Skeletal muscle fibrosis frequently occurs in severe muscle injuries, muscular dystrophies and aging process, leading to profound muscle weakness and heightened vulnerability to re-injury [[1], [2], [3]]. While the extracellular matrix (ECM) is essential for supporting activated resident cells and new myofiber formation, excessive ECM deposition can shift normal muscle regeneration toward pathological fibrotic tissue. [4,5]. Indeed, regenerative fibrogenesis and fibrosis share many of the same cellular players, and fibrosis develops when the balance between ECM synthesis and degradation becomes dysregulated [6]. Fibroblasts are central to this process by producing a broad range of ECM components—such as collagen, fibronectin, and proteoglycans—and can arise from fibroadipogenic progenitors (FAPs) or potentially from myogenic cells. [[7], [8], [9], [10], [11]]. Because fibroblasts serve as key ECM producers, therapeutic strategies that modulate fibroblast behavior are vital to combating muscle fibrosis.

Plasminogen activator inhibitor type-1 (PAI-1, encoded by the Serpine1 gene), a fast-acting inhibitor of urokinase-type (uPA) and tissue-type plasminogen activator (tPA), helps control ECM turnover through its regulation of plasminogen activation. Elevated PAI-1 has been implicated in promoting fibrosis in the lung, liver, and kidney [12,13], whereas paradoxical protective effects have been observed in cardiac fibrosis, suggesting multifunctional roles beyond fibrinolysis [14]. Recent studies showed that elevated expression of cardiac PAI-1 suppresses fibrosis by inhibiting myofibroblast activation [15,16].

As skeletal muscle is also a site of PAl-1 synthesis, PAI-1 plays critical roles in response to muscle injury and in myopathic conditions [17]. PAI-1 deficiency accentuates plasminogen activator activity [18] and promotes muscle regeneration while up-regulation is associated with skeletal muscle atrophy and associated fibrosis [19]. Although several studies highlighted the importance of PAI-1 in ECM remodeling, the precise mechanisms by which PAI-1 governs muscle regeneration remain incompletely understood. Here, we focus on the specific contributions of PAI-1 to fibroblast activity and ECM dynamics following skeletal muscle injury, aiming to establish a clearer link between PAI-1 signaling and muscle repair.