Reversing age-related dysfunction of skeletal muscle stem cells

项目概要/摘要： 多细胞生物体的衰老通常涉及身体维持 稳态细胞替换和损伤后组织和器官再生。尤其是骨骼肌， 在成年期的大部分时间里都能强劲地再生，但在老年时却不能。年龄获得性肌肉缺陷 功能深刻影响老年人的健康，导致与年龄相关的高发病率 肌肉退化（肌肉减少症）和老年人受伤后恢复不充分或不完全。精确 衰老是如何导致肌肉功能退化的还不清楚，但有几条证据， 包括我实验室的初步数据表明，骨骼肌干细胞的丧失或功能受损， 直接导致组织修复中的年龄依赖性失败。 根据这些数据，本申请的主要焦点是鉴定年龄调节基因和途径 可以在老化的肌肉中进行操作，以逆转年龄对肌肉干细胞数量的不利影响 并改善肌肉干细胞功能。为此，我们已经生成了大量的初步数据， 这强烈表明，与年龄相关的肌肉干细胞功能受损可能是由增加的 暴露在促炎环境中特别是，我们发现肌肉干细胞的老化是 并伴有多种炎症相关基因的诱导表达。此外，我们还发现， 异时共生可以诱导肌源性功能的恢复， 这些年龄调节的促炎靶标中的至少一些的表达正常化。 因此，本申请中描述的实验被设计为（1）更好地系统地理解本发明的方法。 在老年骨骼肌干细胞中发生的炎症基因的调节诱导，（2）检查是否 抑制炎症可以预防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 老年肌肉的慢性炎症。这些研究将使用完善的小鼠模型 已经提供给我们和细胞分离策略开创了我的实验室，并将提供一个坚实的基础， 临床扩展到人类年龄相关性肌肉疾病的新型治疗。

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.