TNF-alpha acts via TNFR1 and muscle-derived oxidants to depress myofibrillar force in murine skeletal muscle.
Tumor necrosis factor-alpha (TNF) diminishes specific force of skeletal muscle. To address the mechanism of this response, we tested the hypothesis that TNF acts via the type 1 (TNFR1) receptor subtype to increase oxidant activity and thereby depress myofibrillar function. Experiments showed that a single intraperitoneal dose of TNF (100 microg/kg) increased cytosolic oxidant activity (P < 0.05) and depressed maximal force of male ICR mouse diaphragm by approximately 25% within 1 h, a deficit that persisted for 48 h. Pretreating animals with the antioxidant Trolox (10 mg/kg) lessened oxidant activity (P < 0.05) and abolished contractile losses in TNF-treated muscle (P < 0.05). Genetic TNFR1 deficiency prevented the rise in oxidant activity and fall in force stimulated by TNF; type 2 TNF receptor deficiency did not. TNF effects on muscle function were evident at the myofibrillar level. Chemically permeabilized muscle fibers from TNF-treated animals had lower maximal Ca2+-activated force (P < 0.02) with no change in Ca2+ sensitivity or shortening velocity. We conclude that TNF acts via TNFR1 to stimulate oxidant activity and depress specific force. TNF effects on force are caused, at least in part, by decrements in function of calcium-activated myofibrillar proteins.
Hardin
Brian J
BJ
Dept. of Physiology, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0298, USA.
Campbell
Kenneth S
KS
Smith
Jeffrey D
JD
Arbogast
Sandrine
S
Smith
Jacqueline
J
Moylan
Jennifer S
JS
Reid
Michael B
MB
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D003964:Diaphragm / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D004558:Electric Stimulation; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects; D053580:Muscle Strength / Q000187:drug effects; D009210:Myofibrils / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000378:metabolism*
D000975:Antioxidants; D002839:Chromans; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D002118:Calcium