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.
Highlights
Ras homologue enriched in brain gene (Rheb) (Ras homologue enriched in brain) regulates mammalian target of rapamycin complex 1
Immunoblot analysis of heart extracts from mice indicated that there were no significant differences in Rheb protein level in Rhebϩ/ϩ hearts among at postnatal day 3, 5, and 8 (Fig. 1C)
We analyzed the in vivo function of Rheb, a vital regulator of mammalian target of rapamycin complex 1 (mTORC1) signaling, in the heart by conditionally deleting Rheb from cardiomyocytes
Summary
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. Ablation of eukaryotic initiation factor 4E-binding protein 1 in Rheb؊/؊ mice improved mRNA translation, cardiac hypertrophic growth, sarcomere maturation, and survival. We generated floxed Rheb mice to obtain cardiacspecific Rheb-deficient mice to elucidate the role of Rheb in the in vivo heart and examine the contribution of Rheb to mTORC1 signaling in postnatal cardiac development. We found that Rheb is not required for mTORC1 signaling during the early postnatal period but becomes essential for mTORC1 signaling and normal cardiac development after transition from proliferation to hypertrophy
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