Effects of R92 mutations in mouse cardiac troponin T are influenced by changes in myosin heavy chain isoform.
Effects of R92 mutations in mouse cardiac troponin T are influenced by changes in myosin heavy chain isoform.
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DOI：
10.1016/j.yjmcc.2012.07.018
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发表时间：
2012-10
影响因子：
5
通讯作者：
Chandra M
中科院分区：
文献类型：
--
作者：
Ford SJ;Mamidi R;Jimenez J;Tardiff JC;Chandra M
了解不同的家族性肥厚性心肌病相关突变如何导致心脏表型差异的一个限制是，此类突变通常在含有快速循环肌球蛋白重链亚型(α-MHC)的转基因(TG)小鼠心脏中研究。然而，人类心脏中含有一种慢循环MHC亚型(β-MHC)。鉴于MHC-肌钙蛋白相互作用对心脏收缩功能的生理意义，我们假设心肌肌钙蛋白T(CTnT)突变对心脏收缩功能的影响依赖于肌节中MHC亚型的类型。我们使用了两种含有FHC热点R92(R92L或R92Q)突变的cTnT变体来验证我们的假设，这两种突变在α-MHC或β-MHC背景下在TG小鼠心脏中表达。我们的研究发现，只有当β-MHC存在时，R92L才能减弱肌丝张力的长度依赖性增加，并取消肌丝钙敏感性的长度依赖性增加。此外，α-和β-MHC亚型不同地影响R92突变如何改变CrosBridge(XB)招募动态。例如，当β-MHC存在时，XB在R92L或R92Q纤维中的募集速度更快，但当α-MHC存在时，XB的募集速度不受影响。在β-MHC存在时，R92Q突变加速XB脱离，而在α-MHC存在时，R92Q突变不加速XB脱离。R92Q影响XB菌株对XB招募动力学的依赖影响，R92L没有观察到这种影响。我们的发现不仅对理解R92突变对心脏表型的不同影响具有重要意义，而且对于了解MHC亚型在决定cTnT突变结局方面的独特作用也具有重要意义。
One limitation in understanding how different familial hypertrophic cardiomyopathy (FHC)-related mutations lead to divergent cardiac phenotypes is that such mutations are often studied in transgenic (TG) mouse hearts which contain a fast cycling myosin heavy chain isoform (α-MHC). However, the human heart contains a slow cycling MHC isoform (β-MHC). Given the physiological significance of MHC-troponin interplay effects on cardiac contractile function, we hypothesized that cardiac troponin T (cTnT) mutation-mediated effects on contractile function depend on the type of MHC isoform present in the sarcomere. We tested our hypothesis using two variants of cTnT containing mutations at FHC hotspot R92 (R92L or R92Q), expressed against either an α-MHC or β-MHC background in TG mouse hearts. One finding from our study was that R92L attenuated the length-dependent increase in tension and abolished the length-dependent increase in myofilament Ca2+sensitivity only when β-MHC was present. In addition, α- and β-MHC isoforms differentially affected how R92 mutations altered crossbridge (XB) recruitment dynamics. For example, the rate of XB recruitment was faster in R92L or R92Q fibers when β-MHC was present, but was unaffected when α-MHC was present. The R92Q mutation sped XB detachment in the presence of β-MHC, but not in the presence of α-MHC. R92Q affected the XB strain-dependent influence on XB recruitment dynamics, an effect not observed for R92L. Our findings have major implications for understanding not only the divergent effects of R92 mutations on cardiac phenotype, but also the distinct effects of MHC isoforms in determining the outcome of mutations in cTnT.
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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：
5.5
作者：
Fitzsimons, DP;Patel, JR;Moss, RL
通讯作者：
Moss, RL
DOI：
10.1152/ajpregu.00157.2007
发表时间：
2007-10-01
影响因子：
2.8
作者：
Chandra, Murali;Tschirgi, Matthew L.;Campbell, Kenneth B.
通讯作者：
Campbell, Kenneth B.
DOI：
10.1073/pnas.0509181102
发表时间：
2005-12-13
影响因子：
11.1
作者：
Ertz-Berger, BR;He, HM;Tardiff, JC
通讯作者：
Tardiff, JC
影响因子：
4.8
作者：
Manning, Edward P.;Guinto, Pia J.;Tardiff, Jil C.
通讯作者：
Tardiff, Jil C.