Doxorubicin acts through tumor necrosis factor receptor subtype 1 to cause dysfunction of murine skeletal muscle

Laura A.A. Gilliam, Leonardo F. Ferreira, Joseph D. Bruton, Jennifer S. Moylan, Håkan Westerblad, Daret K. St. Clair, Michael B. Reid

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

Cancer patients receiving doxorubicin chemotherapy experience both muscle weakness and fatigue. One postulated mediator of the muscle dysfunction is an increase in tumor necrosis factor-α (TNF), a proinflammatory cytokine that mediates limb muscle contractile dysfunction through the TNF receptor subtype 1 (TNFR1). Our main hypothesis was that systemic doxorubicin administration would cause muscle weakness and fatigue. Systemic doxorubicin administration (20 mg/kg) depressed maximal force of the extensor digitorum longus (EDL; P < 0.01), accelerated EDL fatigue (P < 0.01), and elevated serum TNF levels (P < 0.05) 72 h postinjection. Genetic TNFR1 deficiency prevented the fall in specific force caused by systemic doxorubicin, without protecting against fatigue (P < 0.01). These results demonstrate that clinical doxorubicin concentrations disrupt limb muscle function in a TNFR1-dependent manner.

Original languageEnglish
Pages (from-to)1935-1942
Number of pages8
JournalJournal of Applied Physiology
Volume107
Issue number6
DOIs
StatePublished - Dec 2009

Keywords

  • Cachexia
  • Cancer
  • Chemotherapy
  • Fatigue
  • Weakness

ASJC Scopus subject areas

  • General Medicine

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