Abstract P111: Rheb-mTOR Signaling Pathway Regulates Cardiomyocyte Mass During Post-Neonatal Period
Rheb (Ras homologue enriched in brain) is a major activator of mTOR. Rheb-mTOR pathway is a critical mechanism for maintenance of homeostasis, cell growth and stress response by regulating both protein synthesis and degradation. In this study, we attempted to clarify the role of Rheb-mTOR pathway in the heart using cardiac-specific Rheb-deficient mice (Rheb−/−). We generated floxed Rheb mice and crossed them with transgenic mice expressing Cre recombinase in cardiac-specific mannner to generate Rheb−/−. Rheb−/− were born in Mendelian ratio, but they started to die 8 days after birth and all of them had died until 10 days after birth. Echocardiographic analysis revealed that chamber dimension and contractile function of Rheb−/− were indistinguishable from those of control mice (Rheb+/+) 5 days after birth. However, Rheb−/− exhibited cardiac dilatation and reduced contractility 8 days after birth (LV end diastolic dimension, Rheb−/−: 2.5±0.2 mm vs. Rheb+/+: 2.1±0.2 mm, p<0.01, fractional shortening, Rheb−/−: 19.7 ± 9.7 % vs. Rheb+/+: 48.6 ± 8.8 %, p<0.01). These suggest that Rheb−/− died of cardiac dysfunction and heart failure. Heart weight and cross-sectional area of cardiomyocytes were significantly lower in Rheb−/− 8 days after birth. Electron microscopic analysis revealed that the area of sarcomere was significantly lower in Rheb−/− cardiomyocytes. Expressions of sarcomeric proteins, such as myosin heavy chain, actin or desmin, were decreased in Rheb−/−, while the mRNA expression of desmin was significantly increased in Rheb−/−. Thus impairment of cardiomyocyte growth observed in Rheb−/− could be due to either increased degradation or decreased translation. Although autophagic activity was enhanced in Rheb−/− heart, ablation of Atg5, an essential molecule for autophagy, could not prevent premature death of Rheb−/−. On the other hand, polysome analysis revealed that the mRNA translation activity had decreased in Rheb−/− heart compared with Rheb+/+. Thus, we concluded that Rheb-mTOR pathway in the heart is essential to regulate mRNA translation activity and protein synthesis, thereby to cardiomyocyte growth in neonatal period.
- © 2011 by American Heart Association, Inc.