Amino acid primed mTOR activity is essential for heart regeneration

Abstract

Summary Heart disease is the leading cause of death with no method to repair damaged myocardium due to the limited proliferative capacity of adult cardiomyocytes. Curiously, mouse neonates and zebrafish can regenerate their hearts via cardiomyocyte de-differentiation and proliferation. However, a molecular mechanism of why these cardiomyocytes can re-enter cell cycle is poorly understood. Here, we identify a unique metabolic state that primes adult zebrafish and neonatal mouse ventricular cardiomyocytes to proliferate. Zebrafish and neonatal mouse hearts display elevated glutamine levels, predisposing them to amino-acid-driven activation of TOR, and that TOR activation is required for zebrafish cardiomyocyte regeneration in vivo . Through a multi-omics approach with cellular validation we identify metabolic and mitochondrial changes during the first week of regeneration. These data suggest that regeneration of zebrafish myocardium is driven by metabolic remodeling and reveals a unique metabolic regulator, TOR-primed state, in which zebrafish and mammalian cardiomyocytes are regeneration competent.

Single-cell transcriptome analysis reveals heterogeneity and a dynamic regenerative response of quiescent radial glia in adult zebrafish brain

“…During activation of mTOR signaling, mammalian TOR complex 1 (mTORC1) activates ribosomal protein S6 kinase (S6K) (Magnuson et al, 2012), which subsequently induces phosphorylation of ribosomal protein S6 (rpS6), a component of the S40 ribosome (Ruvinsky and Meyuhas, 2006). Furthermore, rpS6 phosphorylation by S6K is required for regeneration of zebrafish fin (Hirose et al, 2014), heart (Miklas et al, 2022), and retinal pigment epithelium (Lu et al, 2022). Thus, we conducted labeling of zebrafish telencephalon at 3 dpl with anti-phospho-rpS6 antibody.…”

Metabolic Regulation of Cardiac Regeneration

“…Since leucine concentration rises in the postnatal week, does the concentration of BCAA also affect the ability of cardiomyocytes to proliferate? Researchers found that cardiomyocyte injury initiated Wnt/βcatenin signaling during zebrafish cardiomyocyte regeneration, which in turn initiated mTOR activation and metabolic remodeling (97). As previously described, Wnt/β-catenin signaling pathway promoted glycolysis and activated mTOR signaling pathway together with BCAAs (91,98).…”

Using human induced pluripotent stem cell-derived cardiomyocytes to understand the mechanisms driving cardiomyocyte maturation

“…According to a recent study by Miklas et al, amino acid-induced activation of mTOR signaling is required for zebrafish heart regeneration. Moreover, CM cell cycle reentry and proliferation (suppressed as part of CM maturation) in the first week of neonatal mouse heart development and in vitro hESC-CMs were also shown to be dependent on activation of Wnt/B-catenin and mTORC1 signaling ( 56 ). In fact, Wnt/B-catenin activates the mTOR pathway through inhibition of GSK3, an activator of the mTOR upstream inhibitor TSC2.…”