Emerging importance of oxidative stress in regulating striated muscle elasticity.
Emerging importance of oxidative stress in regulating striated muscle elasticity.
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DOI：
10.1007/s10974-014-9392-y
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发表时间：
2015-02
影响因子：
2.7
通讯作者：
Linke WA
中科院分区：
文献类型：
--
作者：
Beckendorf L;Linke WA
横纹肌细胞的收缩功能被氧化/亚硝化应激改变，这可以在生理条件下观察到，也可以在心力衰竭或肌营养不良症等疾病中观察到。氧化应激引起肌丝蛋白的氧化修饰，并可损害肌细胞收缩性。最近的证据还表明，通过修饰巨大的蛋白质肌联蛋白，氧化应激对肌肉弹性和被动刚度的重要影响。在这篇综述中，我们提供了一个简短的概述已知的氧化修饰在薄和厚丝蛋白，然后更详细地讨论那些氧化应激相关的修改改变肌联蛋白刚度直接或间接。肌联蛋白的直接修饰包括心脏特异性N2-Bus结构域内的可逆二硫键，其增加肌联蛋白刚度，以及免疫球蛋白样结构域中隐蔽半胱氨酸的可逆S-谷胱甘肽化，其仅在结构域展开后发生，并且其降低心脏和骨骼肌中的肌联蛋白刚度。氧化应激对肌联蛋白的间接影响可以通过蛋白激酶信号通路（特别是NO-cGMP-PKG轴）的可逆修饰发生，其改变某些无序肌联蛋白结构域的磷酸化水平，从而调节肌联蛋白刚度。氧化应激还激活蛋白酶，如基质金属蛋白酶-2和（间接通过增加细胞内钙水平）钙蛋白酶-1，这两种蛋白酶都裂解肌联蛋白以不可逆地降低肌联蛋白的硬度。虽然这些机制中的一些需要在体内环境中确认，但有证据表明，肌联蛋白的氧化应激相关修饰在生物标志物设计的背景下是相关的，并且代表了某些形式的肌肉和心脏疾病的治疗干预的潜在靶点。
The contractile function of striated muscle cells is altered by oxidative/nitrosative stress, which can be observed under physiological conditions but also in diseases like heart failure or muscular dystrophy. Oxidative stress causes oxidative modifications of myofilament proteins and can impair myocyte contractility. Recent evidence also suggests an important effect of oxidative stress on muscle elasticity and passive stiffness via modifications of the giant protein titin. In this review we provide a short overview of known oxidative modifications in thin and thick filament proteins and then discuss in more detail those oxidative stress-related modifications altering titin stiffness directly or indirectly. Direct modifications of titin include reversible disulfide bonding within the cardiac-specific N2-Bus domain, which increases titin stiffness, and reversible S-glutathionylation of cryptic cysteines in immunoglobulin-like domains, which only takes place after the domains have unfolded and which reduces titin stiffness in cardiac and skeletal muscle. Indirect effects of oxidative stress on titin can occur via reversible modifications of protein kinase signalling pathways (especially the NO-cGMP-PKG axis), which alter the phosphorylation level of certain disordered titin domains and thereby modulate titin stiffness. Oxidative stress also activates proteases such as matrix-metalloproteinase-2 and (indirectly via increasing the intracellular calcium level) calpain-1, both of which cleave titin to irreversibly reduce titin-based stiffness. Although some of these mechanisms require confirmation in the in vivo setting, there is evidence that oxidative stress-related modifications of titin are relevant in the context of biomarker design and represent potential targets for therapeutic intervention in some forms of muscle and heart disease.