STING deficiency differentially affects skeletal muscle responses to high-intensity interval training and mechanical overload.

Skeletal muscle adapts to mechanical stress through inflammatory, mitochondrial and translational responses, but upstream sensors remain unclear. Stimulator of interferon genes (STING) links cytosolic DNA sensing to inflammatory signaling. We examined its role using STING-knockout (KO) mice. The STING agonist diamidobenzimidazole (diABZI) elicited a genotype-dependent Tnfα response. During four-week high-intensity interval training (HIIT), KO mice showed lower absolute running performance, but changes from baseline did not differ between genotypes. Overload increased plantaris mass across genotypes without an interaction. Phosphorylated 4E-BP1 abundance showed a significant genotype × overload interaction, whereas the p-4E-BP1/total 4E-BP1 ratio showed an overall genotype difference without a significant interaction. The ratio was lower overall in KO muscle, while overload-induced p70S6K responses were preserved. Tnfα, Il-6 and TBK1 responses to HIIT and overload were stimulus dependent. These findings suggest that STING contributes selectively, rather than uniformly, to metabolic, translational and inflammatory regulation during skeletal muscle adaptation.