Javadpour Maryam M, Tardiff Jil C, Pinz Ilka, Ingwall Joanne S
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
J Clin Invest. 2003 Sep;112(5):768-75. doi: 10.1172/JCI15967.
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.
细肌丝蛋白心肌肌钙蛋白T（cTnT）是肌丝激活的重要调节因子。在此，我们报告了携带cTnT原肌球蛋白结合域错义突变R92Q的转基因小鼠心脏能量代谢的显著变化，该突变与临床上严重的家族性肥厚型心肌病相关。尽管cTnT的这一功能域并不直接与肌球蛋白头部的ATP水解位点相互作用，但最近已证明它是收缩功能的关键调节因子。使用31P NMR光谱法同时测量心脏能量代谢以及完整跳动心脏的收缩性能，结果显示R92Q小鼠心脏中可用于支持收缩功的ATP水解自由能降低，并且在急性强心刺激后明显无法提高收缩性能。这些结果表明，细肌丝蛋白结构和功能的改变可导致心肌能量代谢和收缩储备的显著缺陷。
