Thrombospondin1-regulated atrophy in the heart

摘要 像骨骼肌肌纤维一样，心脏中的心肌细胞根据自身的生理变化不断调整其大小。 感知的工作负荷或疾病刺激，其中肥大与萎缩途径在 平衡，以实现与实时工作负载相匹配的适当平衡。以一种不那么 值得赞赏的过程中，心脏和骨骼肌都可以通过分子减少大小 调节途径导致组织catalysis。这种体积的减少被称为萎缩 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），其中两个组织都可以作为代谢库。 在这里，我们发现了血小板反应蛋白1作为心脏和脑血管的调节因子的一种新功能。 骨骼肌萎缩我们以前已经证明，血小板反应蛋白基因家族（Thbs 1-Thbs 2）， 5)通过影响ER应激反应在膜稳定性中起关键作用， 分泌途径，以及控制整合素和肌营养不良蛋白-糖蛋白复合物 出现肌膜。然而，最近我们发现Thbs 1是唯一的 由与心脏重塑和热量限制相关的疾病刺激诱发， Thbs 1通过细胞内的细胞内途径独特地调节细胞萎缩和自噬。 ER/SR在两个级别上发挥作用。1)Thbs 1直接结合并调节ER应激因子 PERK和eIF 2 α通过转录因子ATF 4介导心肌细胞萎缩，以及2） thbs 1选择性扩张溶酶体和自噬的囊泡途径。所以我们 假设Thbs 1是一种ER依赖性伴侣，介导心肌细胞大小 减少，部分是通过自噬驱动分解代谢过程。调查这一 假设，我们将询问2个具体目标：1）检查心脏萎缩的机制 ER内Thbs 1介导的PERK/eIF 2 α/ATF 4信号通路介导的自噬 车厢2)研究Thbs 1介导心脏自噬的机制， 溶酶体的依赖性形成和相关的分解代谢囊泡活性。拟议 研究过程将在培养的心肌细胞和遗传学上进行。 修改小鼠模型，以便可以采取还原论和机械论方法， 以及在生理学相关背景下的体内评估。拟议的申请是 创新，因为它将首次定义似乎是一种新的细胞生物学途径， 通过萎缩和自噬控制横纹肌重塑的thbs 1。

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.