Sepsis-associated skeletal muscle wasting is ameliorated by pharmacological inhibition of the STAT3 signaling pathway in mice

Patients with sepsis frequently experience skeletal muscle atrophy and weakness, which adversely affect survival and hinder functional recovery. Currently, no approved treatments are available for sepsis-associated muscle wasting. In this study, we investigated the effects of C188-9, a STAT3-specific signaling inhibitor, on sepsis-induced muscle wasting in vivo and myotube atrophy in vitro. In wild-type male C57BL/6mice, sepsis induced by cecal slurry injection elevated interleukin-6 levels in both plasma and tibialis anterior muscles, increased phosphorylated STAT3, and activated the ubiquitin–proteasome and autophagy pathways in a severity-dependent manner. Similar dose-dependent responses were observed in lipopolysaccharide-treated C2C12 myotubes. In septic mice, intraperitoneal injection of C188-9 (50 mg/kg) suppressed activation of the STAT3 pathway and the ubiquitin–proteasome degradation pathway—but not autophagy pathways—and alleviated sepsis-associated skeletal muscle wasting. Likewise, pretreatment of C2C12 myotubes with C188-9 (10 µM) mitigated activation of the same inflammatory and proteolytic pathways and ameliorated myotube atrophy induced by lipopolysaccharide administration. In human sepsis patients, plasma interleukin-6 levels at intensive care unit admission positively correlated with sepsis severity and the degree of skeletal muscle wasting. Collectively, our findings highlight the therapeutic potential of targeting STAT3 signaling through pharmacological inhibition to combat sepsis-associated skeletal muscle wasting.