Faster cross‐bridge detachment and increased tension cost in human hypertrophic cardiomyopathy with the R403Q MYH7 mutation
Faster cross‐bridge detachment and increased tension cost in human hypertrophic cardiomyopathy with the R403Q MYH7 mutation
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R403Q MYH7 突变的人类肥厚型心肌病中更快的桥脱离和张力成本增加
DOI：
10.1113/jphysiol.2014.274571
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
van der Velden J
中科院分区：
文献类型：
--
作者：
Witjas-Paalberends ER;Ferrara C;Scellini B;Piroddi N;Montag J;Tesi C;Stienen GJ;Michels M;Kraft T;Poggesi C;van der Velden J
R403Q突变位于β -肌球蛋白重链的S1结构域，与肥厚性心肌病（HCM）的严重表型相关。R403Q突变引起的过桥松弛动力学的增加可能是肌肉张力产生的能量消耗增加的基础；然而，缺乏直接证据。我们研究了携带和不携带R403Q突变的HCM组织中单个心肌原纤维和多细胞心肌条的过桥动力学和能量学之间的关系。在携带R403Q突变的人类HCM中，跨桥弛豫更快，并且与张力产生的能量成本上升密切相关。我们的数据表明，张力成本的增加是R403Q突变患者心肌病发展的潜在原因之一。与肥厚性心肌病（HCM）相关的第一个突变是编码β -肌球蛋白重链（β - MyHC）基因的R403Q突变。R403Q位于肌凝蛋白（S1）的球状头，负责与肌动蛋白相互作用，从而发挥肌凝蛋白的运动功能。R403Q突变引起的过桥松弛动力学增加可能是张力产生能量成本增加的基础；然而，缺乏直接证据。在这里，我们研究了3例R403Q突变HCM患者和9例肌节突变阴性HCM患者（HCMsmn）的单心肌原纤维和多细胞心肌条带的过桥动力学和能量学在多大程度上相关。R403Q的平均表达量为总myh7mrna的41±4%。单个R403Q肌原纤维的过桥慢弛豫动力学显著高于hcmsmn肌原纤维（分别为0.47±0.02和0.30±0.02 s−1）（P< 0.0001）。此外，与HCMsmn相比，3例R403Q患者的肌条张力成本（分别为2.93±0.25和1.78±0.10 μmol l-1s−1kN−1m−2）显著高于HCMsmn，这与相应肌原纤维制剂的松弛动力学呈线性正相关。这一相关性表明，与HCMsmn相比，更快的过桥松弛动力学导致R403Q突变的HCM中张力产生的能量成本增加。因此，张力成本的增加可能导致携带R403Q突变的患者发生HCM疾病。
Key pointsThe R403Q mutation, located in the S1 domain of the β‐myosin heavy chain, is associated with a severe phenotype of hypertrophic cardiomyopathy (HCM).Increased cross‐bridge relaxation kinetics caused by the R403Q mutation might underlie increased energetic cost of sarcomeric tension generation; however, direct evidence is absent.We studied the relationship between cross‐bridge kinetics and energetics in single cardiac myofibrils and multicellular cardiac muscle strips in human HCM tissue with and without the R403Q mutation.In human HCM with the R403Q mutation, cross‐bridge relaxation was faster and correlated well with a rise in energetic cost of tension generation.Our data suggest that an increase in tension cost is one of the causes underlying cardiomyopathy development in patients with the R403Q mutation.AbstractThe first mutation associated with hypertrophic cardiomyopathy (HCM) is the R403Q mutation in the gene encoding β‐myosin heavy chain (β‐MyHC). R403Q locates in the globular head of myosin (S1), responsible for interaction with actin, and thus motor function of myosin. Increased cross‐bridge relaxation kinetics caused by the R403Q mutation might underlie increased energetic cost of tension generation; however, direct evidence is absent. Here we studied to what extent cross‐bridge kinetics and energetics are related in single cardiac myofibrils and multicellular cardiac muscle strips of three HCM patients with the R403Q mutation and nine sarcomere mutation‐negative HCM patients (HCMsmn). Expression of R403Q was on average 41 ± 4% of totalMYH7mRNA. Cross‐bridge slow relaxation kinetics in single R403Q myofibrils was significantly higher (P< 0.0001) than in HCMsmnmyofibrils (0.47 ± 0.02 and 0.30 ± 0.02 s−1, respectively). Moreover, compared to HCMsmn, tension cost was significantly higher in the muscle strips of the three R403Q patients (2.93 ± 0.25 and 1.78 ± 0.10 μmol l–1s−1kN−1m−2, respectively) which showed a positive linear correlation with relaxation kinetics in the corresponding myofibril preparations. This correlation suggests that faster cross‐bridge relaxation kinetics results in an increase in energetic cost of tension generation in human HCM with the R403Q mutation compared to HCMsmn. Therefore, increased tension cost might contribute to HCM disease in patients carrying the R403Q mutation.
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兔腰肌皮纤维的肌原纤维 ATP 酶活性和机械性能。
DOI：
10.1113/jphysiol.1994.sp020023
发表时间：
1994
期刊：
The Journal of Physiology
影响因子：
--
作者：
E. Potma;G. Stienen;J. P. Barends;G. Elzinga
通讯作者：
G. Elzinga
家族性肥厚型心肌病中 MYH7 突变相关的等位基因失衡：分子机制及其与疾病预后的相关性
DOI：
--
发表时间：
2012
期刊：
影响因子：
--
作者：
J. Montag;Snigdha Tripathi;Anna L. Weber;I. Schulte;E. Becker;B. Borchert;F. Navarro‐López;A. Francino;A. Perrot;Özcelik Cemil;W. McKenna;K. Osterziel;B. Brenner;T. Kraft
通讯作者：
T. Kraft
由于 MYH7 突变，人类肥厚型心肌病的肌动蛋白羰基化程度较高
DOI：
--
发表时间：
2014
期刊：
影响因子：
--
作者：
Rosalie Witjas;M. Canton;M. Michels;Carolyn Y. Ho;C. Poggesi;F. Lisa;J. Velden
通讯作者：
J. Velden
骨骼肌单个肌原纤维中 Ca(2) 突然减少后的松弛动力学。
影响因子：
3.4
作者：
C. Tesi;N. Piroddi;F. Colomo;C. Poggesi
通讯作者：
C. Poggesi
DOI：
10.1161/circheartfailure.108.817346
发表时间：
2009-05
期刊：
Circulation. Heart failure
影响因子：
--
作者：
Hershberger RE;Cowan J;Morales A;Siegfried JD
通讯作者：
Siegfried JD