Complement C3a signaling facilitates skeletal muscle regeneration by regulating monocyte function and trafficking

Area of Science:

• Immunology
• Muscle Biology
• Regenerative Medicine

Background:

• Skeletal muscle regeneration after injury involves a complex inflammatory response.
• The role of the complement system in this process remains largely undefined.

Purpose of the Study:

• To investigate the role of complement activation in skeletal muscle regeneration.
• To elucidate the specific complement components and pathways involved in muscle repair.

Main Methods:

• Utilized mouse models with genetic ablation or pharmacological inactivation of complement components (C3, Cfb, C3aR).
• Induced skeletal muscle injury using cardiotoxin.
• Assessed muscle regeneration, inflammatory cell infiltration, and monocyte/macrophage function via molecular and cellular assays.
• Administered recombinant CCL5 to rescue regeneration defects.

Main Results:

• Genetic or pharmacological blockade of complement C3 impaired skeletal muscle regeneration.
• The alternative pathway and complement C3a receptor (C3aR) signaling were critical for regeneration.
• C3aR deficiency led to reduced monocyte/macrophage infiltration and altered their functional gene expression.
• CCL5 administration rescued regeneration defects in C3aR-deficient mice.

Conclusions:

• Complement C3a plays a significant role in skeletal muscle regeneration by regulating inflammatory cell recruitment and function.
• Targeting the complement system, particularly C3aR signaling, presents a potential therapeutic strategy for muscle injury and regeneration.