Absence of complement factor H reduces physical performance in C57BL6 mice

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.