The effect of cardiomyopathy mutation (R97L) in mouse cardiac troponin T on the muscle length-mediated recruitment of crossbridges is modified divergently by α- and β-myosin heavy chain
The effect of cardiomyopathy mutation (R97L) in mouse cardiac troponin T on the muscle length-mediated recruitment of crossbridges is modified divergently by α- and β-myosin heavy chain
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DOI：
10.1016/j.abb.2016.01.008
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发表时间：
2016-07-01
影响因子：
3.9
通讯作者：
Chandra, Murali
中科院分区：
文献类型：
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作者：
Gollapudi, Sampath K.;Chandra, Murali
肥厚型心肌病心肌肌钙蛋白 T (TnT) 突变会导致心源性猝死。肌丝 Ca2+ 敏感性增强是 TnT 突变体的一个常见特征，但此类观察结果未能为严重的心脏表型提供合理的解释。为了更好地了解突变对心脏表型的影响，必须确定对动态收缩特征的影响，例如肌肉长度 (ML) 介导的针对 α 和 β 肌球蛋白重链 (MHC) 亚型的激活。 α-和β-MHC 不仅在啮齿类动物和人类心脏中表达差异，而且它们还以不同方式改变 ML 介导的激活。将人 TnT(R94L) (TnT(R97L)) 或野生型 TnT 的小鼠类似物重构为来自正常 (α-MHC) 和转基因 (β-MHC) 小鼠心脏的脱膜肌纤维。 TnT(R97L) 在 α- 和 β-MHC 纤维中以相似的量增强肌丝 Ca2+ 敏感性。然而，TnT(R97L) 在 α-MHC 纤维中将应变横桥对其他横桥（γ）的负面影响增强了 22%，但在 β-MHC 纤维中将γ减弱了 21%。 TnT(R97L) 使 α-MHC 纤维中 ML 介导的横桥 (E-R) 募集量降低了 37%，但使 β-MHC 纤维中的 E-R 增加了 35%。我们为 TnT(R97L) 诱导的 α-和 β-MHC 纤维效应提供了机制基础，并讨论了与人类心脏的相关性。 (C) 2016 Elsevier Inc. 保留所有权利。
Hypertrophic cardiomyopathy mutations in cardiac troponin T (TnT) lead to sudden cardiac death. Augmented myofilament Ca2+ sensitivity is a common feature in TnT mutants, but such observations fail to provide a rational explanation for severe cardiac phenotypes. To better understand the mutation induced effect on the cardiac phenotype, it is imperative to determine the effects on dynamic contractile features such as the muscle length (ML)-mediated activation against alpha- and beta-myosin heavy chain (MHC) isoforms. alpha- and beta-MHC are not only differentially expressed in rodent and human hearts, but they also modify ML-mediated activation differently. Mouse analog of human TnT(R94L) (TnT(R97L)) or wild-type TnT was reconstituted into de-membranated muscle fibers from normal (alpha-MHC) and transgenic (beta-MHC) mouse hearts. TnT(R97L) augmented myofilament Ca2+ sensitivity by a similar amount in alpha- and beta-MHC fibers. However, TnT(R97L) augmented the negative impact of strained crossbridges on other cross-bridges (gamma) by 22% in alpha-MHC fibers, but attenuated gamma by 21% in beta-MHC fibers. TnT(R97L) decreased the magnitude of ML-mediated recruitment of crossbridges (E-R) by 37% in alpha-MHC fibers, but increased E-R by 35% in beta-MHC fibers. We provide a mechanistic basis for the TnT(R97L)-induced effects in alpha- and beta-MHC fibers and discuss the relevance to human hearts. (C) 2016 Elsevier Inc. All rights reserved.