The extrinsic caspase pathway modulates endotoxin-induced diaphragm contractile dysfunction

Gerald S. Supinski, Xinying Ji, Wenyi Wang, Leigh A. Callahan

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


The mechanisms by which infections induce diaphragm dysfunction remain poorly understood. The purpose of this study was to determine which caspase pathways (i.e., the extrinsic, death receptor-linked caspase-8 pathway, and/or the intrinsic, mitochondrial-related caspase-9 pathway) are responsible for endotoxin-induced diaphragm contractile dysfunction. We determined 1) whether endotoxin administration (12 mg/kg IP) to mice induces caspase-8 or -9 activation in the diaphragm; 2) whether administration of a caspase-8 inhibitor (N-acetyl-Ile-Glu-Thr-Asp-CHO, 3 mg/kg iv) or a caspase-9 inhibitor (N-acetyl-Leu-Glu-His-Asp-CHO, 3 mg/kg iv) blocks endotoxin-induced diaphragmatic weakness and caspase-3 activation; 3) whether TNF receptor 1-deficient mice have reduced caspase activation and diaphragm dysfunction following endotoxin; and 4) whether cytokines (TNF-α or cytomix, a mixture of TNF-α, interleukin-1β, interferon-γ, and endotoxin) evoke caspase activation in C2C12 myotubes. Endotoxin markedly reduced diaphragm force generation (P < 0.001) and induced increases in caspase-3 and caspase-8 activity (P < 0.03), but failed to increase caspase-9. Inhibitors of caspase-8, but not of caspase-9, prevented endotoxin-induced reductions in diaphragm force and caspase-3 activation (P < 0.01). Mice deficient in TNF receptor 1 also had reduced caspase-8 activation (P < 0.001) and less contractile dysfunction (P < 0.01) after endotoxin. Furthermore, incubation of C2C12 cells with either TNF-α or cytomix elicited significant caspase-8 activation. The caspase-8 pathway is strongly activated in the diaphragm following endotoxin and is responsible for caspase-3 activation and diaphragm weakness.

Original languageEnglish
Pages (from-to)1649-1657
Number of pages9
JournalJournal of Applied Physiology
Issue number4
StatePublished - Apr 2007


  • Sepsis
  • Skeletal muscle
  • Tumor necrosis factor receptor 1
  • Tumor necrosis factor-α
  • Weakness

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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