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

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: Comparative gene expression profiling analysis of RNA-seq data for 7 different wild-type zebrafish strains (AB, KCL, NA, SAT, TL, TU and WIK). Zebrafish underwent cryo-injury of the cardiac ventricle and hearts were isolated at 1 and 7 days post cryo-injury as well as uninjured control.