Reversing age-related dysfunction of skeletal muscle stem cells

描述（由申请人提供）：肌肉减少症，或年龄相关的骨骼肌损失，部分原因是由于受伤后身体再生骨骼肌的能力逐渐下降。一些证据表明，肌肉减少症可能与慢性肌肉特异性炎症有关。基于肌肉减少症的实验模型，炎症最有可能由NF-κ B信号传导机制调节。这种慢性炎症可能通过引起骨骼肌干细胞（SMP）的功能障碍和骨骼肌修复的缺陷而导致骨骼肌随时间推移而丧失。这项研究旨在进一步表征可以在肌肉中操纵的时间调节基因和途径，以逆转年龄对SMP的不利影响。第一个具体目标将集中在评估老年SMP中NF-κ B活性以及炎症基因表达的增加。具体而言，将通过FACS分选纯化的SMP老化并分析NF-κ B活性、炎性基因表达和与年轻对照相比的肌生成潜能的相关变化。这一目标将确定骨骼肌干细胞损伤与衰老发生的可能途径，并进一步表征NF-κ B在这一过程中的作用。该项目的第二个目的是确定抑制NF-κ B是否可以逆转或限制与年龄相关的SMP损伤。通过利用转基因和药理学手段，该目的提出使用完善的肌肉减少症小鼠模型来评估是否可以通过抑制NF-κ B介导的炎症来保护整体骨骼肌功能和SMP增殖潜力。基于先前的研究，假设逆转与肌肉老化相关的慢性炎症将保留SMP增殖潜力和骨骼肌质量和功能。相关性：肌肉萎缩相关的肌肉损失是老年人群中功能障碍的主要来源，并导致独立性降低，日常生活活动能力降低，以及损伤后的恢复。通过确定逆转或限制与年龄相关的肌肉损失的方法，老年人可以保持他们的独立性，从受伤/住院中更快地恢复，并且总体上需要更少的医疗保健资源。

DESCRIPTION (provided by applicant): Sarcopenia, or age-related skeletal muscle loss, is In part due to a progressive decline in the body's ability to regenerate skeletal muscle following injury. Several lines of evidence suggest that sarcopenia may be related to chronic, muscle specific inflammation. Based on experimental models of sarcopenia, the inflammation is most likely regulated by NF-kappaB signaling mechanisms. This chronic inflammation may contribute to skeletal muscle loss over time by causing a functional impairment of skeletal muscle stem cells (SMPs) and a resultant deficit in skeletal muscle repair. The proposed study aims to further characterize temporally-regulated genes and pathways which can be manipulated in muscle to reverse the detrimental effects of age on SMPs. The first specific aim will focus on evaluating increases in NF-kappaB activity as well as inflammatory gene expression in aged SMPs. Specifically, SMPs, purified by FACS sorting, will be aged and analyzed for NF-kappaB activity, inflammatory gene expression, and correlate changes in myogenic potential in comparison to young controls. This aim will identify possible pathways by which skeletal muscle stem cell impairment occurs with aging and further characterize the role of NF-kappaB in this process. The second aim of this project is to determine if inhibition of NF-kappaB can reverse or limit age-associated impairment of SMPs. By utilizing both transgenic and pharmacologic means, this aim proposes to use a well-established mouse model of sarcopenia to evaluate if overall skeletal muscle function and SMP proliferative potential can be protected by inhibiting NF-kappaB mediated inflammation. Based on previous studies, it is hypothesized that reversing the chronic inflammation associated with muscle aging will preserve SMP proliferative potential and skeletal muscle mass and function. Relevance: Age-associated muscle loss is a major source of functional impairment in the elderly population and leads to decreased independence, ability to perform activities of daily living, and recovery following injury. By identifying methods to reverse or limit age associated muscle loss, the elderly population may keep their independence, recover quicker from injuries/hospitalizations, and overall require fewer healthcare resources.