Cardiomyopathy mutation (F88L) in troponin T abolishes length dependency of myofilament Ca(2+) sensitivity.
Cardiomyopathy mutation (F88L) in troponin T abolishes length dependency of myofilament Ca(2+) sensitivity.
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DOI：
10.1085/jgp.201711974
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发表时间：
2018-06-04
期刊：
影响因子：
--
通讯作者：
Chandra M
中科院分区：
文献类型：
--
作者：
Reda SM;Chandra M
心肌肌钙蛋白T（TnTF 88 L）中的F88 L突变与肥厚型心肌病相关。Reda和Chandra揭示，它废除了长度介导的肌丝Ca 2+敏感性增加，并减弱了长度依赖性激活的合作机制。最近的临床研究发现了一个新的肥厚性心肌病相关突变（F87 L）在人类心肌肌钙蛋白T（TnT）的中心区域。然而，尽管F87 L与年轻人和老年人的心源性猝死的发生率有关，但其是否与心脏收缩功能障碍有关尚不清楚。由于TnT的中心区域对于调节肌肉长度介导的新的受力横桥（XB）的招募是重要的，我们假设F87 L突变导致与心肌肌丝的长度依赖性激活相关的分子变化。长度依赖性激动是重要的，因为它对Frank-Starling机制有显著贡献，该机制使心脏能够根据静脉回流的变化来改变每搏输出量。我们测量了用重组豚鼠野生型TnT（TnTWT）或人突变的豚鼠类似物（TnTF 88 L）在两种不同肌节长度（SL）下重建的清洁剂皮肤豚鼠心肌纤维的稳态和动态收缩参数：短（1.9 µm）和长（2.3 µm）。TnTF 88 L在短SL时比长SL时更大程度地增加pCa 50（半最大激活所需的无-log [Ca 2 +]）;例如，pCa 50在短SL时增加0.25 pCa单位，在长SL时增加0.17 pCa单位。短SL时pCa 50的增加导致TnTF 88 L纤维中肌丝Ca 2+敏感性（Δ pCa 50）的SL依赖性增加（Δ pCa 50）的消除，TnTWT纤维中Δ pCa 50为0.10单位，而TnTF 88 L纤维中仅为0.02单位。此外，在短SL下，TnTF 88 L减弱了应变XB对受力XB的负面影响，并增加了肌肉长度介导的新的受力XB募集的幅度。我们的研究结果表明，TnTF 88 L介导的心脏细丝的影响可能会导致对Frank-Starling机制的负面影响。
The F88L mutation in cardiac troponin T (TnTF88L) is associated with hypertrophic cardiomyopathy. Reda and Chandra reveal that it abolishes length-mediated increase in myofilament Ca2+ sensitivity and attenuates cooperative mechanisms governing length-dependent activation. Recent clinical studies have revealed a new hypertrophic cardiomyopathy–associated mutation (F87L) in the central region of human cardiac troponin T (TnT). However, despite its implication in several incidences of sudden cardiac death in young and old adults, whether F87L is associated with cardiac contractile dysfunction is unknown. Because the central region of TnT is important for modulating the muscle length–mediated recruitment of new force-bearing cross-bridges (XBs), we hypothesize that the F87L mutation causes molecular changes that are linked to the length-dependent activation of cardiac myofilaments. Length-dependent activation is important because it contributes significantly to the Frank–Starling mechanism, which enables the heart to vary stroke volume as a function of changes in venous return. We measured steady-state and dynamic contractile parameters in detergent-skinned guinea pig cardiac muscle fibers reconstituted with recombinant guinea pig wild-type TnT (TnTWT) or the guinea pig analogue (TnTF88L) of the human mutation at two different sarcomere lengths (SLs): short (1.9 µm) and long (2.3 µm). TnTF88L increases pCa50 (−log [Ca2+]free required for half-maximal activation) to a greater extent at short SL than at long SL; for example, pCa50 increases by 0.25 pCa units at short SL and 0.17 pCa units at long SL. The greater increase in pCa50 at short SL leads to the abolishment of the SL-dependent increase in myofilament Ca2+ sensitivity (ΔpCa50) in TnTF88L fibers, ΔpCa50 being 0.10 units in TnTWT fibers but only 0.02 units in TnTF88L fibers. Furthermore, at short SL, TnTF88L attenuates the negative impact of strained XBs on force-bearing XBs and augments the magnitude of muscle length–mediated recruitment of new force-bearing XBs. Our findings suggest that the TnTF88L-mediated effects on cardiac thin filaments may lead to a negative impact on the Frank–Starling mechanism.
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影响因子：
5
作者：
Ford SJ;Mamidi R;Jimenez J;Tardiff JC;Chandra M
通讯作者：
Chandra M
DOI：
10.1152/ajpheart.00571.2005
发表时间：
2005-11-01
影响因子：
4.8
作者：
Chandra, M;Tschirgi, ML;Tardiff, JC
通讯作者：
Tardiff, JC
影响因子：
5.6
作者：
Gollapudi, Sampath K.;Gallon, Clare E.;Chandra, Murali
通讯作者：
Chandra, Murali
影响因子：
3.9
作者：
Gollapudi, Sampath K.;Chandra, Murali
通讯作者：
Chandra, Murali
影响因子：
5.5
作者：
Arteaga, GM;Palmiter, KA;Solaro, RJ
通讯作者：
Solaro, RJ