Critical roles of junctophilin-2 in T-tubule and excitationcontraction coupling maturation during postnatal development
Critical roles of junctophilin-2 in T-tubule and excitationcontraction coupling maturation during postnatal development
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DOI：
10.1093/cvr/cvt180
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发表时间：
2013-10-01
影响因子：
10.8
通讯作者：
Song, Long-Sheng
中科院分区：
文献类型：
--
作者：
Chen, Biyi;Guo, Ang;Song, Long-Sheng
新的证据表明，junctophilin-2 (JP2) 在成人心室肌细胞 T 管完整性和心脏二元体组装中发挥着关键作用。在出生后阶段，肌细胞成熟的关键特征之一是 T 管系统的发育，尽管其机制仍知之甚少。在本研究中，我们旨在确定正常心脏 T 管成熟是否需要 JP2。使用完整小鼠心脏的原位共聚焦成像，我们发现出生后第 8 天左心室和右心室肌细胞中均不存在 T 管，直到第 10 天才出现。使用 T 管功率 (TTpower) 指数对 T 管结构完整性进行量化显示，出生后第 10 天之间 TTpower 逐渐增加19. 到出生后第 19 天，TTpower 与成年小鼠心肌细胞相似，表明 T 管网络接近成熟。 JP2 水平在发育过程中急剧增加，在出生后第 14 天达到成人心脏中观察到的水平。JP2 缺乏（使用在胚胎发育过程中表达 JP2 特异性 shRNA 的小鼠模型）会严重损害 T 管成熟，左心室和右心室 TT 功率相应降低。我们还检测到发育过程中横管的密度逐渐增加，但纵管的密度没有逐渐增加，JP2 缺陷消除了横管元件密度的增加。 T 管的改变导致 Ca-2 瞬态幅度显着降低，Ca-2 释放不同步、Ca-2 交替和自发 Ca-2 波显着增加，导致收缩衰竭。我们的数据确定了 JP2 在 T 管和发育过程中激发收缩耦合成熟中的关键作用。
Emerging evidence indicates a critical role for junctophilin-2 (JP2) in T-tubule integrity and assembly of cardiac dyads in adult ventricular myocytes. In the postnatal stage, one of the critical features of myocyte maturation is development of the T-tubule system, though the mechanisms remain poorly understood. In this study, we aim to determine whether JP2 is required for normal cardiac T-tubule maturation.Using in situ confocal imaging of intact murine hearts, we found T-tubules were absent in both left- and right-ventricular myocytes at postnatal Day 8 and did not appear until Day 10. Quantification of T-tubule structural integrity using the T-tubule power (TTpower) index revealed a progressive increase in TTpower between postnatal Days 10 and 19. By postnatal Day 19, TTpower was similar to that in adult murine cardiomyocytes, indicative of a nearly matured T-tubule network. JP2 levels increased dramatically during development, reaching levels observed in adult hearts by postnatal Day 14. Deficiency of JP2, using a mouse model in which a JP2-specific shRNA is expressed during embryonic development, severely impaired T-tubule maturation, with equivalent decreases in the left- and right-ventricular TTpower. We also detected a gradual increase in the density of transverse but not longitudinal tubules during development, and JP2 deficiency abolished the increase in the density of transverse elements. Alterations in T-tubules caused significant reduction in Ca-2 transient amplitude and marked increase in Ca-2 release dyssynchrony, Ca-2 alternans, and spontaneous Ca-2 waves, leading to contractile failure.Our data identify a critical role for JP2 in T-tubule and excitationcontraction coupling maturation during development.