Celecoxib disrupts temporal coordination of TGF-β/α-SMA signaling in skeletal muscle repair: a time-dependent study of fibrosis and inflammation.

BACKGROUND: The role of cyclooxygenase-2 (COX-2) inhibitors in skeletal muscle repair remains controversial due to their potential dual effects on inflammation and fibrosis. This study investigates the time-dependent impacts of the selective COX-2 inhibitor celecoxib on skeletal muscle regeneration, focusing on its modulation of α-smooth muscle actin (α-SMA), transforming growth factor-beta (TGF-β), and COX-2 pathways, to guide optimized therapeutic strategies. METHODS: Seventy-two C57BL/6 mice with blunt-impact gastrocnemius muscle injuries were divided into three groups: normal (no injury + saline), model (injury + saline), and celecoxib (injury + 100 mg/kg celecoxib). Tissue samples were collected at 3, 7, 14, and 21 days post-injury. Histopathological changes were assessed via hematoxylin-eosin (HE) and Masson staining. Molecular expression of α-SMA and TGF-β was analyzed by immunohistochemistry, COX-2 by immunofluorescence, and protein levels by Western blot. RESULTS: Celecoxib significantly reduced early-phase inflammation (3-7 days; P < 0.05) and fibrosis (P < 0.001) but delayed fibrosis resolution at 14-21 days. In the model group, α-SMA and TGF-β expression peaked at day 3 and day 7, respectively, followed by gradual declines. Celecoxib elevated α-SMA at day 3 (P < 0.05) but suppressed TGF-β from day 7 onward (P < 0.01). COX-2 expression was inhibited by celecoxib from day 3 to day 14 (P < 0.001), and α-SMA/TGF-β co-localization was disrupted, with minimal overlap after day 7. CONCLUSIONS: Celecoxib mitigates early-phase inflammation, its prolonged use may compromise late-stage tissue maturation. These findings advocate for time-restricted administration of celecoxib in muscle injury therapy, emphasizing the need to balance acute symptom management with long-term functional recovery.