Sarcomeric perturbations of myosin motors lead to dilated cardiomyopathy in genetically modified MYL2 mice.
Sarcomeric perturbations of myosin motors lead to dilated cardiomyopathy in genetically modified MYL2 mice.
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肌球蛋白马达的肌节紊乱会在基因改造的MYL2小鼠中引发扩张型心肌病。
DOI：
10.1073/pnas.1716925115
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发表时间：
2018-03-06
影响因子：
11.1
通讯作者：
Szczesna-Cordary D
中科院分区：
文献类型：
--
作者：
Yuan CC;Kazmierczak K;Liang J;Zhou Z;Yadav S;Gomes AV;Irving TC;Szczesna-Cordary D
扩张型心肌病(DCM)是一种进行性心脏病，目前尚无治疗方法，通常在心脏移植中达到顶峰。建立了MYL2基因编码心肌肌球蛋白调节轻链的新的DCM致病突变的转基因D94A(天冬氨酸-丙氨酸)小鼠，并对其进行了超声心动图、有创血流动力学、分子结构和功能评估。我们的数据显示，肌球蛋白马达收缩不足和肌节水平的结构紊乱引发D94A心脏异常的功能重构和DCM的发展，这与临床表型密切相关。在D94A心脏中观察到的左室腔扩张和射血分数降低表明心脏收缩功能障碍，这是扩张型心肌病的一个标志。我们的研究表明，MYL2可能被认为是扩张型心肌病的治疗靶点。扩张型心肌病(DCM)是一种破坏性的心脏病，在美国约有100万人受到影响，但其潜在机制仍鲜为人知。在这项研究中，我们的目的是在携带编码心肌肌球蛋白调节轻链的MYL2基因新突变的转基因小鼠中确定DCM的生物力学和结构原因。建立了转基因D94A(天冬氨酸转丙氨酸)小鼠，并对其进行了超声心动图、有创血流动力学、分子结构和功能评估。与DCM表型一致，∼5和∼12个月龄的雄性和雌性D94A株的射血分数(EF)显著低于各自的WT对照。年轻的雄性D94A小鼠表现出比雌性小鼠更明显的左心室(LV)腔扩张，但D94A品系的两种性别在12个月龄时都出现了DCM。D94A肌球蛋白马达的低收缩活动导致力-PCA依赖性右移，肌动蛋白激活的肌球蛋白ATPase活性降低。在D94A纤维中进行的小角X射线衍射研究显示，在低于最大钙浓度时，D94A跨桥质量块向支持D94A肌球蛋白马达低收缩状态的粗丝主干重新定位，这与收缩压力对钙的敏感性降低相一致。我们的数据表明，肌节水平的结构紊乱导致心肌细胞结构异常，导致左室腔扩张和射血分数降低，表现为D94A心脏的收缩功能障碍。D94A诱导的小鼠扩张型心肌病的发生与临床表型密切相关，提示MYL2可能成为扩张型心肌病新的治疗靶点。
Dilated cardiomyopathy (DCM) is a progressive heart disease with no current cure, often culminating in heart transplantation. Transgenic D94A (aspartic acid-to-alanine) mice carrying a novel DCM-causative mutation in the MYL2 gene, encoding the cardiac myosin regulatory light chain, were created and investigated by echocardiography and invasive hemodynamic and molecular structural and functional assessments. Our data show that hypocontractile myosin motors and structural perturbations at the level of sarcomeres trigger aberrant functional remodeling in D94A hearts and the development of DCM, which closely follows the clinical phenotype. Left ventricular chamber dilation and decreased ejection fraction, observed in D94A hearts, were indicative of systolic dysfunction, a hallmark of DCM. Our study suggests that MYL2 may be considered a therapeutic target for dilated cardiomyopathy. Dilated cardiomyopathy (DCM) is a devastating heart disease that affects about 1 million people in the United States, but the underlying mechanisms remain poorly understood. In this study, we aimed to determine the biomechanical and structural causes of DCM in transgenic mice carrying a novel mutation in the MYL2 gene, encoding the cardiac myosin regulatory light chain. Transgenic D94A (aspartic acid-to-alanine) mice were created and investigated by echocardiography and invasive hemodynamic and molecular structural and functional assessments. Consistent with the DCM phenotype, a significant reduction of the ejection fraction (EF) was observed in ∼5- and ∼12-mo-old male and female D94A lines compared with respective WT controls. Younger male D94A mice showed a more pronounced left ventricular (LV) chamber dilation compared with female counterparts, but both sexes of D94A lines developed DCM by 12 mo of age. The hypocontractile activity of D94A myosin motors resulted in the rightward shift of the force–pCa dependence and decreased actin-activated myosin ATPase activity. Consistent with a decreased Ca2+ sensitivity of contractile force, a small-angle X-ray diffraction study, performed in D94A fibers at submaximal Ca2+ concentrations, revealed repositioning of the D94A cross-bridge mass toward the thick-filament backbone supporting the hypocontractile state of D94A myosin motors. Our data suggest that structural perturbations at the level of sarcomeres result in aberrant cardiomyocyte cytoarchitecture and lead to LV chamber dilation and decreased EF, manifesting in systolic dysfunction of D94A hearts. The D94A-induced development of DCM in mice closely follows the clinical phenotype and suggests that MYL2 may serve as a new therapeutic target for dilated cardiomyopathy.
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影响因子：
15.9
作者：
McConnell, BK;Jones, KA;Seidman, JG
通讯作者：
Seidman, JG
影响因子：
20.1
作者：
Rajan, Sudarsan;Ahmed, Rafeeq P. H.;Wieczorek, David F.
通讯作者：
Wieczorek, David F.
影响因子：
56.9
作者：
Schmitt, JP;Kamisago, M;Seidman, CE
通讯作者：
Seidman, CE
DOI：
10.1126/science.1200113
发表时间：
2011-03-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Malik FI;Hartman JJ;Elias KA;Morgan BP;Rodriguez H;Brejc K;Anderson RL;Sueoka SH;Lee KH;Finer JT;Sakowicz R;Baliga R;Cox DR;Garard M;Godinez G;Kawas R;Kraynack E;Lenzi D;Lu PP;Muci A;Niu C;Qian X;Pierce DW;Pokrovskii M;Suehiro I;Sylvester S;Tochimoto T;Valdez C;Wang W;Katori T;Kass DA;Shen YT;Vatner SF;Morgans DJ
通讯作者：
Morgans DJ
影响因子：
7.4
作者：
Liu, HB;Sadygov, RG;Yates, JR
通讯作者：
Yates, JR