Regulation of macrophage metabolism in aged muscle during recovery

衰老肌肉恢复过程中巨噬细胞代谢的调节

基本信息

批准号：
10460028
负责人：
Micah J Drummond
金额：
$ 62.69万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10460028
关键词：
Adopted Aging Anti-Inflammatory Agents Attenuated Automobile Driving Bone Marrow Bone Marrow Cell Transplantation Bone Marrow Cells Bone Marrow Transplantation Cell physiology Cells Characteristics Chemicals Citric Acid Cycle Coupled Data Defect Development Disuse Atrophy Elderly Enzymes Event Exhibits Fibrosis Functional disorder Future Genetic Genetic Transcription Glycolysis Growth Factor Health Hematopoietic Hindlimb Suspension Human Immobilization Immune system Impairment In Vitro Individual Inflammation Inflammatory Inflammatory Response Interleukin-1 beta Interruption Knowledge Lead Limb structure Literature Macrophage Activation Mediating Metabolic Metabolic Diseases Metabolism Methodology Mus Muscle Muscle function Muscle satellite cell Operative Surgical Procedures Oxidative Phosphorylation Phenotype Recovery Recovery Support Regulation Resolution Rodent Role Serum Skeletal Muscle Stimulus Succinates Suggestion Testing Therapeutic Transcript Translating age related aged bone aging cytokine disability experimental study extracellular fall risk falls hypoxia inducible factor 1 in vivo macrophage mitochondrial dysfunction mouse genetics mouse model muscle aging muscle regeneration novel pre-clinical precursor cell prevent programs reduced muscle mass response restoration sarcopenia single-cell RNA sequencing stem stem cell function therapeutic development transcription factor transcriptome young adult

项目摘要

Abstract Muscle regrowth and function following disuse atrophy in aged muscle is significantly compromised, and this increases the risk for falls, long-term disability and loss of independence. Therapeutic strategies to enhance muscle recovery are non-existent stemming from a poor understanding of cellular mechanism during regrowth in aging muscle. Invasion of muscle macrophages and polarization to pro- and anti-inflammatory states are critical to promote muscle stem cell function and the full resolution of muscle and function following disuse. More recently, macrophage metabolism has been shown to be tightly coupled to the inflammatory state of activated macrophages and regulated by transcription factors such as HIF-1α and accumulation of TCA intermediates such as succinate. Our preliminary data in impaired aged muscle during early recovery supports decreased macrophage succinate and HIF-1α corresponding to a reduced macrophage glycolytic and inflammatory program and functional characteristics. Therefore, using novel mouse genetic and bone marrow transfer experiments, along with chemical approaches and in vitro studies, we will test if succinate and HIF-1α are key regulatory steps for macrophage metabolic and inflammatory activation during regrowth from disuse in aging muscle and if this dysfunction arises from an aged immune system. In Aim 2, we will translate our pre-clinical findings to young and older humans and confirm our hypothesis by extensively characterizing muscle macrophage metabolic and inflammatory functional states in vivo and in vitro during recovery from disuse atrophy. We anticipate that the findings will identify macrophage metabolism as a future target to accelerate the recovery of aged muscle following disuse related events (e.g., surgery, illness).

抽象的老年肌肉中废除萎缩后的肌肉后悔和功能受到了严重损害，这增加了跌倒，长期残疾和独立丧失的风险。增强治疗策略肌肉恢复是不存在的，这是由于对谣言中细胞机制的理解不足在衰老的肌肉中。肌肉巨噬细胞的侵袭以及对促和抗炎状态的极化是促进肌肉干细胞功能以及废弃后肌肉和功能的全部分辨率至关重要。更多的最近，巨噬细胞代谢已被证明与激活的炎症状态紧密耦合巨噬细胞和受转录因子（例如HIF-1α和TCA中间体的积累）调节例如琥珀酸酯。我们在早期恢复支持期间老年肌肉受损的初步数据下降了巨噬细胞琥珀酸酯和HIF-1α对应于降低的巨噬细胞糖酵解和炎症程序和功能特征。因此，使用新型的小鼠遗传和骨髓转移实验，以及化学方法和体外研究，我们将测试琥珀酸酯和HIF-1α是否是关键巨噬细胞代谢和炎症激活的调节步骤在衰老中遗憾期间肌肉，如果这种功能障碍来自老年免疫系统。在AIM 2中，我们将翻译我们的临床前对年轻人和年龄较大的人的发现，并通过广泛表征肌肉来证实我们的假设巨噬细胞代谢和炎症功能状态在体内和体外恢复中恢复萎缩。我们预计这些发现将确定巨噬细胞代谢是加速的未来目标废弃相关事件后，恢复老年肌肉（例如，手术，疾病）。