Abstract 051: Growth Plasticity Of The Prenatal Murine Heart Depends On Amino Acid Availability
Intrauterine development influences the susceptibility to cardiovascular disease in adulthood, although the underlying molecular mechanisms are vastly unknown. We have recently shown that the prenatal mouse heart has an impressive regenerative capacity in response to tissue mosaicism for mitochondrial dysfunction caused by a heart specific knockout of holocytochrome c synthase (Hccs) - an X-linked gene required for mitochondrial respiration. In heterozygous Hccs knockout (Hccs+/-) embryos, hyperproliferation of healthy cardiomyocytes compensates for the functional loss of 50% of Hccs deficient cells, ensuring formation of a normally contracting heart at birth. In order to uncover molecular mechanisms enabling compensatory growth of the prenatal myocardium, we performed microarray RNA expression analyses on neonatal Hccs+/- and control hearts. These data revealed numerous genes involved in amino acid metabolism and protein homeostasis being differentially expressed in the neonatal Hccs+/- myocardium. We, therefore, hypothesized that amino acid availability is crucial for compensatory growth of Hccs+/- hearts to build a regularly sized organ and allow normal postnatal function. Thus, we studied the effects of in utero amino acid restriction on growth and development of Hccs+/- hearts by feeding dams a low protein diet (LPD) throughout pregnancy and keeping the offspring on LPD until adulthood. On standard protein diet heart weight to body weight ratio of Hccs+/- mice (n=26) born at gestational age 20.5 dpc does not differ compared to littermate controls (n=21). In contrast, Hccs+/- offspring on LPD (n=20) were found to have a significantly reduced heart weight to body weight ratio compared to control animals (n=19) at postnatal day 1. Importantly, cardiomyocyte size and proliferation were unaffected in neonatal Hccs+/- hearts on LPD, suggesting that amino acid restriction rather inhibits prenatal cardiac growth. This was in line with normal heart size and function in adult LPD Hccs+/- mice, confirming normal postnatal development. In conclusion, metabolic adaptations regulating amino acid availability might be required for growth plasticity of the fetal heart to prevent postnatal dysfunction after impaired intrauterine development.
- © 2013 by American Heart Association, Inc.