Metabolic reprogramming of skeletal muscle by resident macrophages points to CSF1R inhibitors as muscular dystrophy therapeutics (scRNA-Seq).

The role of tissue resident macrophages during tissue regeneration or fibrosis is not well-understood, mainly due to the lack of a specific marker for their identification. Here, we identified two populations of skeletal muscle resident macrophages: TIM4- macrophages which are replenished from the blood and LYVE1+TIM4+ macrophages that locally self-renew (self-renewing resident macrophages, SRRMs). Using a CSF1R inhibition/withdrawal approach to specifically deplete SRRMs, we found that they provide a non-redundant function in clearing damage-induced apoptotic cells early after extensive acute injury. In contrast, in chronic mild injury as seen in a mouse model of Duchenne muscular dystrophy, we showed that depletion of both resident populations through long term CSF1R inhibition changes muscle fiber composition from damage-sensitive glycolytic fibers towards damage-resistant glycolytic-oxidative fibers protecting muscle against contraction induced injury. This later finding reveals a new role for resident macrophages in modulating tissue metabolism and has therapeutic potential in light of the ongoing clinical testing of CSF1R inhibitors. Overall design: Characterization of skeletal muscle resident macroophages; identification of their role in muscle regeneration and fibrosis;

组织驻留巨噬细胞在组织再生或纤维化进程中的作用尚未明确，这主要源于缺乏可用于其鉴定的特异性标志物。
本研究中，我们鉴定出两类骨骼肌驻留巨噬细胞：一类是可由血液补充的TIM4-巨噬细胞，另一类是可局部自我更新的LYVE1+TIM4+巨噬细胞（自我更新型驻留巨噬细胞，SRRMs）。通过采用集落刺激因子1受体（CSF1R）抑制/撤除策略特异性清除SRRMs，我们发现其在广泛急性损伤早期可清除损伤诱导的凋亡细胞，发挥非冗余功能。与之相反，在杜氏肌营养不良症小鼠模型所模拟的慢性轻度损伤场景下，我们证实通过长期CSF1R抑制同时清除两类驻留巨噬细胞群后，肌纤维组成会从损伤敏感型糖酵解纤维转向损伤耐受型糖酵解-氧化混合型纤维，进而保护肌肉免受收缩诱导的损伤。这一发现揭示了驻留巨噬细胞在调控组织代谢方面的全新作用，鉴于当前CSF1R抑制剂正处于临床测试阶段，该研究成果具有潜在治疗价值。
整体实验设计：骨骼肌驻留巨噬细胞的特征鉴定；其在肌肉再生与纤维化过程中的作用探究；