INTEGRATED STUDY OF MUSCULOSKELETAL LOSS AND RESTORATION

肌肉骨骼损失和恢复的综合研究

• 批准号: 7139462
• 负责人: Esther E Dupont-Versteegden
• 金额: $ 29.11万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7139462
• 关键词: age difference; aging; apoptosis; atrophy; biological signal transduction; bone; bone disuse atrophy; bone morphogenetic proteins; cell differentiation; cell population study; cell proliferation; hematopoietic stem cells; immobilization of body part; insulinlike growth factor; laboratory rat; male; muscle; musculoskeletal regeneration; myoblasts; protein structure function; restraint; restricted physical activity; sarcopenia; stem cells

DESCRIPTION (provided by applicant): Mechanisms controlling musculoskeletal recovery following disuse are poorly understood. However, there is evidence that the restoration of lost tissue is impaired with aging. Precursor cell function in both muscle and bone is altered with advancing age, which may contribute to the decreased recovery. The goal of this proposal is to investigate the role of tissue-specific precursor cells during the recovery from bone loss and muscle atrophy in response to hind-limb suspension (HS) in rats, and to determine whether there are age- associated differences in this process. We hypothesize that changes in the function of tissue-specific precursor cells impair the restoration of musculoskeletal mass with advancing age. The strength of our approach is that both muscle and skeletal components will be studied in the same animals, facilitating evaluation of the interaction between the two systems and the integration of common mechanisms. In Aim 1, we will investigate whether advancing age decreases the capacity to recover (by reambulation) the musculoskeletal atrophy induced by HS. The temporal correlation between loss of muscle and bone and their capacity for restoration will be investigated. Aim 2 addresses whether the underlying mechanisms of precursor cell function and apoptosis in bone and muscle are changed with aging and contribute to the impaired recovery from lost tissue in vivo. In Aim 3, bone marrow stem cells and myoblasts will be isolated, and proliferation, differentiation, and apoptotic responses in vitro determined to investigate whether age- associated changes in these processes contribute to atrophy and impaired restoration of musculoskeletal mass. Our preliminary data suggest an age-dependent role for altered BMP signaling, that may account for diminished restorative capacity in bone. Whether BMP is a common target underlying the mechanistic basis of bone and muscle regulation during aging and disuse will be determined. Finally, in Aim 4 we will investigate in vitro and in vivo whether changes in the insulin-like growth factor (IGF)-1 pathway are involved in the impaired restoration of musculoskeletal mass with aging. Together, these studies will provide important insight into the cellular mechanisms underlying the impaired ability of older animals to recover musculoskeletal integrity after disuse. Our proven integrative approach for studying muscle and bone will enable us to elucidate common mechanisms underlying the responsiveness of the musculoskeletal system during aging. Relevance to public health: Advancing age is associated with a loss of muscle as well as bone mass and it is unknown whether the musculoskeletal system in older individuals differs in its restorative capacity after periods of disuse. In this study we will identify common mechanisms underlying age-related changes in progenitor cell function. Identifying these common pathways influencing muscle and bone integrity could lead to putative targets for pharmacologic or therapeutic interventions.

描述（由申请人提供）：无法理解控制肌肉骨骼恢复的机制。但是，有证据表明，衰老的恢复损失会因衰老而受损。随着年龄的增长，肌肉和骨骼中的前体细胞功能都会改变，这可能导致恢复降低。该提案的目的是研究组织特异性前体细胞在大鼠中后LIMB悬浮液（HS）中恢复中组织特异性前体细胞的作用，并确定此过程中是否存在与年龄相关的差异。我们假设组织特异性前体细胞功能的变化会随着年龄的增长而损害肌肉骨骼质量的恢复。我们方法的优势在于，将在同一动物中研究肌肉和骨骼成分，从而促进对这两种系统之间的相互作用的评估以及共同机制的整合。在AIM 1中，我们将调查增长年龄是否会降低（通过反射）HS诱导的肌肉骨骼萎缩的能力。将研究肌肉和骨骼丧失及其恢复能力之间的时间相关性。 AIM 2解决了前体细胞功能的潜在机制和骨骼和肌肉中的凋亡是否会随着衰老而改变，并导致体内失去的组织恢复受损。在AIM 3中，将分离骨髓干细胞和成肌细胞，并在体外的增殖，分化和凋亡反应确定，以研究这些过程中与年龄相关的变化是否有助于萎缩和肌肉骨骼质量的恢复受损。我们的初步数据表明，改变BMP信号的年龄依赖性作用，这可能解释了骨骼的恢复能力的降低。 BMP是否是在衰老和废弃过程中骨骼和肌肉调节机械基础的基础的常见目标。最后，在AIM 4中，我们将在体外和体内研究胰岛素样生长因子（IGF）-1途径的变化是否参与衰老肌肉骨骼质量的恢复受损。总之，这些研究将提供有关老年动物在废弃后恢复肌肉骨骼完整性受损能力下的细胞机制的重要见解。我们对研究肌肉和骨骼进行验证的综合方法将使我们能够阐明衰老期间肌肉骨骼系统反应性的共同机制。与公共卫生相关：促进年龄与肌肉和骨骼质量的损失有关，未知老年人的肌肉骨骼系统在废弃时期后是否以其恢复能力有所不同。在这项研究中，我们将确定祖细胞功能中与年龄相关的变化的基础机制。确定影响肌肉和骨骼完整性的这些常见途径可能会导致对药理或治疗干预措施的假定靶标。