Decreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T.
Decreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T.
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DOI：
10.1172/jci15967
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发表时间：
2003-09
期刊：
影响因子：
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通讯作者：
M. Javadpour;J. Tardiff;I. Pinz;J. Ingwall
中科院分区：
文献类型：
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作者：
M. Javadpour;J. Tardiff;I. Pinz;J. Ingwall
心肌肌钙蛋白T（cTnT）是肌丝激活的重要调节因子。在这里，我们报告了一个显着的变化，心脏能量的转基因小鼠轴承错义突变R92Q内的肌钙蛋白T，与临床严重的家族性肥厚型心肌病的突变结合域。cTnT的这个功能域最近被证明是收缩功能的重要调节剂，尽管它不直接与肌球蛋白头部的ATP水解位点相互作用。使用31P NMR光谱和完整跳动心脏的收缩性能的心脏能量学的同时测量揭示了可用于支持收缩工作的ATP水解的自由能的减少和在来自R92Q小鼠的心脏的急性正性肌力挑战后显著不能增加收缩性能。这些结果表明，细丝蛋白结构和功能的改变可导致心肌能量和收缩储备的显着缺陷。
The thin filament protein cardiac troponin T (cTnT) is an important regulator of myofilament activation. Here we report a significant change in cardiac energetics in transgenic mice bearing the missense mutation R92Q within the tropomyosin-binding domain of cTnT, a mutation associated with a clinically severe form of familial hypertrophic cardiomyopathy. This functional domain of cTnT has recently been shown to be a crucial modulator of contractile function despite the fact that it does not directly interact with the ATP hydrolysis site in the myosin head. Simultaneous measurements of cardiac energetics using 31P NMR spectroscopy and contractile performance of the intact beating heart revealed both a decrease in the free energy of ATP hydrolysis available to support contractile work and a marked inability to increase contractile performance upon acute inotropic challenge in hearts from R92Q mice. These results show that alterations in thin filament protein structure and function can lead to significant defects in myocardial energetics and contractile reserve.