Complement (C) system is a double edge sword acting as the first line of defense on the one hand and causing aggravation of disease on the other. C activation when unregulated affects different organs including muscle regeneration. However, the effect of factor H (FH), a critical regulator of the alternative C pathway in muscle remains to be studied. FH deficiency results in excessive C activation and generates proinflammatory fragments C5a and C3a as byproducts. C3a and C5a signal through their respective receptors, C5aR and C3aR. In this study, we investigated the role of FH and downstream C5a/C5aR signaling in muscle architecture and function. Using the FH knockout (fh-/-) and fh-/-/C5aR-/double knockout mice we explored the role of C, specifically the alternative C pathway in muscle dysfunction. Substantial C3 and C9 deposits occur along the walls of the fh-/- muscle fibers indicative of unrestricted C activation. Physical performance assessments of the fh-/- mice show reduced grip endurance (76 %), grip strength (14 %) and rotarod balance (36 %) compared to controls. Histological analysis revealed a shift in muscle fiber populations indicated by an increase in glycolytic MHC IIB fibers and reduction in oxidative MHC IIA fibers. Consistent with this finding, mitochondrial DNA (mtDNA) and citrate synthase (CS) expression were both reduced indicating possible reduction in mitochondrial biomass. In addition, our results showed a significant increase in TGFβ expression and altered TGFβ localization in this setting. The architecture of cytoskeletal proteins actin and vimentin in the fh-/- muscle was changed that could lead to contractile weakness and loss of skeletal muscle elasticity. The muscle pathology in fh-/- mice was reduced in fh-/-/C5aR-/- double knockout (DKO) mice, highlighting partial C5aR dependence. Our results for the first time demonstrate an important role of FH in physical performance and skeletal muscle health.

补体（C）系统是一把双刃剑，一方面充当第一道防线，另一方面导致疾病加重。不受管制时的 C 激活会影响不同的器官，包括肌肉再生。然而，H 因子 (FH) 是肌肉中替代 C 通路的关键调节因子，其作用仍有待研究。FH 缺乏导致 C 过度活化并产生促炎片段 C5a 和 C3a 作为副产物。C3a 和 C5a 通过它们各自的受体 C5aR 和 C3aR 发出信号。在这项研究中，我们研究了 FH 和下游 C5a/C5aR 信号在肌肉结构和功能中的作用。使用 FH 敲除 (fh-/-) 和 fh-/-/C5aR-/双敲除小鼠，我们探索了 C 的作用，特别是肌肉功能障碍中的替代 C 通路。大量的 C3 和 C9 沉积物沿着 fh-/- 肌纤维的壁发生，表明 C 激活不受限制。与对照组相比，fh-/- 小鼠的身体性能评估显示握力耐力 (76%)、握力 (14%) 和转杆平衡 (36%) 降低。组织学分析显示，糖酵解 MHC IIB 纤维增加和氧化 MHC IIA 纤维减少表明肌纤维数量发生了变化。与这一发现一致，线粒体 DNA (mtDNA) 和柠檬酸合酶 (CS) 表达均降低，表明线粒体生物量可能减少。此外，我们的结果显示在此设置中 TGFβ 表达显着增加并改变 TGFβ 定位。fh-/- 肌肉中细胞骨架蛋白肌动蛋白和波形蛋白的结构发生改变，可能导致收缩无力和骨骼肌弹性丧失。fh-/- 小鼠的肌肉病理学在 fh-/-/C5aR-/- 双敲除 (DKO) 小鼠中减少，突出部分 C5aR 依赖性。我们的结果首次证明 FH 在身体表现和骨骼肌健康中的重要作用。