TNF-α acts via TNFR1 and muscle-derived oxidants to depress myofibrillar force in murine skeletal muscle
TNF-α acts via TNFR1 and muscle-derived oxidants to depress myofibrillar force in murine skeletal muscle
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DOI：
10.1152/japplphysiol.00898.2007
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发表时间：
2008-03-01
影响因子：
3.3
通讯作者：
Reid, Michael B.
中科院分区：
文献类型：
--
作者：
Hardin, Brian J.;Campbell, Kenneth S.;Reid, Michael B.
肿瘤坏死因子-α（TNF）降低骨骼肌的比力。为了解决这种反应的机制，我们测试了TNF通过1型（TNFR 1）受体亚型增加氧化活性，从而抑制肌原纤维功能的假设。实验表明，单次腹腔注射TNF（100 μ g/kg）可增加细胞溶质的氧化活性（P < 0.05），并在1小时内使雄性ICR小鼠膈肌的最大力降低约25%，这种缺陷可持续48小时。用抗氧化剂Trolox（10 mg/kg）预处理动物可降低TNF处理的肌肉的氧化活性（P < 0.05），并消除收缩损失（P < 0.05）。遗传性TNFR 1缺陷阻止了TNF刺激的氧化活性的升高和力的下降; 2型TNF受体缺陷没有。TNF对肌肉功能的影响在肌原纤维水平上是明显的。TNF处理动物的化学透化肌纤维具有较低的最大Ca 2+激活力（P < 0.02），而Ca 2+敏感性或缩短速度没有变化。我们的结论是，TNF通过TNFR 1的行为，刺激氧化活性和抑制比力。TNF对力的影响至少部分是由钙激活的肌原纤维蛋白的功能下降引起的。
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 mu g/kg) increased cytosolic oxidant activity (P < 0.05) and depressed maximal force of male ICR mouse diaphragm by similar to 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.