Functions of myelomonocytic lineage cells in aging muscle

描述（由申请人提供）：我们过去20年的长期研究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，我们将研究一种特定免疫细胞群的功能，这种免疫细胞群有可能影响肌肉减少症，即衰老过程中肌肉质量的损失。目前，除了运动和饮食干预之外，没有治疗人类肌肉减少症的方法，这些方法可能不适用于老年人。我们的免疫细胞调节肌肉减少症模型的验证可以为减缓肌肉减少症的新治疗策略提供一个门户。这一结果对于治疗老龄人口中的主要健康问题具有重大意义，在这些问题中，老年人口肌肉质量和体力活动的减少可能导致生活方式的退化、独立功能的丧失和不活动相关疾病的发展。我们假设免疫系统的衰老通过两个过程导致肌肉减少：1)骨髓来源的骨髓单核细胞与骨骼肌融合能力的降低，以及2)巨噬细胞向促进肌肉萎缩的表型转变。我们的实验旨在验证这一假设，将解决以下目标：目标1：确定老化肌肉中选定免疫细胞群的命运。目的2：确定在衰老过程中减少选定的免疫细胞群是否会影响肌肉减少症或肌肉的再生能力。目的3：测试是否操纵特定免疫细胞群的发育可以影响肌肉减少症。这项研究的发现将提供关于衰老肌肉中髓细胞系细胞命运的第一个信息，并为髓细胞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老年人主要健康问题肌肉减少症的新治疗策略提供基础。

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.