Reversing age-related dysfunction of skeletal muscle stem cells

描述(申请人提供)：多细胞生物体的衰老通常涉及身体维持体内平衡细胞替代和损伤后再生组织和器官的能力的进行性下降。尤其是骨骼肌，在成年生活的大部分时间里都能旺盛地再生，但在老年时却无法做到这一点。年龄获得性肌肉功能缺陷深刻影响老年人的健康，导致老年人与年龄相关的肌肉退化(骨质疏松症)的发生率很高，老年人的受伤恢复效率低下或不完全。人们对衰老如何导致肌肉功能恶化知之甚少，但包括我的实验室的初步数据在内的几条证据表明，骨骼肌干细胞的丢失或功能障碍直接导致了组织修复中与年龄相关的失败。根据这些数据，这一应用的主要焦点是识别衰老肌肉中可以操纵的年龄调节基因和途径，以逆转年龄对肌肉干细胞数量的不利影响，并改善肌肉干细胞的功能。为此，我们产生了大量的初步数据，这些数据有力地表明，与年龄相关的肌肉干细胞功能损害可能是通过增加对促炎环境的暴露而调节的。特别是，我们发现肌肉干细胞的老化伴随着多种炎症相关基因的诱导表达。此外，我们还发现，异慢性异种共生可以诱导肌原功能的恢复，伴随着至少部分这些受年龄调节的促炎靶点的正常表达。因此，本申请中描述的实验旨在(1)更好地了解老年骨骼肌干细胞中发生的炎症基因的系统调控诱导，(2)检查抑制炎症是否可以防止或逆转与年龄相关的肌肉干细胞增殖和肌肉再生功能抑制，以及(3)确定最终导致老年肌肉慢性炎症增强的生理机制(S)。这些研究将使用我们已有的成熟的小鼠模型和我的实验室开创的细胞分离策略，并将为临床推广到治疗人类年龄相关肌肉疾病的新疗法提供坚实的基础。公共卫生相关性：我们在小鼠身上的数据表明，肌肉干细胞的进行性丧失和功能失调是老年肌肉退化的重要潜在原因。因此，在这些研究中，我们将使用遗传和生化方法来确定肌肉干细胞年龄相关功能障碍的介体，以及可以恢复其年轻功能的因素。这项工作为阻止和潜在地逆转肌肉再生功能中与年龄相关的缺陷带来了巨大的希望。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Our data in mice suggest that progressive loss of muscle stem cells and dysregulation of their function is an important underlying cause of muscle deterioration in old age. Therefore, in these studies, we will use genetic and biochemical approaches to identify the mediators of age-associated dysfunction of muscle stem cells, as well as factors that can restore their "youthful" function. This work holds tremendous promise for halting and potentially reversing age-related defects in muscle regenerative function.