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).

抽象的老化肌肉废用性萎缩后的肌肉再生和功能显着受损，这增加跌倒、长期残疾和丧失独立性的风险。由于对再生过程中的细胞机制了解不足，肌肉恢复不存在肌肉巨噬细胞的侵袭以及促炎和抗炎状态的极化。对于促进肌肉干细胞功能以及废弃后肌肉和功能的完全解决至关重要。最近，巨噬细胞代谢已被证明与活化的炎症状态紧密相关。巨噬细胞并受 HIF-1α 等转录因子和 TCA 中间体积累的调节例如琥珀酸，我们对早期恢复期间受损的老年肌肉的初步数据支持减少。巨噬细胞琥珀酸和 HIF-1α 对应于巨噬细胞糖酵解和炎症的减少因此，使用新型小鼠遗传和骨髓移植。实验以及化学方法和体外研究，我们将测试琥珀酸和 HIF-1α 是否是关键衰老废用再生过程中巨噬细胞代谢和炎症激活的调节步骤如果这种功能障碍是由老化的免疫系统引起的，那么在目标 2 中，我们将转化我们的临床前研究成果。对年轻人和老年人的研究结果，并通过主要表征肌肉来证实我们的假设废用恢复期间体内和体外巨噬细胞代谢和炎症功能状态我们预计这些发现将确定巨噬细胞代谢作为加速萎缩的未来目标。废用相关事件（例如手术、疾病）后老化肌肉的恢复。