Abstract 70: mTOR Is Essential for Normal Heart Development and Compensatory Cardiac Growth in Fetal Mice
Remarkable growth plasticity enables the prenatal mammalian heart to counteract various unfavorable intrauterine conditions and build a functional and normally sized organ at birth. We have recently shown that the murine embryonic and fetal heart has a substantial regenerative capacity in response to tissue mosaicism for mitochondrial dysfunction caused by heart specific inactivation of the X-linked holocytochrome c synthase (Hccs) gene. In heterozygous Hccs knockout (Hccs+/-) embryos, hyperproliferation of healthy cardiomyocytes compensates for the functional loss of 50% cardiac cells, ensuring formation of a functional heart at birth. However, we hypothesized that embryonic heart regeneration alters peri- and postnatal cardiac growth mechanisms. Indeed, neonatal Hccs+/- hearts are hypoplastic containing a reduced number of cardiomyocytes, whereas in adult Hccs+/- hearts compensatory cellular hypertrophy normalizes morphology and size. We aimed at identifying postnatal adaptive growth mechanisms utilized by the hypoplastic Hccs+/- heart to restore organ size and allow normal heart function throughout lifetime. Microarray RNA expression analyses revealed numerous genes involved in amino acid metabolism, protein homeostasis and translational control being differentially expressed in neonatal Hccs+/- hearts. Subsequently, western blot analyses evidenced significantly increased mammalian target of rapamycin (mTOR) activity, a major regulator of translation and cell growth, in Hccs+/- hearts compared to controls. To clarify its role for compensatory growth of the Hccs+/- myocardium, we inhibited mTOR in fetal and neonatal mice by rapamycin treatment of pregnant dams. Rapamycin treated Hccs+/- neonates (n=17) show significantly reduced heart weight to body weight ratios compared to controls (n=18) or vehicle treated animals (n=12 and n=13). Furthermore, Hccs+/- hearts after prenatal mTOR inhibition are morphologically characterized by developmental delay. In conclusion, our data revealed mTOR being essential for normal as well as compensatory growth of the fetal heart. Thus, metabolic adaptations converging on mTOR might be required to prevent postnatal heart disease after impaired intrauterine development.
- © 2012 by American Heart Association, Inc.