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/jc1200315967
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发表时间：
2003-09-01
影响因子：
15.9
通讯作者：
Ingwall, JS
中科院分区：
文献类型：
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作者：
Javadpour, MM;Tardiff, JC;Ingwall, JS
细丝蛋白心肌肌钙蛋白T （cTnT）是肌丝活化的重要调节因子。在这里，我们报道了在cTnT原肌球蛋白结合区域携带错义突变R92Q的转基因小鼠心脏能量学的显著变化，这种突变与临床上严重的家族性肥厚性心肌病有关。cTnT的这个功能域最近被证明是收缩功能的关键调节剂，尽管它不直接与肌凝蛋白头部的ATP水解位点相互作用。使用（31）P核磁共振波谱同时测量心脏能量和完整跳动心脏的收缩性能显示，R92Q小鼠心脏在急性肌力刺激下，可用于支持收缩工作的ATP水解自由能减少，明显无法增加收缩性能。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著缺陷。
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 (31)P 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.