Targeting FoxO1/3a, NF-κB, and mTOR signaling attenuates muscle atrophy in sepsis.

Sepsis frequently leads to skeletal muscle atrophy, but its molecular mechanisms remain unclear. Using a mouse model of cecal ligation and puncture and LPS-treated C2C12 myotubes, we found that sepsis activates autophagy, the ubiquitin-proteasome system (UPS), and calpain pathways, resulting in muscle wasting and functional decline. These changes were linked to upregulated FoxO1/3a and NF-κB signaling and suppressed mTOR activity. Pharmacological inhibition or genetic deletion of key components in these pathways, especially MuRF1, mitigated muscle atrophy and preserved function. Our findings reveal that sepsis-induced muscle loss is driven by coordinated activation of proteolytic systems regulated by the FoxO1/3a, NF-κB, and mTOR signaling pathway, offering potential therapeutic targets.