title: TNF/TNFR1 signaling mediates doxorubicin-induced diaphragm weakness.
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.
authors.affiliation: Department of Physiology, Center for Muscle Biology, University of Kentucky, Lexington, 40536-0298, USA.
authors.forename: Laura A A
authors.initials: LA
authors.lastname: Gilliam
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Moylan
authors.forename: Leonardo F
authors.initials: LF
authors.lastname: Ferreira
authors.forename: Michael B
authors.initials: MB
authors.lastname: Reid
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D003964:Diaphragm / Q000187:drug effects* / Q000503:physiopathology*; D004317:Doxorubicin / Q000009:adverse effects*; D000068800:Etanercept; D007074:Immunoglobulin G / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018908:Muscle Weakness / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D007074:Immunoglobulin G; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C506237:Tnfrsf1a protein, rat; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D000068800:Etanercept