Regulation of macrophage metabolism in aged muscle during recovery

摘要 在老年肌肉中废用性萎缩后的肌肉再生和功能显著受损，并且这 增加了福尔斯跌倒、长期残疾和丧失独立性的风险。治疗策略，以提高 肌肉恢复是不存在的，这是由于对再生过程中的细胞机制缺乏理解 老化的肌肉。肌肉巨噬细胞的侵袭和向促炎和抗炎状态的极化是 关键是促进肌肉干细胞功能和废用后肌肉和功能的完全解决。更 最近，巨噬细胞代谢已被证明与活化的巨噬细胞的炎症状态紧密相关， 巨噬细胞和调节转录因子，如HIF-1α和积累TCA中间体 如琥珀酸盐。我们的初步数据，在受损的老年肌肉在早期恢复支持减少 巨噬细胞琥珀酸和HIF-1α对应于减少的巨噬细胞糖酵解和炎症 程序和功能特性。因此，使用新的小鼠遗传和骨髓移植， 沿着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 衰老废用再生期间巨噬细胞代谢和炎症激活的调节步骤 肌肉，如果这种功能障碍是由老化的免疫系统引起的。在目标2中，我们将把临床前 研究结果对年轻人和老年人，并证实了我们的假设，通过广泛表征肌肉 废用恢复期间体内和体外巨噬细胞代谢和炎症功能状态 萎缩我们预计，这些发现将确定巨噬细胞代谢作为未来的目标，以加速 在废用相关事件后老化肌肉的恢复（例如，手术、疾病）。

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).