title: 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.
abstract: 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.
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Takahito
authors: T
authors: Tamai
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Osamu
authors: O
authors: Yamaguchi
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Shungo
authors: S
authors: Hikoso
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Toshihiro
authors: T
authors: Takeda
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Cardiovascular Division, King's College London British Heart Foundation Centre, London SE5 9NU, United Kingdom.
authors: Manabu
authors: M
authors: Taneike
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Takafumi
authors: T
authors: Oka
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Jota
authors: J
authors: Oyabu
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Tomokazu
authors: T
authors: Murakawa
authors: Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Hiroyuki
authors: H
authors: Nakayama
authors: Laboratory of Reproductive Engineering, The Institute of Experimental Animal Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Yoshihiro
authors: Y
authors: Uno
authors: Department of Social and Environmental Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Kyoji
authors: K
authors: Horie
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Cardiovascular Division, King's College London British Heart Foundation Centre, London SE5 9NU, United Kingdom.
authors: Kazuhiko
authors: K
authors: Nishida
authors: Department of Biochemistry and McGill Cancer Centre, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors: Nahum
authors: N
authors: Sonenberg
authors: Cardiovascular Division, King's College London British Heart Foundation Centre, London SE5 9NU, United Kingdom.
authors: Ajay M
authors: AM
authors: Shah
authors: Department of Social and Environmental Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Junji
authors: J
authors: Takeda
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Issei
authors: I
authors: Komuro
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Cardiovascular Division, King's College London British Heart Foundation Centre, London SE5 9NU, United Kingdom. Electronic address: kinya.otsu@kcl.ac.uk.
authors: Kinya
authors: K
authors: Otsu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy; D015139:Blotting, Southern; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D022202:Chromosomes, Artificial, Bacterial; D004452:Echocardiography / Q000379:methods; D039642:Eukaryotic Initiation Factors; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000254:growth & development* / Q000502:physiology; D006984:Hypertrophy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D032342:Muscle Cells / Q000166:cytology; D009206:Myocardium / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000737:chemistry*; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D009479:Neuropeptides; D010750:Phosphoproteins; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins