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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月21日

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  • Donglin Fu,
  • Min Zhou,
  • Yingxiao Zhang,
  • Pan Cheng,
  • Yue Shu,
  • Qian Xiao,
  • Meng Zhang

摘要

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.