miR-15a-3p promotes excessive autophagy and drives skeletal muscle atrophy in sepsis.

Abstract

Approximately 50% of sepsis patients develop acute skeletal muscle atrophy and dysfunction. Autophagy plays an important role in skeletal muscle atrophy and dysfunction, and skeletal muscle autophagy is known to be regulated by multiple miRNAs. In this study, we found that miR-15a-3p was significantly upregulated in published Gene Expression Omnibus (GEO) datasets of septic patients and septic mouse skeletal muscle. Correlation analysis revealed that miR-15a-3p was associated with autophagy activation in septic patients and septic mouse skeletal muscle. Inhibition of miR-15a-3p attenuated excessive autophagy and ameliorated skeletal muscle atrophy in septic mice and differentiated C2C12 myotubes. Overexpression of miR-15a-3p increased autophagy and skeletal muscle atrophy in mice and differentiated C2C12 myotubes. Furthermore, we identified peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) as a direct target of miR-15a-3p. Our findings elucidate the molecular mechanisms underlying miR-15a-3p in sepsis-induced autophagy and skeletal muscle injury, highlighting its potential as a therapeutic target.