Thrombospondin1-regulated atrophy in the heart

摘要 就像骨骼肌肌纤维一样，心脏中的心肌细胞不断地根据 感觉到的工作量或疾病刺激，其中肥大与萎缩的通路处于 平衡，以实现与实时工作负载匹配的适当平衡。在更短的时间内 欣赏的过程，心脏和骨骼肌都可以通过分子缩小尺寸 引起组织分解代谢的调节途径。这种大小的减少称为萎缩。 这一过程可能是组织重塑和对疾病刺激或丧失的反应的基础 足够的营养(如饥饿)，使两种组织都能作为新陈代谢储存库。 在这里，我们发现了血栓蛋白1作为心脏和心脏的调节因子的一种新功能。 骨骼肌萎缩。我们以前已经证明，凝血酶敏感蛋白基因家族(Thbs1- 5)通过影响内质网应激反应，在膜的稳定性中起关键作用 分泌途径，以及控制整合素和营养不良蛋白-糖蛋白复合体 出现肌膜。然而，最近我们发现Thbs1是唯一的 由与心脏重构和热量限制相关的疾病刺激诱导，并且 Thbs1通过细胞内途径独特地调节细胞萎缩和自噬 ER/SR在两个级别上起作用。1)Thbs1直接结合和调节内质网应激因子 PERK和eIF2α通过转录因子ATF4介导心肌细胞萎缩，和2) Thbs1选择性地扩展溶酶体和自噬的囊泡途径。因此，我们 假设Thbs1是调节心肌细胞大小的内质网依赖的伴侣蛋白 减少，部分是通过自噬驱动分解代谢过程。来调查这件事 假设，我们将询问两个特定的目的：1)检查心脏萎缩的机制 并通过内质网内Thbs1介导的PERK/eIF2α/ATF4信号途径实现自噬 车厢。2)研究Thbs1介导心脏自噬的机制- 依赖于溶酶体的形成和相关的分解代谢囊泡活性。建议数 研究过程将在培养的心肌细胞和遗传学上进行。 修改了小鼠模型，以便可以采用简化论和机械论的方法，如 以及在生理相关背景下的活体评估。建议的应用程序是 因为它将首次定义一种新的细胞生物学途径， Thbs1通过萎缩和自噬控制横纹肌的重塑。

Abstract Like skeletal muscle myofibers, cardiomyocytes in the heart constantly adjust their size based on perceived workload or disease stimulation, in which hypertrophic versus atrophic pathways are in balance to achieve an appropriate equilibrium matched to real-time workloads. In a less appreciated process, both heart and skeletal muscle can reduce size through molecular regulatory pathways that cause tissue catabolism. This reduction in size is referred to as atrophy and this process can underlie tissue remodeling and responses to disease stimulation or loss of sufficient nutrients (such as starvation) in which both tissues can serve as metabolic reservoirs. Here we uncovered a novel function for thrombospondin1 as a regulator of both cardiac and skeletal muscle atrophy. We have previously shown that the thrombospondin gene family (Thbs1- 5) plays a critical role in membrane stability through effects on the ER stress response and secretory pathways, as well as controlling the integrin and dystrophin-glycoprotein complexes present with the sarcolemma. However, more recently we have discovered that Thbs1 is uniquely induced by disease stimuli associated with cardiac remodeling and caloric restriction, and that Thbs1 uniquely regulates cellular atrophy and autophagy through an intracellular pathway within the ER/SR that functions at 2 levels. 1) Thbs1 directly binds and regulates the ER stress factor PERK and eIF2α to mediate cardiomyocyte atrophy through the transcription factor ATF4, and 2) Thbs1 selectively expands lysosomes and the vesicular pathway of autophagy. Hence, we hypothesize that Thbs1 is an ER-dependent chaperone that mediates cardiomyocyte size reduction, in part, by driving the catabolic process through autophagy. To investigate this hypothesis, we will interrogate 2 specific aims: 1) To examine the mechanisms of cardiac atrophy and autophagy through PERK/eIF2α/ATF4 signaling mediated by Thbs1 within the ER compartment. 2) To examine a mechanism whereby cardiac autophagy is mediated by Thbs1- dependent formation of lysosomes and associated catabolic vesicular activity. The proposed course of investigation will be conducted in both cultured cardiomyocytes and in genetically modified mouse models so that both reductionist and mechanistic approaches can be taken, as well as in vivo assessment in a physiologically relevant context. The proposed application is innovative as it will define for the first time what appears to be a novel cell biology pathway through Thbs1 that controls striated muscle remodeling through atrophy and autophagy.