Figure 5. Macrophages are involved in skeletal muscle regeneration.

Skeletal muscle is a highly vascularized tissue and endothelial cells are the main cell type of blood vessels. During muscle regeneration, endothelial cells release lactic acid, which directly controls macrophage function. Under lactic acid stimulation, pro-inflammatory macrophages differentiate into reparative macrophages, which secrete large amounts of vascular endothelial growth factor (VEGF), actively supporting muscle vascularization and forming a positive feedback pathway. VEGF also induces the proliferation and differentiation of myogenic progenitor cells (MPCs) in skeletal muscle. Muscle regeneration depends on the self-renewal of MPCs to replenish the muscle stem cell pool, and MPCs repair damaged muscle by differentiating and fusing with each other; following injury to skeletal muscle, membrane linked protein A1 (Annexin A1), which is secreted in large numbers by neutrophils, activates the FPR2/ALX receptor on the surface of macrophages and the downstream adenylate-activated protein kinase signaling (AMPK) pathway, promoting the conversion of pro-inflammatory macrophages to reparative macrophages.