Sepsis–induced skeletal muscle wasting is ameliorated by the pharmacological inhibition of STAT3 signaling in mice [16S-Metagenome]
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: Tibialis anterior muscle, blood, liver, and spleen were collected from septic C57BL/6 mice (8–10 weeks old, weighing 22–26 g) 24 hours after cecal slurry injection. Total cDNA from these samples and CS stock was obtained as described in extract protocol. The extracted cDNA samples were subjected to microbiota analysis using 16S rRNA gene sequencing on the MiSeq (Illumina, San Diego, CA, USA).