Rheb (Ras Homologue Enriched in Brain)-dependent Mammalian Target of Rapamycin Complex 1 (mTORC1) Activation Becomes Indispensable for Cardiac Hypertrophic Growth after Early Postnatal Period
Rheb (Ras Homologue Enriched in Brain)-dependent Mammalian Target of Rapamycin Complex 1 (mTORC1) Activation Becomes Indispensable for Cardiac Hypertrophic Growth after Early Postnatal Period
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DOI：
10.1074/jbc.m112.423640
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发表时间：
2013-04-05
影响因子：
4.8
通讯作者：
Otsu, Kinya
中科院分区：
文献类型：
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作者：
Tamai, Takahito;Yamaguchi, Osamu;Otsu, Kinya
心肌细胞在胎儿期增殖，但在出生后不久就失去增殖能力，并且通过细胞大小的增加或肥大实现心脏质量的进一步增加。哺乳动物雷帕霉素复合物靶标 1 (mTORC1) 对于细胞生长和增殖至关重要。 Rheb（大脑中富集的 Ras 同源物）是 mTORC1 最重要的上游调节因子之一。在这里，我们尝试使用心脏特异性 Rheb 缺陷小鼠 (Rheb(-/-)) 来阐明 Rheb 在心脏中的作用。 Rheb(-/-)小鼠在出生后第8天至第10天死亡。Rheb(-/-)小鼠的心脏与体重比（心肌细胞肥大的指标）在出生后第8天低于对照（Rheb(+/+)）。从出生后第5天至第8天，从小鼠心脏中分离出的心肌细胞表面积在Rheb(+/+)小鼠中增加，但在Rheb(-/-)小鼠中没有增加。超微结构分析表明，新生儿期 Rheb(-/-) 心脏的肌节成熟受损。 Rheb(-/-)心脏在出生后第3天表现出mTORC1下游S6或4E-BP1的磷酸化水平没有差异，但在出生后第5或8天与对照相比表现出减弱。多核糖体分析显示，出生后第 8 天，Rheb(-/-) 心脏中的 mRNA 翻译活性下降。此外，Rheb(-/-) 小鼠中真核起始因子 4E 结合蛋白 1 的消除改善了 mRNA 翻译、心脏肥大生长、肌节成熟和存活。因此，Rheb 依赖性 mTORC1 激活对于产后早期心肌细胞肥大生长至关重要。
Cardiomyocytes proliferate during fetal life but lose their ability to proliferate soon after birth and further increases in cardiac mass are achieved through an increase in cell size or hypertrophy. Mammalian target of rapamycin complex 1 (mTORC1) is critical for cell growth and proliferation. Rheb (Ras homologue enriched in brain) is one of the most important upstream regulators of mTORC1. Here, we attempted to clarify the role of Rheb in the heart using cardiac-specific Rheb-deficient mice (Rheb(-/-)). Rheb(-/-) mice died from postnatal day 8 to 10. The heart-to-body weight ratio, an index of cardiomyocyte hypertrophy, in Rheb(-/-) was lower than that in the control (Rheb(+/+)) at postnatal day 8. The cell surface area of cardiomyocytes isolated from the mouse hearts increased from postnatal days 5 to 8 in Rheb(+/+) mice but not in Rheb(-/-) mice. Ultrastructural analysis indicated that sarcomere maturation was impaired in Rheb(-/-) hearts during the neonatal period. Rheb(-/-) hearts exhibited no difference in the phosphorylation level of S6 or 4E-BP1, downstream of mTORC1 at postnatal day 3 but showed attenuation at postnatal day 5 or 8 compared with the control. Polysome analysis revealed that the mRNA translation activity decreased in Rheb(-/-) hearts at postnatal day 8. Furthermore, ablation of eukaryotic initiation factor 4E-binding protein 1 in Rheb(-/-) mice improved mRNA translation, cardiac hypertrophic growth, sarcomere maturation, and survival. Thus, Rheb-dependent mTORC1 activation becomes essential for cardiomyocyte hypertrophic growth after early postnatal period.