 消融细胞特异性IGF-I产生的模型，由PI开发。肌肉的肥大反应 来自IGF-I的床具有可能为骨骼提供机械加载的好处。的确，肌肉发达 收缩促进了对骨骼的机械刺激；然而，在老龄化人口中，缺乏运动 降低骨骼对机械力的感知和反应能力，这是导致 骨密度和强度。骨细胞是一种成熟的骨细胞，能够感知机械刺激并对其做出反应 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。骨桥蛋白(Perlecan，PLN)是骨细胞机械转导所必需的；然而，PLN的可用性 由于机械转导功能减弱，随着年龄的增长而减少。尽管如此，骨骼重塑的影响 减少PLN在骨细胞基质中的表达仍不清楚。此外，众所周知，PLN会自动隔离 多种生长因子；然而，PLN是否作为生长因子储存库来诱导骨形成 完全没有被探索过。因此，这项建议的目标2是确定PLN是否起到生长因子的作用 位于骨细胞周围的细胞外基质中的贮存库，进一步促进骨重建。这项提议将 研究生长因子增加肌肉和骨量的机制，以增强肌肉和骨量 老龄化社区中的肌肉骨骼系统。在这项拟议研究的F99阶段，PI将是 接受肌肉生理学方面的培训和指导，以测试卫星细胞中IGF-I消融减缓 增殖率，并损害肌肉生长和再生。她的作品将在芝加哥大学演出。 佛罗里达州的Myology Institute从广泛的肌肉专业知识中提供了丰富的资源。在.期间 在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 为了验证PLN作为骨细胞基质中生长因子的储存库的假设 改建。这项工作的完成将提供对必要的增长因素的机械性洞察 增加肌肉和骨骼的质量，并将揭示在肌肉-骨骼单位相互作用的潜在因素。这 奖学金将帮助成功地从博士后培训过渡到博士后培训，并培养训练有素的 初级科学家准备独立研究衰老和疾病中的肌肉-骨骼相互作用。

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.