Muscle regeneration is sustained by infiltrating macrophages and the consequent activation of satellite cells 1 – 4 . Macrophages and satellite cells communicate in different ways 1 – 5 , but their metabolic interplay has not been investigated. Here we show, in a mouse model, that muscle injuries and ageing are characterized by intra-tissue restrictions of glutamine. Low levels of glutamine endow macrophages with the metabolic ability to secrete glutamine via enhanced glutamine synthetase (GS) activity, at the expense of glutamine oxidation mediated by glutamate dehydrogenase 1 (GLUD1). Glud1 -knockout macrophages display constitutively high GS activity, which prevents glutamine shortages. The uptake of macrophage-derived glutamine by satellite cells through the glutamine transporter SLC1A5 activates mTOR and promotes the proliferation and differentiation of satellite cells. Consequently, macrophage-specific deletion or pharmacological inhibition of GLUD1 improves muscle regeneration and functional recovery in response to acute injury, ischaemia or ageing. Conversely, SLC1A5 blockade in satellite cells or GS inactivation in macrophages negatively affects satellite cell functions and muscle regeneration. These results highlight the metabolic crosstalk between satellite cells and macrophages, in which macrophage-derived glutamine sustains the functions of satellite cells. Thus, the targeting of GLUD1 may offer therapeutic opportunities for the regeneration of injured or aged muscles. Mouse models of muscle injuries and ageing characterized by low levels of intra-tissue glutamine are ameliorated by macrophage-specific deletion or systemic pharmacological inhibition of glutamate dehydrogenase 1, which results in constitutively high activity of glutamine synthetase.

中文翻译：

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巨噬细胞衍生的谷氨酰胺促进卫星细胞和肌肉再生

肌肉再生是通过浸润巨噬细胞和随之而来的卫星细胞 1-4 的激活来维持的。巨噬细胞和卫星细胞以不同的方式进行通信 1 – 5 ，但尚未研究它们的代谢相互作用。在这里，我们在小鼠模型中展示了肌肉损伤和衰老的特征在于谷氨酰胺的组织内限制。低水平的谷氨酰胺赋予巨噬细胞通过增强的谷氨酰胺合成酶 (GS) 活性分泌谷氨酰胺的代谢能力，以谷氨酸脱氢酶 1 (GLUD1) 介导的谷氨酰胺氧化为代价。Glud1 基因敲除巨噬细胞显示出高 GS 活性，可防止谷氨酰胺短缺。卫星细胞通过谷氨酰胺转运蛋白 SLC1A5 摄取巨噬细胞来源的谷氨酰胺激活 mTOR 并促进卫星细胞的增殖和分化。因此，GLUD1 的巨噬细胞特异性缺失或药理抑制可改善肌肉再生和功能恢复，以应对急性损伤、缺血或衰老。相反，卫星细胞中的 SLC1A5 阻断或巨噬细胞中的 GS 失活会对卫星细胞功能和肌肉再生产生负面影响。这些结果突出了卫星细胞和巨噬细胞之间的代谢串扰，其中巨噬细胞衍生的谷氨酰胺维持卫星细胞的功能。因此，GLUD1 的靶向可能为受伤或老化肌肉的再生提供治疗机会。