Functions of myelomonocytic lineage cells in aging muscle

描述(申请人提供)：我们过去20年研究的一个长期目标是了解免疫系统调节骨骼肌功能和功能障碍的机制。在我们请求支持的项目中，我们将检查特定免疫细胞群体的功能，这些细胞可能会影响骨骼肌减少，即在衰老过程中肌肉质量的丧失。目前，除了可能不适用于老年人的运动和饮食干预外，还没有针对人类石棺减少症的治疗方法。对免疫细胞调节骨质疏松症模型的验证可以为减缓骨质疏松症提供一种新的治疗策略。这一结果将对治疗老龄化人口中的主要健康问题具有重要意义，在老龄化人口中，生活方式的退化、独立功能的丧失以及与缺乏活动相关的疾病的发展可能是由于老年人的肌肉质量和体力活动的丧失。我们假设免疫系统的老化通过两个过程导致骨骼肌减少：1)骨髓来源的骨髓单核细胞与骨骼肌融合的能力降低，2)巨噬细胞转变为促进肌肉萎缩的表型。我们旨在测试这一假说的实验将解决以下目标：目标1：确定选定的免疫细胞群在衰老肌肉中的命运。目的2：确定选定免疫细胞数量的减少是否会影响骨骼肌减少或肌肉在衰老过程中的再生能力。目的3：测试对特定免疫细胞群体发育的控制是否会影响骨质疏松症。这项研究的结果将首次提供有关单核细胞系细胞在衰老肌肉中的命运的信息，并为该系细胞影响衰老肌肉再生能力的机制提供新的见解。这些信息可以为解决骨质疏松症的新治疗策略提供基础，骨质疏松症是老年人的一个主要健康问题。

DESCRIPTION (provided by applicant): A long-term goal of our research for the past 20 years has been to understand mechanisms through which the immune system modulates function and dysfunction of skeletal muscle. In the project for which we request support, we will examine the function of a specific population of immune cells that have the potential to influence sarcopenia, the loss of muscle mass during aging. Currently, there are no treatments for sarcopenia in humans other than exercise and dietary interventions that may not be applicable for the aged. Validation of our model for immune-cell modulation of sarcopenia could provide a gateway to new therapeutic strategies for the slowing of sarcopenia. This outcome would have substantial significance for treating major health problems in the aging human population in which degradation of lifestyle, loss of independent function and development of inactivity-associated diseases can arise from the loss of muscle mass and physical activity in the elderly population. We hypothesize that aging of the immune system contributes to sarcopenia through two processes: 1) reductions in the capacity of bone marrow derived myelomonocytic cells to fuse with skeletal muscle, and 2) shifts in macrophages to a phenotype that promotes muscle wasting. Our experiments that are designed to test this hypothesis will address the following aims: Aim 1: Determine the fate of select immune cell populations in aging muscle. Aim 2: Determine whether diminishing selected immune cell populations affects sarcopenia or the regenerative capacity of muscle during aging. Aim 3: Test whether manipulation of the development of specific immune cell populations can influence sarcopenia. The findings of this investigation will provide the first information concerning the fate of cells of the myelomonocytic lineage in aging muscle and provide new insights into the mechanisms through which cells of that lineage can affect the regenerative capacity of aging muscle. That information can provide the foundation for new therapeutic strategies for addressing sarcopenia, a major health problem in the elderly.