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Updated: Dec 8, 2025
Assessing Functional Performance in the Mdx Mouse Model
Published on: March 27, 2014
Absence of complement factor H reduces physical performance in C57BL6 mice
Kenneth L Seldeen1, Ramkumar Thiyagarajan1, Yonas Redae2
1Geriatrics and Palliative Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
Insights
Factor H (FH) deficiency dysregulates the complement system, impairing skeletal muscle function and architecture. Downstream C5a/C5aR signaling partially mediates this FH-dependent muscle pathology.
Area of Science:
- Immunology
- Muscle Biology
- Physiology
Background:
- The complement (C) system is crucial for innate immunity but can exacerbate disease when dysregulated.
- Uncontrolled C activation impacts various organs, including muscle regeneration.
- The role of factor H (FH), a key regulator of the alternative C pathway, in muscle health is largely unstudied.
Purpose of the Study:
- To investigate the role of FH and C5a/C5aR signaling in skeletal muscle architecture and function.
- To explore the impact of the alternative C pathway on muscle dysfunction using FH knockout models.
Main Methods:
- Utilized FH knockout (fh-/-) and FH/C5aR double knockout (DKO) mice.
- Assessed physical performance through grip endurance, grip strength, and rotarod balance tests.
- Conducted histological analysis of muscle fiber types, mitochondrial markers (mtDNA, CS), TGFβ expression, and cytoskeletal proteins (actin, vimentin).
Main Results:
- FH deficiency led to significant C3 and C9 deposition in muscle fibers, indicating uncontrolled C activation.
- fh-/- mice exhibited reduced physical performance and a shift towards glycolytic MHC IIB fibers with decreased oxidative MHC IIA fibers.
- Mitochondrial biomass indicators (mtDNA, CS) and cytoskeletal protein organization were altered, alongside increased TGFβ expression.
- Muscle pathology was partially ameliorated in DKO mice, suggesting C5aR involvement.
Conclusions:
- FH plays a critical role in maintaining skeletal muscle health and physical performance.
- Dysregulation of the alternative C pathway, driven by FH deficiency, contributes to muscle dysfunction.
- C5a/C5aR signaling is a partially involved pathway in FH-dependent muscle pathology.
Abstract:
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.
