Oxidative stress of myosin contributes to skeletal muscle dysfunction in rats with chronic heart failure
Oxidative stress of myosin contributes to skeletal muscle dysfunction in rats with chronic heart failure
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DOI：
10.1152/ajpheart.00438.2006
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发表时间：
2007-02-01
影响因子：
4.8
通讯作者：
Lecarpentier, Yves
中科院分区：
文献类型：
--
作者：
Coirault, Catherine;Guellich, Aziz;Lecarpentier, Yves
在慢性心力衰竭（CHF）期间，经常报告影响骨骼肌的内在肌异常。由于肌球蛋白是产生力的分子马达，我们试图确定其功能障碍是否有助于CHF骨骼肌无力，如果是这样，以确定潜在的致病因素。主动脉瓣狭窄诱导大鼠重度CHF。在隔膜和比目鱼肌中，我们研究了体外机械性能、基于肌球蛋白的肌动蛋白丝运动性、肌球蛋白重链（MHC）和轻链（MLC）亚型组成、MLC完整性、半胱天冬酶-3激活和氧化损伤。膈肌和比目鱼肌从CHF表现出抑郁症的机械性能。CHF中隔膜（1.9 +/- 0.1 vs. 1.6 +/-0.1 μ m/s）和比目鱼肌（0.6 +/-0.1 vs. 0.5 +/-0.1 μ m/s）的肌球蛋白滑动速度分别比假手术慢16%和20%（均P < 0.05）。慢-快肌球蛋白亚型的比例在假手术组和CHF组之间没有差异。用抗MLC抗体的免疫印迹没有检测到蛋白质片段的存在，并且没有证明半胱天冬酶-3的活化。免疫标记显示CHF肌肉中存在氧化损伤，MHC是主要的氧化蛋白。CHF组脂质过氧化反应和氧化型MHC的表达明显高于假手术组。在体外肌球蛋白暴露于增加ONOO-浓度与增加量的氧化MHC和降低肌球蛋白的速度。这些数据提供了实验证据，内在肌球蛋白功能障碍发生在CHF，可能与氧化损伤肌球蛋白。
Intrinsic muscle abnormalities affecting skeletal muscle are often reported during chronic heart failure (CHF). Because myosin is the molecular motor of force generation, we sought to determine whether its dysfunction contributes to skeletal muscle weakness in CHF and, if so, to identify the underlying causative factors. Severe CHF was induced in rats by aortic stenosis. In diaphragm and soleus muscles, we investigated in vitro mechanical performance, myosin-based actin filament motility, myosin heavy (MHC) and light (MLC) chain isoform compositions, MLC integrity, caspase-3 activation, and oxidative damage. Diaphragm and soleus muscles from CHF exhibited depressed mechanical performance. Myosin sliding velocities were 16 and 20% slower in CHF than in sham in diaphragm (1.9 +/- 0.1 vs. 1.6 +/- 0.1 mu m/s) and soleus (0.6 +/- 0.1 vs. 0.5 +/- 0.1 mu m/s), respectively (each P < 0.05). The ratio of slow-to-fast myosin isoform did not differ between sham and CHF. Immunoblots with anti-MLC antibodies did not detect the presence of protein fragments, and no activation of caspase-3 was evidenced. Immunolabeling revealed oxidative damage in CHF muscles, and MHC was the main oxidized protein. Lipid peroxidation and expression of oxidized MHC were significantly higher in CHF than in shams. In vitro myosin exposure to increasing ONOO- concentrations was associated with an increasing amount of oxidized MHC and a reduced myosin velocity. These data provide experimental evidence that intrinsic myosin dysfunction occurs in CHF and may be related to oxidative damage to myosin.