A balanced circadian glycolytic rhythm drives cardiomyocyte cell cycle progression during fish heart regeneration.

Abstract

The ability of heart tissue to repair itself after injury has fascinated scientists for decades1,2. Researchers have long studied the internal body clock, or circadian rhythm, for its role in coordinating daily cycles of metabolism and cell activity3,4, but its relevance to heart repair has remained unknown. This study explores, for the first time, whether natural daily rhythms influence heart regeneration--a process driven by cardiomyocyte proliferation. We discovered that DNA replication, mitosis, oxidative phosphorylation, and glycolysis follow a precise daily order in regenerating zebrafish hearts. Disrupting core clock gene expression abolishes the rhythms of glycolysis and mitosis, preventing cardiomyocyte cell cycle progression and regeneration. Insulin-resistant Astyanax mexicanus cavefish, which have adapted to dark caves, similarly show a loss of mitosis rhythm and cardiomyocyte cell cycle progression, which we find is caused by reduced glycolysis. Despite this reduction, glycolysis rhythm displays a larger amplitude in cavefish--a pattern recapitulated in insulin-resistant zebrafish. Insulin resistance resets metabolic rhythms to the morning, which is equally detrimental to regeneration. Here, we show that successful cardiac regeneration depends on synchronised clock and glucose rhythms, which together orchestrate the cell cycle events essential for cardiomyocyte proliferation and tissue repair.