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首页> 外文期刊>Circulation: An Official Journal of the American Heart Association >Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice.
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Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice.

机译：心脏猛禽消融会损害适应性肥大，改变代谢基因的表达，并引起小鼠心力衰竭。

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BACKGROUND: Cardiac hypertrophy involves growth responses to a variety of stimuli triggered by increased workload. It is an independent risk factor for heart failure and sudden death. Mammalian target of rapamycin (mTOR) plays a key role in cellular growth responses by integrating growth factor and energy status signals. It is found in 2 structurally and functionally distinct multiprotein complexes called mTOR complex (mTORC) 1 and mTORC2. The role of each of these branches of mTOR signaling in the adult heart is currently unknown. METHODS AND RESULTS: We generated mice with deficient myocardial mTORC1 activity by targeted ablation of raptor, which encodes an essential component of mTORC1, during adulthood. At 3 weeks after the deletion, atrial and brain natriuretic peptides and beta-myosin heavy chain were strongly induced, multiple genes involved in the regulation of energy metabolism were altered, but cardiac function was normal. Function deteriorated rapidly afterward, resulting in dilated cardiomyopathy and high mortality within 6 weeks. Aortic banding-induced pathological overload resulted in severe dilated cardiomyopathy already at 1 week without a prior phase of adaptive hypertrophy. The mechanism involved a lack of adaptive cardiomyocyte growth via blunted protein synthesis capacity, as supported by reduced phosphorylation of ribosomal S6 kinase 1 and 4E-binding protein 1. In addition, reduced mitochondrial content, a shift in metabolic substrate use, and increased apoptosis and autophagy were observed. CONCLUSIONS: Our results demonstrate an essential function for mTORC1 in the heart under physiological and pathological conditions and are relevant for the understanding of disease states in which the insulin/insulin-like growth factor signaling axis is affected such as diabetes mellitus and heart failure or after cancer therapy.
机译：背景：心脏肥大涉及对工作量增加引发的各种刺激的生长反应。它是心力衰竭和猝死的独立危险因素。雷帕霉素的哺乳动物靶标（mTOR）通过整合生长因子和能量状态信号在细胞生长反应中起关键作用。它在2种结构和功能上不同的多蛋白复合物中发现，称为mTOR复合物（mTORC）1和mTORC2。目前尚不知道mTOR信号转导的这些分支在成年心脏中的作用。方法和结果：在成年期，我们通过有针对性的猛禽消融产生了心肌mTORC1活性不足的小鼠，猛禽编码mTORC1的重要成分。删除后3周，强烈诱导心房和脑利钠肽和β-肌球蛋白重链，参与能量代谢调节的多个基因发生改变，但心功能正常。此后功能迅速恶化，导致扩张型心肌病，并在6周内导致高死亡率。主动脉束带引起的病理性超负荷导致严重扩张性心肌病已经在第1周出现，而没有适应性肥大的前期阶段。该机制涉及通过减弱的蛋白质合成能力而缺乏适应性心肌细胞生长，这是由核糖体S6激酶1和4E结合蛋白1的磷酸化减少所支持的。此外，线粒体含量减少，代谢底物用途的改变以及凋亡和自噬被观察到。结论：我们的结果证明了mTORC1在生理和病理条件下在心脏中的基本功能，并且与理解胰岛素/类胰岛素生长因子信号传导轴受到影响的疾病状态（例如糖尿病和心力衰竭）或之后的疾病相关。癌症治疗。

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