TNF/TNFR1 signaling mediates doxorubicin-induced diaphragm weakness

Laura A.A. Gilliam, Jennifer S. Moylan, Leonardo F. Ferreira, Michael B. Reid

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Doxorubicin, a common chemotherapeutic agent, causes respiratory muscle weakness in both patients and rodents. Tumor necrosis factor-α (TNF), a proinflammatory cytokine that depresses diaphragm force, is elevated following doxorubicin chemotherapy. TNF-induced diaphragm weakness is mediated through TNF type 1 receptor (TNFR1). These findings lead us to hypothesize that TNF/TNFR1 signaling mediates doxorubicin-induced diaphragm muscle weakness. We tested this hypothesis by treating C57BL/6 mice with a clinical dose of doxorubicin (20 mg/kg) via intravenous injection. Three days later, we measured contractile properties of muscle fiber bundles isolated from the diaphragm. We tested the involvement of TNF/TNFR1 signaling using pharmaceutical and genetic interventions. Etanercept, a soluble TNF receptor, and TNFR1 deficiency protected against the depression in diaphragm-specific force caused by doxorubicin. Doxorubicin stimulated an increase in TNFR1 mRNA and protein (P < 0.05) in the diaphragm, along with colocalization of TNFR1 to the plasma membrane. These results suggest that doxorubicin increases diaphragm sensitivity to TNF by upregulating TNFR1, thereby causing respiratory muscle weakness.

Original languageEnglish
Pages (from-to)L225-L231
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume300
Issue number2
DOIs
StatePublished - Feb 2011

Funding

FundersFunder number
National Heart, Lung, and Blood Institute (NHLBI)T32HL086341

    Keywords

    • Cancer
    • Chemotherapy
    • Inflammation
    • Skeletal muscle

    ASJC Scopus subject areas

    • Physiology
    • Pulmonary and Respiratory Medicine
    • Physiology (medical)
    • Cell Biology

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