AMPKα1 Deficiency in Macrophages Impairs Tendon Regeneration and Tendon Stem Cell Function via TNF-α-FBP2 Signaling

Tendon healing is limited by the minimal intrinsic regenerative capacity of the tissue, resulting in the formation of fibrovascular scar tissue rather than functional regeneration. Macrophage immunometabolism governs the balance between inflammation and repair; however, its effects on tendon regeneration are poorly understood. In this study, we investigated the differential activation of macrophage AMP-activated protein kinase (AMPK) and its phenotypic alterations in neonatal and adult tendon injury models. Using myeloid-specific AMPKα1 knockout (<i>LysM-Cre; Ampkα1^fl/fl</i> ) mice, we found that macrophage AMPKα1 deficiency impairs tendon regeneration and repair capacity, leading to compromised proliferation, migration, and differentiation functions of tendon stem/progenitor cells (TSPCs). Mechanistically, AMPKα1-deficient macrophages exhibited increased TNF-α production, which promoted the expression of Fructose-bisphosphatase 2 (FBP2) in a PI3K/AKT-dependent manner. In addition, FBP2 can modulate mitochondrial biogenesis and dynamics through a non-enzymatic mechanism and facilitate tissue repair and regeneration. Collectively, these findings underscore the immunometabolism mechanism linking macrophage AMPKα1 activity to stem cell injury responses via a TNF-α-FBP2 axis and provide new insights into the role of FBP2 for regulating stem cells.