Nitrosative modifications of the Ca2+ release complex and actin underlie arthritis-induced muscle weakness.
Nitrosative modifications of the Ca2+ release complex and actin underlie arthritis-induced muscle weakness.
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DOI：
10.1136/annrheumdis-2013-205007
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发表时间：
2015-10
影响因子：
27.4
通讯作者：
Lanner JT
中科院分区：
文献类型：
--
作者：
Yamada T;Fedotovskaya O;Cheng AJ;Cornachione AS;Minozzo FC;Aulin C;Fridén C;Turesson C;Andersson DC;Glenmark B;Lundberg IE;Rassier DE;Westerblad H;Lanner JT
骨骼肌无力是类风湿关节炎（RA）患者的一个突出临床特征，但其潜在机制尚不清楚。在这里，我们研究关节炎引起的骨骼肌无力背后的机制，特别关注亚硝化应激对细胞内Ca 2+处理和比力产生的作用。一氧化氮合酶（NOS）的表达，亚硝化应激的程度和组成的主要细胞内钙释放通道（ryanodine受体1，RyR 1）复合物在肌肉中进行了测定。在单肌纤维和分离的肌原纤维中，使用原子力杠杆评估胞质游离钙浓度（[Ca 2 +]i）和力产生的变化。胶原诱导性关节炎（CIA）小鼠和RA患者肌肉中神经元NOS（nNOS）总水平均升高。在CIA小鼠肌肉收缩过程中，与RyR 1相关的nNOS增加，并伴随[Ca 2 +]i增加。过氧亚硝酸盐衍生的亚硝化应激（3-硝基酪氨酸，3-NT）的标志物增加RyR 1复合物和肌动蛋白的CIA小鼠的肌肉。尽管增加[Ca 2 +]i，个别CIA肌纤维弱于健康对照组，也就是说，单位横截面积的力下降。此外，CIA肌原纤维中的力和动力学受损，因此肌动蛋白和肌球蛋白表现出相互作用的能力降低，这可能是肌动蛋白上3-NT含量增加的结果。关节炎诱导的肌无力与RyR 1蛋白复合物和肌动蛋白的亚硝化修饰有关，这是由与RyR 1相关的nNOS增加和Ca 2+激活逐渐增加驱动的。
Skeletal muscle weakness is a prominent clinical feature in patients with rheumatoid arthritis (RA), but the underlying mechanism(s) is unknown. Here we investigate the mechanisms behind arthritis-induced skeletal muscle weakness with special focus on the role of nitrosative stress on intracellular Ca2+ handling and specific force production. Nitric oxide synthase (NOS) expression, degree of nitrosative stress and composition of the major intracellular Ca2+ release channel (ryanodine receptor 1, RyR1) complex were measured in muscle. Changes in cytosolic free Ca2+ concentration ([Ca2+]i) and force production were assessed in single-muscle fibres and isolated myofibrils using atomic force cantilevers. The total neuronal NOS (nNOS) levels were increased in muscles both from collagen-induced arthritis (CIA) mice and patients with RA. The nNOS associated with RyR1 was increased and accompanied by increased [Ca2+]i during contractions of muscles from CIA mice. A marker of peroxynitrite-derived nitrosative stress (3-nitrotyrosine, 3-NT) was increased on the RyR1 complex and on actin of muscles from CIA mice. Despite increased [Ca2+]i, individual CIA muscle fibres were weaker than in healthy controls, that is, force per cross-sectional area was decreased. Furthermore, force and kinetics were impaired in CIA myofibrils, hence actin and myosin showed decreased ability to interact, which could be a result of increased 3-NT content on actin. Arthritis-induced muscle weakness is linked to nitrosative modifications of the RyR1 protein complex and actin, which are driven by increased nNOS associated with RyR1 and progressively increasing Ca2+ activation.