Doxorubicin acts through tumor necrosis factor receptor subtype 1 to cause dysfunction of murine skeletal muscle.
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.
Department of Physiology, 3Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536-0298, USA.
Laura A A
LA
Gilliam
Leonardo F
LF
Ferreira
Joseph D
JD
Bruton
Jennifer S
JS
Moylan
Håkan
H
Westerblad
Daret K
DK
St Clair
Michael B
MB
Reid
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage*; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects*; D018763:Muscle Fatigue / Q000187:drug effects; D053580:Muscle Strength / Q000187:drug effects*; D018908:Muscle Weakness / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D002118:Calcium