Yuan Baiyin, Wan Ping, Chu Dandan, Nie Junwei, Cao Yunshan, Luo Wen, Lu Shuangshuang, Chen Jiong, Yang Zhongzhou
MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, China.
MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, China; Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, China.
Am J Pathol. 2014 Jul;184(7):1967-80. doi: 10.1016/j.ajpath.2014.04.007. Epub 2014 May 16.
Actin dynamics are critical for muscle development and function, and mutations leading to deregulation of actin dynamics cause various forms of heritable muscle diseases. AIP1 is a major cofactor of the actin depolymerizing factor/cofilin in eukaryotes, promoting actin depolymerizing factor/cofilin-mediated actin disassembly. Its function in vertebrate muscle has been unknown. To investigate functional roles of AIP1 in myocardium, we generated conditional knockout (cKO) mice with cardiomyocyte-specific deletion of Wdr1, the mammalian homolog of yeast AIP1. Wdr1 cKO mice began to die at postnatal day 13 (P13), and none survived past P24. At P12, cKO mice exhibited cardiac hypertrophy and impaired contraction of the left ventricle. Electrocardiography revealed reduced heart rate, abnormal P wave, and abnormal T wave at P10 and prolonged QT interval at P12. Actin filament (F-actin) accumulations began at P10 and became prominent at P12 in the myocardium of cKO mice. Within regions of F-actin accumulation in myofibrils, the sarcomeric components α-actinin and tropomodulin-1 exhibited disrupted patterns, indicating that F-actin accumulations caused by Wdr1 deletion result in disruption of sarcomeric structure. Ectopic cofilin colocalized with F-actin aggregates. In adult mice, Wdr1 deletion resulted in similar but much milder phenotypes of heart hypertrophy, F-actin accumulations within myofibrils, and lethality. Taken together, these results demonstrate that AIP1-regulated actin dynamics play essential roles in heart function in mice.
肌动蛋白动力学对于肌肉发育和功能至关重要，导致肌动蛋白动力学失调的突变会引发各种形式的遗传性肌肉疾病。AIP1是真核生物中肌动蛋白解聚因子/丝切蛋白的主要辅助因子，促进肌动蛋白解聚因子/丝切蛋白介导的肌动蛋白解聚。其在脊椎动物肌肉中的功能尚不清楚。为了研究AIP1在心肌中的功能作用，我们构建了条件性敲除（cKO）小鼠，其心肌细胞特异性缺失酵母AIP1的哺乳动物同源物Wdr1。Wdr1 cKO小鼠在出生后第13天（P13）开始死亡，没有一只存活超过P24。在P12时，cKO小鼠表现出心脏肥大和左心室收缩功能受损。心电图显示在P10时心率降低、P波异常和T波异常，在P12时QT间期延长。肌动蛋白丝（F-肌动蛋白）积累在P10开始，在cKO小鼠心肌中P12时变得明显。在肌原纤维中F-肌动蛋白积累的区域内，肌节成分α-辅肌动蛋白和原肌球蛋白-1呈现出紊乱的模式，表明Wdr1缺失导致的F-肌动蛋白积累会导致肌节结构破坏。异位丝切蛋白与F-肌动蛋白聚集体共定位。在成年小鼠中，Wdr1缺失导致类似但程度较轻的心脏肥大、肌原纤维内F-肌动蛋白积累和致死表型。综上所述，这些结果表明AIP1调节的肌动蛋白动力学在小鼠心脏功能中起着至关重要的作用。
