cGAS-STING-NFκB pathway plays a role in burn injury-induced muscle wasting

Abstract Background Muscle wasting (MW) is a ubiquitous and debilitating consequence of major burn injury (BI), leading to both short- and long-term health complications. The cGAS-STING-NFκB pathway is a key mediator of inflammatory responses triggered by infection, cellular stress, and tissue damage. This study investigated whether activation of this pathway contributes to BI-induced MW and whether C176, a STING inhibitor, could mitigate the MW of BI. Methods Male C57BL/6 J mice received sham or 30% body BI, with or without daily C176 treatment for 14 days. Hindlimb muscles were analyzed at day 7 and 14 for cytokine expression (RT-qPCR, ELISA), immune cell infiltration (immunohistochemistry), cGAS-STING-NFκB signaling, muscle proteolytic proteins evidenced as MuRF1 and atrogin-1 expression (Western blot), and muscle weight. C2C12 cells (a murine skeletal muscle myoblast cell line) were transfected with Raw 264.7 murine macrophage cell-derived mitochondrial DNA (mtDNA) to mimic BI-induced damage-associated molecular pattern inflammation, with and without C176, to assess muscle inflammatory responses. Results C176 treatment mitigated MW (22 % in tibialis, 13 % in gastrocnemius, p < 0.05) and inhibited the cGAS-STING-NFκB pathway in BI mice. It also decreased infiltration of inflammatory cells into muscle and preserved neuromuscular junction integrity in BI mice. In C2C12 cells, C176 suppressed not only LPS- and mtDNA-induced inflammatory cytokine (IL-1β, TNF-α) release but also muscle proteolytic proteins (MuRF1 and atrogin-1) expression. Conclusions Activation of the cGAS-STING-NFκB pathway contributes to BI-induced MW, and C176 effectively reduces muscle loss by inhibiting this inflammatory signaling pathway.