PAI-1 regulates extracellular matrix remodeling and alters fibroblast profibrotic ability in skeletal muscle repair

Excessive accumulation of extracellular matrix (ECM) and fibrosis severely impair skeletal muscle function, underscoring the urgent need to explore new strategies for improving muscle regeneration. Fibroblasts, as the primary source of ECM in skeletal muscle, can trigger persistent ECM deposition when aberrantly activated. Here, we identify a pivotal role for plasminogen activator inhibitor type-1 (PAI-1) in modulating fibroblast profibrotic activity and ECM remodeling. Our results show that PAI-1 expression rises at the early stages of muscle repair, and pharmacologic inhibition of PAI-1 increases transient ECM deposition. In vitro, PAI-1 inhibition promotes fibroblast proliferation, activation, and ECM production partly via the Notch signaling pathway, a finding further supported by in vivo evidence of early Notch activation in PAI-1–inhibited muscle. These insights reveal an expanded function for PAI-1 in regulating the behavior of muscle fibroblasts beyond its well-known fibrinolytic role, providing a promising therapeutic avenue for enhancing muscle regeneration and preserving muscle homeostasis.