Sepsis–induced skeletal muscle wasting is ameliorated by the pharmacological inhibition of STAT3 signaling in mice [RNA-seq]

Septic patients frequently develop skeletal muscle wasting and weakness, which adversely affects survival and functional outcomes. Currently, no drugs are available for the treatment of sepsis-associated skeletal muscle wasting. Here, we tested the effects of C188-9, a STAT3-specific signaling inhibitor, on muscle wasting in vivo and myotube atrophy in vitro induced by sepsis. In mice, sepsis severity-dependently phosphorylated STAT3, which subsequently activated the ubiquitin–proteasome and autophagy proteolytic pathways, resulting in skeletal muscle atrophy. Similar dose-dependent responses were observed in lipopolysaccharide-treated C2C12 myotubes. In human septic patients, plasma interleukin-6 levels positively correlated with the extent of sepsis-associated skeletal muscle wasting. STAT3 inhibition in mice or cells treated with C188-9 suppressed activation of the ubiquitin–proteasome degradation pathway—but not autophagy pathways—and alleviated sepsis-associated skeletal muscle wasting. Overall, our results indicate that pharmacological inhibition of STAT3 signaling may represent a novel therapeutic strategy for sepsis-associated skeletal muscle wasting. Overall design: RNA sequencing profiling was performed on wild-type male sham control and septic C57BL/6 mice (8–10 weeks old, weighing 22–26 g). To induce polymicrobial sepsis, mice received an intraperitoneal (i.p.) injection of cecal slurry (CS) at 1.0 mg/g body weight using a 1-mL syringe and a 27G needle (septic mice). Control mice were injected with an equal volume of vehicle (7.5% glycerol-PBS). After 24 hours of treatment, tibialis anterior muscles were removed and subjected to RNA sequencing analysis.