Pathological cardiac hypertrophy is an independent risk for heart failure (HF) and sudden death. Deciphering signaling pathways regulating intracellular Ca2+ homeostasis that control adaptive and pathological cardiac growth may enable identification of novel therapeutic targets. The objective of the present study is to determine the role of the store-operated calcium entry-associated regulatory factor (Saraf), encoded by the Tmem66 gene, on cardiac growth control in vitro and in vivo. Saraf is a single-pass membrane protein located at the sarco/endoplasmic reticulum and regulates intracellular calcium homeostasis. We found that Saraf expression was upregulated in the hypertrophied myocardium and was sufficient for cell growth in response to neurohumoral stimulation. Increased Saraf expression caused cell growth, which was associated with dysregulation of calcium-dependent signaling and sarcoplasmic reticulum calcium content. In vivo, Saraf augmented cardiac myocyte growth in response to angiotensin II and resulted in increased cardiac remodeling together with worsened cardiac function. Mechanistically, Saraf activated mTORC1 (mechanistic target of rapamycin complex 1) and increased protein synthesis, while mTORC1 inhibition blunted Saraf-dependent cell growth. In contrast, the hearts of Saraf knockout mice and Saraf-deficient myocytes did not show any morphological or functional alterations after neurohumoral stimulation, but Saraf depletion resulted in worsened cardiac function after acute pressure overload. SARAF knockout blunted transverse aortic constriction cardiac myocyte hypertrophy and impaired cardiac function, demonstrating a role for SARAF in compensatory myocyte growth. Collectively, these results reveal a novel link between sarcoplasmic reticulum calcium homeostasis and mTORC1 activation that is regulated by Saraf.

中文翻译：

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依赖于Saraf的mTORC1激活调节心脏的生长。

病理性心脏肥大是心力衰竭（HF）和猝死的独立风险。调节细胞内Ca2 +稳态以控制适应性和病理性心脏生长的信号通路可能使新治疗靶标的鉴定成为可能。本研究的目的是确定由Tmem66基因编码的储库操作的钙进入相关调节因子（Saraf）在体外和体内对心脏生长的控制作用。Saraf是位于肌膜/内质网的单程膜蛋白，可调节细胞内钙稳态。我们发现，Saraf表达在肥厚的心肌中被上调，并且足以响应神经体液刺激而使细胞生长。Saraf表达增加导致细胞生长，这与钙依赖性信号传导和肌浆网钙含量的失调有关。在体内，萨拉夫响应血管紧张素II增强了心肌细胞的生长，并导致心脏重塑增加以及心脏功能恶化。机械上，萨拉夫激活mTORC1（雷帕霉素复合物1的机械靶标）并增加了蛋白质的合成，而mTORC1抑制则抑制了萨拉夫依赖性细胞的生长。相比之下，Saraf基因敲除小鼠和Saraf缺陷型心肌细胞的心脏在神经体液刺激后未显示任何形态或功能改变，但Saraf耗竭导致急性压力超负荷后心脏功能恶化。SARAF基因敲除使主动脉缩窄使心肌肥大和心脏功能受损，证明SARAF在代偿性心肌细胞生长中的作用。总的来说，这些结果揭示了肌浆网钙动态平衡与Saraf调节的mTORC1活化之间的新型联系。