• Laura A A Gilliam, Leonardo F Ferreira, Joseph D Bruton, Jennifer S Moylan, Håkan Westerblad, Daret K St Clair, and Michael B Reid.
• Department of Physiology, 3Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536-0298, USA.
• J. Appl. Physiol. 2009 Dec 1;107(6):1935-42.

AbstractCancer patients receiving doxorubicin chemotherapy experience both muscle weakness and fatigue. One postulated mediator of the muscle dysfunction is an increase in tumor necrosis factor-alpha (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.

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