The effects of exercise on fibro-adipogenic progenitors (FAPs) are unclear, and the direct molecular link is still unknown. In this study, we reveal that exercise reduces the frequency of FAPs and attenuates collagen deposition and adipose formation in injured or disused muscles through Musclin. Mechanistically, Musclin inhibits FAP proliferation and promotes apoptosis in FAPs by upregulating FILIP1L. Chromatin immunoprecipitation (ChIP)-qPCR confirms that FoxO3a is the transcription factor of FILIP1L. In addition, the Musclin/FILIP1L pathway facilitates the phagocytosis of apoptotic FAPs by macrophages through downregulating the expression of CD47. Genetic ablation of FILIP1L in FAPs abolishes the effects of exercise or Musclin on FAPs and the benefits on the reduction of fibrosis and fatty infiltration. Overall, exercise forms a microenvironment of myokines in muscle and prevents the abnormal accumulation of FAPs in a Musclin/FILIP1L-dependent manner. The administration of exogenous Musclin exerts a therapeutic effect, demonstrating a potential therapeutic approach for muscle atrophy or acute muscle injury.

中文翻译：

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运动诱导的肌肉蛋白决定纤维脂肪祖细胞的命运以控制肌肉稳态

运动对纤维脂肪祖细胞（FAP）的影响尚不清楚，直接的分子联系仍不清楚。在这项研究中，我们发现运动可以通过 Musclin 降低 FAP 的频率，并减少受伤或废弃肌肉中的胶原蛋白沉积和脂肪形成。从机制上讲，Musclin 通过上调 FILIP1L 抑制 FAP 增殖并促进 FAP 凋亡。染色质免疫沉淀 (ChIP)-qPCR 证实 FoxO3a 是 FILIP1L 的转录因子。此外，Musclin/FILIP1L 通路通过下调 CD47 的表达促进巨噬细胞对凋亡 FAP 的吞噬。FAP 中 FILIP1L 的基因消除消除了运动或 Musclin 对 FAP 的影响以及减少纤维化和脂肪浸润的益处。总体而言，运动在肌肉中形成肌因子的微环境，并以 Musclin/FILIP1L 依赖性方式防止 FAP 的异常积累。外源性 Musclin 的施用发挥了治疗作用，证明了肌肉萎缩或急性肌肉损伤的潜在治疗方法。