Impact of Aging and Influenza Infection on Muscle Health

项目总结 流感(流感)感染是老年人死亡的主要原因。此外，重要的是，这是一种常见的 然而，对老年人的过度发病率、残疾和丧失独立性认识不足的因素。我们 最近发表的证据表明，流感感染与行动能力下降之间存在首个已知的病理生理联系 利用小鼠模型进行表演。尽管活动性流感感染局限于肺部，但有明显的 肌肉的功能减退和分子改变伴随着肌肉炎症和 萎缩基因和肌肉生长的正向调节因子下调。重要的是，流感感染的影响 在这些分子变化和整体功能衰退更加明显，并随着年龄的增长而延长。我们的 这份R21提案的主要目标是确定将肺部流感感染与 肌肉健康和功能能力。由于我们的数据不支持骨骼肌直接感染病毒，我们 相信系统性因素是流感导致肌肉萎缩的根源。因此，感染会产生系统性的 假设与流感相似的反应也会导致肌肉随着年龄的增长而减少。因此，这项提议 不仅将深入研究流感引起的肌肉萎缩背后的机制，而且还将深入探讨其他 炎症和/或感染导致的肌病和随年龄增长的残疾。确定潜在的机制 在流感引起的肌肉萎缩背后，我们将使用一种基于系统的公正的方法来检查 免疫反应与流感炎症、骨骼肌组织形态、肌肉的关系 功能和完整的肌肉转录组。相关因素和途径将利用体外成肌细胞进行验证 以及肌管培养和体内血清和/或细胞因子/趋化因子注射。最重要的科学 这一建议的前提是我们发表的研究表明，在流感期间肌肉萎缩加剧 随着年龄的增长而感染。我们认为，老年人在流感感染和感染期间挥之不去的全身炎症 肌肉对这种炎症的敏感性增加有助于增加肌肉局部的炎症，细胞 渗入和肌肉萎缩。我们的集成方法将测试这一假设，同时还会产生额外的 基于转录学和统计建模的无偏假设以确定驱动机制 流感导致肌肉萎缩的背后。了解负责的机制将指导预防性和 治疗措施。此外，这项研究具有发现高影响力的翻译的巨大潜力 这些发现将改善对感染流感的老年人的护理，并帮助他们在以后的生活中保持独立性。

PROJECT SUMMARY Influenza (flu) infection is a leading cause of death in the elderly. Additionally, and importantly, it is a common yet under-recognized contributor to excess morbidity, disability and loss of independence in the elderly. We recently published evidence of the first known pathophysiological link between flu infection and declining mobility performance utilizing a murine model. Despite that active flu infection is localized to the lungs, there are clear functional decrements and molecular alterations in the muscle with upregulation of muscle inflammation and atrophy genes and downregulation of positive regulators of muscle growth. Importantly, the impact of flu infection on these molecular changes and overall functional declines is more pronounced and prolonged with aging. Our primary goal in this R21 proposal is to identify specific mechanisms linking pulmonary flu infection to declines in muscle health and functional ability. Since our data does not support direct viral infection of skeletal muscle, we believe systemic factors are at the root of flu-induced muscle atrophy. Thus, infections that generate a systemic response comparable to flu would hypothetically also contribute to muscle loss with aging. Thus, this proposal will delve into mechanisms behind not only flu-induced muscle atrophy, but the underlying mechanisms of other inflammation and/or infection-induced myopathy and disability with aging. To identify potential mechanisms behind flu-induced muscle atrophy, we will employ an unbiased systems-based approach to examine the relationship between immune responses, flu-induced inflammation, skeletal muscle tissue morphology, muscle function, and full muscle transcriptome. Implicated factors and pathways will be verified utilizing in vitro myoblast and myotube cultures and in vivo serum and/or cytokine/chemokine injections. The overarching scientific premise of this proposal is based on our published study that demonstrated increased muscle atrophy during flu infection with aging. We believe that lingering systemic inflammation in aged individuals during flu infection and increased muscle sensitivity to this inflammation contributes to increased muscle-localized inflammation, cellular infiltration, and muscle atrophy. Our integrated approach will test this hypothesis, while also generating additional unbiased hypotheses based on transcriptomics and statistical modeling to determine the driving mechanism behind flu-induced muscle atrophy. Understanding mechanisms responsible will guide preventative and therapeutic measures. Furthermore, this study has significant potential to discover high impact translational findings that will improve care for flu-infected elderly and help them maintain their independence later in life.