Junctophilin-2 is necessary for T-tubule maturation during mouse heart development
Junctophilin-2 is necessary for T-tubule maturation during mouse heart development
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DOI：
10.1093/cvr/cvt133
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发表时间：
2013-10-01
影响因子：
10.8
通讯作者：
Wehrens, Xander H. T.
中科院分区：
文献类型：
--
作者：
Reynolds, Julia O.;Chiang, David Y.;Wehrens, Xander H. T.
横小管（TT）提供了促进兴奋-收缩（EC）偶联的基本亚细胞结构，EC偶联是正常心脏收缩力的基础。先前的研究表明，TT在哺乳动物生命的最初几周内发展，但这种发展的分子决定因素仍然难以捉摸。本研究旨在阐明连接蛋白2（JPH 2）在心肌细胞TTs成熟中的作用，采用一种新的心脏特异性短发夹RNA介导的JPH 2基因敲低小鼠模型（Mus musculus; MHC-shJPH 2），评估JPH 2缺失对心室TT结构成熟的影响。在胚胎第10.5天（E）和出生后第10天（P）之间，MHC-shJPH 2小鼠中JPH 2 mRNA和蛋白水平降低了70。在P8和P10，敲除JPH 2显著抑制TT的成熟，而与TT发育有关的其他基因的表达水平基本保持不变。与此同时，来自MHC-shJPH 2小鼠的心室肌细胞中的细胞内Ca-2处理被破坏，所述小鼠在P10时发生心力衰竭，其特征在于射血分数降低、心室扩张和过早死亡。与此相反，JPH 2转基因小鼠在P8时表现出TT成熟的加速。我们的研究结果表明，JPH 2是小鼠出生后心脏发育过程中TT成熟所必需的。特别是，JPH 2在将内陷肌膜锚定到肌浆网中可能是至关重要的，从而使TT网络成熟。
Transverse tubules (TTs) provide the basic subcellular structures that facilitate excitationcontraction (EC) coupling, the essential process that underlies normal cardiac contractility. Previous studies have shown that TTs develop within the first few weeks of life in mammals but the molecular determinants of this development have remained elusive. This study aims to elucidate the role of junctophilin-2 (JPH2), a junctional membrane complex protein, in the maturation of TTs in cardiomyocytes.Using a novel cardiac-specific short-hairpin-RNA-mediated JPH2 knockdown mouse model (Mus musculus; MHC-shJPH2), we assessed the effects of the loss of JPH2 on the maturation of the ventricular TT structure. Between embryonic day (E) 10.5 and postnatal day (P) 10, JPH2 mRNA and protein levels were reduced by 70 in MHC-shJPH2 mice. At P8 and P10, knockdown of JPH2 significantly inhibited the maturation of TTs, while expression levels of other genes implicated in TT development remained mostly unchanged. At the same time, intracellular Ca-2 handling was disrupted in ventricular myocytes from MHC- shJPH2 mice, which developed heart failure by P10 marked by reduced ejection fraction, ventricular dilation, and premature death. In contrast, JPH2 transgenic mice exhibited accelerated TT maturation by P8.Our findings suggest that JPH2 is necessary for TT maturation during postnatal cardiac development in mice. In particular, JPH2 may be critical in anchoring the invaginating sarcolemma to the sarcoplasmic reticulum, thereby enabling the maturation of the TT network.