Activating proteostasis in aging resident macrophages to prevent muscle and cognitive dysfunction after pneumonia

项目总结 老年肺炎幸存者患骨骼肌萎缩的风险增加，这种萎缩损害了行动能力， 痴呆症和认知功能障碍，这可能是最令人衰弱的限制健康跨度在 老年人。我们在小鼠身上发现了肺炎后这种多器官功能障碍的关键特征， 使我们能够使用小鼠模型来阐明可以作为治疗靶点的机制。在第一个周期中 这个奖项，我们发现，在甲型流感引起的肺炎期间，系统性增加IL-6对于 E3-泛素连接酶阿托金-1的上调与幼年和老年动物的肌肉萎缩。而当 幼年动物的肌肉功能迅速恢复，我们从未观察到年长动物的肌肉功能恢复 肺炎之后的几个月。我们观察到肌肉修复所必需的肌肉卫星细胞无法增殖。 在老年动物肺炎后，但在幼年动物中不是，这与表达减少有关 清道夫受体MerTK。年轻人吞噬功能所需基因(MerTK、C3、CX3CR1)的遗传破坏 老年动物表现为甲型流感肺炎后卫星细胞增殖受损。在……里面 在大脑中进行的平行研究中，我们发现，尽管幼鼠在感染A型流感后恢复了认知功能， 年龄较大的动物会出现持续性的神经认知障碍。高灵敏的Flow转录图谱分析 分选的小胶质细胞显示，衰老的小胶质细胞包括MerTK在内的清道夫受体的表达减少。 这与与轴突发生、学习和记忆相关的基因整体表达减少有关 甲型流感肺炎后老年动物与幼年动物脑转录的比较。组织 幼年小鼠的常驻肌肉巨噬细胞和小胶质细胞有力地激活了整合的应激反应 甲型流感感染后激活转录因子-4(ATF4)表达增加 和分子伴侣，但衰老的小鼠缺乏这种反应。 这些初步数据支持我们的假设，即与年龄相关的清道夫受体功能丧失会损害 骨骼分子和生理恢复所必需的组织驻留巨噬细胞的吞噬作用 肺炎后的肌肉和认知功能。我们将确定这些与年龄相关的变化是否会 通过ISR和/或ATF4在两个相互关联的特定目的中抑制线粒体复合体I而逆转： 目的：1.为了确定常驻骨骼肌巨噬细胞的清道夫受体活性和 小胶质细胞，是甲型流感后认知和骨骼肌功能恢复所必需的。 诱发性肺炎。 目的2.确定线粒体代谢的调节，即综合应激反应 和/或ATF4可恢复小胶质细胞和骨骼肌巨噬细胞的清道夫功能 改善肺炎后老龄小鼠的认知和运动功能。

PROJECT SUMMARY Elderly pneumonia survivors are at increased risk of developing skeletal muscle atrophy that impairs mobility, dementia, and cognitive dysfunction, which are perhaps the most debilitating limitations to health-span in the elderly. We found critical features of this multiple organ dysfunction after pneumonia are recapitulated in mice, allowing us to use mouse models to elucidate mechanisms that can be targeted for therapy. In the first cycle of this award, we found that a systemic increase in IL-6 during influenza A-induced pneumonia was necessary for upregulation of the E3-ubiquitin ligase atrogin-1 and muscle wasting in both young and aged animals. While muscle function was rapidly restored in young animals, we never observed it to recover in older animals even months after pneumonia. We observed that muscle satellite cells necessary for muscle repair failed to proliferate after pneumonia in aged, but not in young animals, which was associated with decreased expression of the scavenger receptor Mertk. Genetic disruption of genes required for phagocytosis (Mertk, C3, Cx3cr1) in young animals phenocopied the impaired satellite cell proliferation after influenza A pneumonia in aged animals. In parallel studies in the brain, we found that while young mice recover cognitive function after influenza A infection, older animals develop persistent neurocognitive impairment. Highly sensitive transcriptomic profiling of flow sorted microglia showed aged microglia exhibited decreased expression of scavenger receptors, including Mertk. This was associated with reduced expression of genes related to axonogenesis, learning and memory in whole brain transcriptomes from aged compared with young animals after influenza A-induced pneumonia. Tissue resident muscle macrophages and microglia from young mice robustly activated the integrated stress response (ISR) after influenza A infection as evidenced by increased expression of Activating Transcription Factor-4 (Atf4) and molecular chaperones, but aged mice lacked this response. These preliminary data support our hypothesis that age-related loss of scavenger receptor function impairs phagocytosis in tissue resident macrophages necessary for the molecular and physiologic recovery of skeletal muscle and cognitive function after pneumonia. We will determine whether these age-related changes can be reversed by inhibition of mitochondrial complex I via the ISR and/or ATF4 in two interrelated specific aims: Aim1. To determine whether scavenger receptor activity in resident skeletal muscle macrophages and microglia and is necessary for the recovery of cognitive and skeletal muscle function after influenza A- induced pneumonia. Aim 2. To determine whether modulation of mitochondrial metabolism, the integrated stress response and/or ATF4 can restore scavenger function of the microglia and skeletal muscle macrophages to improve cognitive and motor function in aged mice after pneumonia.