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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Extreme sarcoplasmic reticulum volume loss and compensatory T-tubule remodeling after Serca2 knockout
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Extreme sarcoplasmic reticulum volume loss and compensatory T-tubule remodeling after Serca2 knockout

机译:Serca2基因敲除后极端的肌质网体积损失和补偿性T管重塑

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摘要

Cardiomyocyte contraction and relaxation are controlled by Ca~(2+) handling, which can be regulated to meet demand. Indeed, major reduction in sarcoplasmic reticulum (SR) function in mice with. Serca2 knockout (KO) is compensated by enhanced plasmalemmal Ca~(2+) fluxes. Here we investigate whether altered Ca~(2+) fluxes are facilitated by reorganization of cardiomyocyte ultrastructure. Hearts were fixed for electron microscopy and enzymatically dissociated for confocal microscopy and electrophysiology. SR relative surface area and volume densities were reduced by 63% and 76%, indicating marked loss and collapse of the free SR in KO. Although overall cardiomyocyte dimensions were unaltered, total surface area was increased. This resulted from increased T-tubule density, as revealed by confocal images. Fourier analysis indicated a maintained organization of transverse T-tubules but an increased presence of longitudinal T-tubules. This demonstrates a remarkable plasticity of the tubular system in the adult myocardium. Immunocytochemical data showed that the newly grown longitudinal T-tubules contained Na~+/Ca~(2+)-exchanger proximal to ryano-dine receptors in the SR but did not contain Ca~(2+)-channels. Ca~(2+) measurements demonstrated a switch from SR-driven to Ca2* influx-driven Ca~(2+) transients in KO. Still, SR Ca~(2+) release constituted 20% of the Ca~(2+) transient in KO. Mathematical modeling suggested that Ca~(2+) influx via Na~(2+)/Ca~(2+)-exchange in longitudinal T-tubules-triggers release from apposing ryanodine receptors in KO, partially compensating for reduced SERCA by allowing for local Ca~(2+) release near the myofilaments. T-tubule proliferation occurs without loss of the original ordered transverse orientation and thus constitutes the basis for compensation of the declining SR function without structural disarrangement.
机译:心肌细胞的收缩和松弛受Ca〜(2+)处理的控制,可以调节以满足需求。确实,小鼠的肌浆网(SR)功能大大降低。 Serca2敲除(KO)被增强的血浆Ca〜(2+)通量补偿。在这里,我们调查是否改变心肌细胞超微结构的重组Ca〜(2+)通量。固定心脏以进行电子显微镜检查,并酶解以进行共聚焦显微镜检查和电生理检查。 SR的相对表面积和体积密度分别降低了63%和76%,表明KO中游离SR的明显损失和破坏。尽管总体心肌细胞尺寸未改变,但总表面积增加。如共焦图像所示,这是由于T管密度增加所致。傅里叶分析表明,横向T管的组织得以维持,但纵向T管的存在却增加了。这证明了成年心肌中管状系统的显着可塑性。免疫细胞化学数据显示,新近生长的纵向T管在SR中含有接近于ryano-dine受体的Na〜+ / Ca〜(2+)交换子,但不包含Ca〜(2+)通道。 Ca〜(2+)的测量证明了KO中从SR驱动到Ca2 *内流驱动的Ca〜(2+)瞬变的转换。 SR Ca〜(2+)的释放仍然占KO中Ca〜(2+)瞬态的20%。数学模型表明,Ca〜(2+)通过纵向T管触发中的Na〜(2 +)/ Ca〜(2+)交换而流入,从KO中相应的雷诺丁受体中释放出来,从而通过补偿SERCA来部分补偿肌丝附近局部Ca〜(2+)释放。 T小管的增殖不会失去原有的有序横向取向,因此构成了补偿SR功能下降而无结构紊乱的基础。

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    Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway,K. G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, 0316 Oslo, Norway;

    Department of Cell and Developmental Biology and Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, PA 19104-6058;

    Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway,K. G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, 0316 Oslo, Norway;

    Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway,K. G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, 0316 Oslo, Norway;

    Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway;

    Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway,K. G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, 0316 Oslo, Norway;

    Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway,K. G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, 0316 Oslo, Norway;

    Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway,K. G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, 0316 Oslo, Norway;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    excitation-contraction coupling; transgenic mice;

    机译:励磁耦合转基因小鼠;

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