Reversing age-related dysfunction of skeletal muscle stem cells

描述（由申请人提供）：骨骼肌减少症，或与年龄相关的骨骼肌损失，部分是由于身体在损伤后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。基于骨骼肌减少症的实验模型，炎症很可能是由NF-kappaB信号机制调节的。随着时间的推移，这种慢性炎症可能会导致骨骼肌干细胞（SMPs）的功能损伤和骨骼肌修复的缺陷，从而导致骨骼肌损失。提出的研究旨在进一步表征暂时调节的基因和途径，这些基因和途径可以在肌肉中被操纵，以逆转年龄对SMPs的有害影响。第一个具体目标将集中于评估NF-kappaB活性的增加以及老年SMPs中炎症基因表达的增加。具体来说，通过FACS分选纯化的SMPs将被老化并分析与年轻对照相比的NF-kappaB活性、炎症基因表达和肌生成电位的相关变化。这一目标将确定骨骼肌干细胞损伤随衰老发生的可能途径，并进一步表征NF-kappaB在这一过程中的作用。该项目的第二个目的是确定抑制NF-kappaB是否可以逆转或限制年龄相关的smp损伤。通过利用转基因和药物手段，本目的建议使用一个成熟的小鼠肌肉减少症模型来评估是否可以通过抑制NF-kappaB介导的炎症来保护整体骨骼肌功能和SMP增殖潜力。根据以往的研究，假设逆转与肌肉衰老相关的慢性炎症将保持SMP的增殖潜力和骨骼肌的质量和功能。相关性：与年龄相关的肌肉损失是老年人功能损伤的主要来源，并导致独立性、日常生活活动能力和损伤后恢复能力下降。通过确定逆转或限制年龄相关肌肉损失的方法，老年人可以保持独立性，从受伤/住院中恢复得更快，并且总体上需要更少的医疗资源。

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.