PT - JOURNAL ARTICLE AU - Viviana M Fajardo Martinez AU - Iris Feng AU - Bao Ying Chen AU - Cesar A Perez AU - Baochen Shi AU - Peter Clark AU - Rong Tian AU - Ching-Ling Lien AU - Matteo Pellegrini AU - Heather Christofk AU - Haruko Nakano AU - Atsushi Nakano TI - Glucose metabolism promotes neonatal heart regeneration AID - 10.1101/865790 DP - 2019 Jan 01 TA - bioRxiv PG - 865790 4099 - http://biorxiv.org/content/early/2019/12/09/865790.short 4100 - http://biorxiv.org/content/early/2019/12/09/865790.full AB - The mammalian heart switches its main metabolic substrate from glucose to fatty acids shortly after birth. This metabolic switch coincides with the loss of regenerative capacity in the heart. However, it is unknown whether glucose metabolism itself regulates heart regeneration. Here, we report that glucose metabolism is a determinant of regenerative capacity in the neonatal mammalian heart. Cardiac-specific overexpression of Glut1, the embryonic form of constitutively active glucose transporter, resulted in an increase in glucose uptake and concomitant glycogen storage in postnatal heart. Upon cryoinjury, Glut1 transgenic hearts showed higher regenerative capacity with less fibrosis than non-transgenic control hearts. Interestingly, flow cytometry analysis revealed two distinct populations of ventricular cardiomyocytes: Tnnt2-high and Tnnt2-low cardiomyocytes, the latter of which showed significantly higher mitotic activity in response to high intracellular glucose in Glut1 transgenic hearts. Metabolic profiling shows that Glut1-transgenic hearts have a significant increase in the glucose metabolites upon injury, and inhibition of the nucleotide biosynthesis abrogated the regenerative advantage of high intra-cardiomyocyte glucose level. Our data suggest that the increased in glucose metabolism promotes cardiac regeneration in neonatal mouse heart.