OXPHOS driven by glycolysis through the malate aspartate shuttle is required for cardiomyocyte re-differentiation and long-term fish heart regeneration [scRNA-seq]

In contrast to humans after myocardial infarction, fish can fully regenerate their hearts. However, not all fish are equally able to regenerate, allowing comparative inter- and intra-species analysis to identify novel mechanisms controlling successful heart regeneration. Here, we report a differential regenerative response to cardiac cryo-injury between seven different wild-type zebrafish strains. Correlating this data to single cell and bulk RNAseq data, we identify oxidative phosphorylation (OXPHOS) as a positive regulator of long-term regenerative outcome. OXPHOS levels, driven by Glycolysis through the Malate aspartate shuttle (MAS), increase as soon as cardiomyocyte proliferation decreases, and this increase is required for cardiomyocyte re-differentiation and successful long-term regeneration. We confirm these findings in Astyanax mexicanus and link it to a dynamic temporal sarcomere gene expression programme during cardiomyocyte re-differentiation. These findings challenge the current stance that OXPHOS inhibits regeneration and provide new targetable pathways to enhance heart repair in humans after myocardial infarction. Overall design: scRNA-seq data on FAC-sorted nppa-positive border zone cardiomyocytes at 1. 3 and 7dpci. Zebrafish underwent cryo-injury of the cardiac ventricle.