Regulation of macrophage metabolism in aged muscle during recovery

摘要 老年肌肉废用性萎缩后的肌肉再生和功能明显受损，这 增加跌倒、长期残疾和丧失独立性的风险。治疗策略以增强 肌肉恢复是不存在的，源于对再生过程中的细胞机制缺乏了解 在老化的肌肉中。肌肉巨噬细胞的入侵以及对促炎和抗炎状态的极化是 对促进肌肉干细胞功能以及停用后肌肉和功能的完全分解至关重要。更多 最近，巨噬细胞的新陈代谢被证明与炎症状态密切相关。 巨噬细胞受HIF-1α等转录因子的调控和三氯乙酸中间体的积聚 如琥珀酸。我们在早期康复期间受损的衰老肌肉的初步数据支持减少 巨噬细胞琥珀酸和低氧诱导因子-1α对应的巨噬细胞糖酵解和炎症反应减少 程序和功能特点。因此，利用新颖的小鼠基因和骨髓移植 实验，以及化学方法和体外研究，我们将测试琥珀酸和缺氧诱导因子-1α是否是关键 老化废弃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衰老的免疫系统引起的。在目标2中，我们将把我们的临床前 对年轻人和老年人的发现，并通过广泛地表征肌肉来证实我们的假设 停用后恢复过程中巨噬细胞在体内和体外的代谢和炎症功能状态 萎缩。我们预计，这些发现将把巨噬细胞代谢确定为未来加速 在停用相关事件(如手术、疾病)后，老化肌肉的恢复。

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).