Reversing age-related dysfunction of skeletal muscle stem cells

项目摘要/摘要： 多细胞生物体的衰老通常涉及身体维持能力的进行性下降 动态平衡细胞置换以及损伤后组织和器官的再生。尤其是骨骼肌， 在成年后的大部分时间里都能旺盛地再生，但到了老年就不能这样做了。肌肉的年龄获得性缺陷 功能严重影响老年人的健康，导致与年龄相关的高发病率 老年人肌肉退化(骨质疏松症)和受伤后恢复效率低或不完全。准确地说 人们对衰老如何导致肌肉功能恶化知之甚少，但有几条证据表明， 包括我实验室的初步数据，表明骨骼肌干细胞的丢失或功能损伤 直接导致组织修复中的年龄相关性失败。 根据这些数据，这一应用的主要焦点是识别年龄调节的基因和途径 这可以在老化的肌肉中进行操纵，以逆转年龄对肌肉干细胞数量的不利影响 改善肌肉干细胞功能。为此，我们生成了大量的初步数据， 强烈提示，与年龄相关的肌肉干细胞功能损害可能是通过增加 暴露在有利于发炎的环境中。特别是，我们发现肌肉干细胞的老化是 伴随着多种炎症相关基因的诱导表达。此外，我们还发现， 这种肌原功能的恢复可以由异慢性异种共生诱导，伴随着 至少部分这些受年龄调节的促炎靶点的表达正常化。 因此，本申请中描述的实验旨在(1)更好地系统地理解 在衰老的骨骼肌干细胞中发生的炎症基因的调节诱导，(2)检查 抑制炎症可以防止或逆转与年龄相关的肌肉干细胞增殖抑制 和肌肉再生功能，以及(3)确定最终导致 老化肌肉中的慢性炎症增强。这些研究将使用成熟的小鼠模型。 已经提供给我们和我的实验室首创的细胞分离策略，将为 临床推广到治疗人类年龄相关性肌肉疾病的新疗法。

Project Summary/Abstract: Aging of multicellular organisms typically involves progressive decline in the body's ability to maintain homeostatic cell replacement and to regenerate tissues and organs after injury. Skeletal muscle, in particular, regenerates robustly through most of adult life but fails to do so in old age. Age-acquired defects in muscle function profoundly impact the health of older individuals, resulting in a high incidence of age-associated muscle deterioration (sarcopenia) and inefficient or incomplete recovery from injury in the elderly. Precisely how aging causes deterioration of muscle function is poorly understood, but several lines of evidence, including preliminary data from my lab, suggest that loss or functional impairment of skeletal muscle stem cells directly contributes to age-dependent failures in tissue repair. In light of these data, the primary focus of this application is to identify age-regulated genes and pathways that can be manipulated in aging muscle to reverse the detrimental effects of age on muscle stem cell number and improve muscle stem cell function. To this end, we have generated extensive preliminary data that strongly suggest that the age-related impairment of muscle stem cell function may be mediated by increased exposure to a pro-inflammatory environment. In particular, we have found that aging of muscle stem cells is accompanied by induced expression of multiple inflammation-associated genes. In addition, we have found that restoration of myogenic function, which can be induced by heterochronic parabiosis, is accompanied by normalization of expression of at least some of these age-regulated, pro-inflammatory targets. Thus, the experiments described in this application are designed to (1) better understand the systemically regulated induction of inflammatory genes that occurs in aged skeletal muscle stem cells, (2) examine whether inhibition of inflammation can prevent or reverse age-associated suppression of muscle stem cell proliferation and muscle regenerative function, and (3) identify the physiological mechanism(s) that ultimately result in enhanced, chronic inflammation in aged muscle. These studies will use well-established mouse models already available to us and cell isolation strategies pioneered by my lab, and will provide a solid basis for clinical extension into novel treatments for human age-associated muscle disease.