Deletion of the titin N2B region accelerates myofibrillar force development but does not alter relaxation kinetics
Deletion of the titin N2B region accelerates myofibrillar force development but does not alter relaxation kinetics
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DOI：
10.1242/jcs.141796
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发表时间：
2014-09-01
影响因子：
4
通讯作者：
Stehle, Robert
中科院分区：
文献类型：
--
作者：
Elhamine, Fatiha;Radke, Michael H.;Stehle, Robert
心脏titin是舒张期肌节僵硬的主要决定因素。为了探讨titin刚度是否影响心肌纤维收缩和舒张的动力学，我们使用了来自纯合和杂合N2B敲除小鼠左心室的亚细胞肌原纤维，这些小鼠表达缺乏独特弹性N2B区域的截断的心脏titin。与野生型小鼠的肌原纤维相比，基因敲除和杂合小鼠的肌原纤维表现出更高的被动肌原纤维硬度。为了确定Ca2+诱导力发展的动力学（速率常数k(ACT)），将敲除、杂合和野生型小鼠的肌原纤维拉伸到相同的肌节长度（2.3 μ m），并迅速被Ca2+激活。此外，机械诱导的力重建动力学（速率常数k(TR)）是通过Ca2+介导的激活过程中肌原纤维的松弛和再拉伸来确定的。基因敲除小鼠的肌原纤维表现出明显高于野生型小鼠的肌原纤维的k（ACT）、k（TR）和最大Ca2+激活张力。相比之下，快速还原[Ca2+]诱导双相力松弛的动力学参数在三个基因型之间没有显著差异。这些结果表明，增加的titin刚度通过加速产生力的交叉桥的形成而不减慢松弛来促进心肌收缩。
Cardiac titin is the main determinant of sarcomere stiffness during diastolic relaxation. To explore whether titin stiffness affects the kinetics of cardiac myofibrillar contraction and relaxation, we used subcellular myofibrils from the left ventricles of homozygous and heterozygous N2B-knockout mice which express truncated cardiac titins lacking the unique elastic N2B region. Compared with myofibrils from wild-type mice, myofibrils from knockout and heterozygous mice exhibit increased passive myofibrillar stiffness. To determine the kinetics of Ca2+-induced force development (rate constant k(ACT)), myofibrils from knockout, heterozygous and wildtype mice were stretched to the same sarcomere length (2.3 mu m) and rapidly activated with Ca2+. Additionally, mechanically induced force-redevelopment kinetics (rate constant k(TR)) were determined by slackening and re-stretching myofibrils during Ca2+-mediated activation. Myofibrils from knockout mice exhibited significantly higher k(ACT), k(TR) and maximum Ca2+-activated tension than myofibrils from wild-type mice. By contrast, the kinetic parameters of biphasic force relaxation induced by rapidly reducing [Ca2+] were not significantly different among the three genotypes. These results indicate that increased titin stiffness promotes myocardial contraction by accelerating the formation of force-generating cross-bridges without decelerating relaxation.