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


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-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.

SUBMITTER: Gilliam LA 

PROVIDER: S-EPMC2793196 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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

Gilliam Laura A A LA   Ferreira Leonardo F LF   Bruton Joseph D JD   Moylan Jennifer S JS   Westerblad Håkan H   St Clair Daret K DK   Reid Michael B MB  

Journal of applied physiology (Bethesda, Md. : 1985) 20090924 6


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-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  ...[more]

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