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

• Published in: The Journal of biological chemistry 2013-04, Vol.288 (14), p.10176-10187
• Main Authors: Tamai, Takahito, Yamaguchi, Osamu, Hikoso, Shungo, Takeda, Toshihiro, Taneike, Manabu, Oka, Takafumi, Oyabu, Jota, Murakawa, Tomokazu, Nakayama, Hiroyuki, Uno, Yoshihiro, Horie, Kyoji, Nishida, Kazuhiko, Sonenberg, Nahum, Shah, Ajay M., Takeda, Junji, Komuro, Issei, Otsu, Kinya
• Format: Article
• Language: English
• Subjects: 4E-BP1; Adaptor Proteins, Signal Transducing; Animals; Animals, Newborn; Autophagy; Blotting, Southern; Carrier Proteins - metabolism; Cell Cycle Proteins; Cell Growth; Cell Proliferation; Chromosomes, Artificial, Bacterial; Developmental Biology; Echocardiography - methods; Eukaryotic Initiation Factors; Gene Expression Regulation, Developmental; Heart; Heart - growth & development; Heart - physiology; Heart Development; Hypertrophy; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Models, Genetic; Monomeric GTP-Binding Proteins - metabolism; mTOR Complex (mTORC); Muscle Cells - cytology; Myocardium - metabolism; Neuropeptides - metabolism; Phosphoproteins - metabolism; Polyribosomes - metabolism; Protein Biosynthesis; Protein Synthesis; Ras Homolog Enriched in Brain Protein; Rheb; Signal Transduction; Time Factors; TOR Serine-Threonine Kinases - chemistry; Translation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.423640

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. Background: Rheb (Ras homologue enriched in brain) regulates mammalian target of rapamycin complex 1 (mTORC1). Results: mTORC1 activity and cardiac hypertrophy are attenuated in Rheb-deficient hearts after the early postnatal period. Conclusion: Rheb-dependent mTORC1 activation becomes essential for cardiomyocyte hypertrophic growth after the early postnatal period. Significance: The findings provide insight into the regulatory mechanism of mTORC1 in postnatal heart development.