Fibrosis is associated with compromised muscle functionality in Duchenne muscular dystrophy (DMD). We report observations with tissues from dystrophic patients and mice supporting a model to explain fibrosis in DMD, which relies on the crosstalk between the complement and the WNT signaling pathways and the functional interactions of two cellular types. Fibro-adipogenic progenitors and macrophages, which populate the inflamed dystrophic muscles, act as a combinatorial source of WNT activity by secreting distinct subunits of the C1 complement complex. The resulting aberrant activation of the WNT signaling in responsive cells, such as fibro-adipogenic progenitors, contributes to fibrosis. Indeed, pharmacological inhibition of the C1r/s subunits in a murine model of DMD mitigated the activation of the WNT signaling pathway, reduced the fibrogenic characteristics of the fibro-adipogenic progenitors, and ameliorated the dystrophic phenotype. These studies shed new light on the molecular and cellular mechanisms responsible for fibrosis in muscular dystrophy and open to new therapeutic strategies.

中文翻译：

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营养不良性肌肉中不同补体亚基对 WNT 依赖性纤维形成程序的组合激活

纤维化与杜氏肌营养不良症 (DMD) 的肌肉功能受损有关。我们报告了对营养不良患者和小鼠组织的观察结果，支持解释 DMD 纤维化的模型，该模型依赖于补体和 WNT 信号通路之间的串扰以及两种细胞类型的功能相互作用。纤维脂肪祖细胞和巨噬细胞填充在发炎的营养不良性肌肉中，通过分泌 C1 补体复合物的不同亚基，充当 WNT 活性的组合来源。由此产生的反应性细胞（例如纤维脂肪形成祖细胞）中 WNT 信号传导的异常激活会导致纤维化。事实上，在 DMD 小鼠模型中对 C1r/s 亚基进行药理抑制可减轻 WNT 信号通路的激活，减少纤维脂肪祖细胞的纤维形成特征，并改善营养不良表型。这些研究为肌营养不良症纤维化的分子和细胞机制提供了新的线索，并为新的治疗策略开辟了道路。