Amino acid primed mTOR activity is essential for heart regeneration
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ABSTRACT:
PROVIDER: PRJNA778001 | ENA |
REPOSITORIES: ENA
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Project description:For a short period of time in mammalian neonates, the mammalian heart can regenerate via cardiomyocyte proliferation. This regenerative capacity is largely absent in adults. In other organisms, including zebrafish, damaged hearts can regenerate throughout their lifespans. Many studies have been performed to understand the mechanisms of cardiomyocyte de-differentiation and proliferation during heart regeneration however, the underlying reason why adult zebrafish and young mammalian cardiomyocytes are primed to enter cell cycle have not been identified. Here we show the primed state of a pro-regenerative cardiomyocyte is dictated by its amino acid profile and metabolic state. Adult zebrafish cardiomyocyte regeneration is a result of amino acid-primed mTOR activation. Zebrafish and neonatal mouse cardiomyocytes display elevated glutamine levels, predisposing them to amino acid-driven activation of mTORC1. Injury initiates Wnt/β-catenin signalling that instigates primed mTORC1 activation, Lin28 expression and metabolic remodeling necessary for zebrafish cardiomyocyte regeneration. These studies reveal a unique mTORC1 primed state in zebrafish and mammalian regeneration competent cardiomyocytes.
2022-02-15 | PXD011791 | Pride
Project description:Amino acid primed mTOR activity is essential for heart regeneration [scRNA-seq]
| PRJNA767032 | ENA
Project description:Heart disease is the leading cause of death as there is no current method to repair damaged myocardium due to the limited proliferative capacity of adult cardiomyocytes. Curiously, mouse neonates and zebrafish, larvae or adult, are able to 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. We show that this TOR activation is required for zebrafish cardiomyocyte regeneration in vivo. After injury we observe pS6 in both the epicardium and ventricular cardiomyocytes suggesting these are amino acid primed cells necessary for regeneration. Through single cell and system-wide RNA-sequencing, LQC proteomics and microscopy we identify dramatic 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.
2022-01-11 | GSE184914 | GEO
Project description:Amino acid primed mTOR activity is essential for heart regeneration [bulk RNA-seq]
| PRJNA778003 | ENA
Project description:Heart disease is the leading cause of death as there is no current method to repair damaged myocardium due to the limited proliferative capacity of adult cardiomyocytes. Curiously, mouse neonates and zebrafish, larvae or adult, are able to 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. We show that this TOR activation is required for zebrafish cardiomyocyte regeneration in vivo. After injury we observe pS6 in both the epicardium and ventricular cardiomyocytes suggesting these are amino acid primed cells necessary for regeneration. Through single cell and system-wide RNA-sequencing, LQC proteomics and microscopy we identify dramatic 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.
2022-01-11 | GSE188243 | GEO
Project description: Not available
| S-EPMC8704488 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-01-11 | GSE188244 | GEO
Project description:Zebrafish is capable of endogenously regenerating functional retina pigment epithelium (RPE) after widespread genetic ablation which involves a series of cellular and molecular events that remain to be defined. Here, using the RPE genetic ablation model in zebrafish, we observed that mTOR signaling was activated in the RPE cells post-ablation. Pharmacological and genetic inhibition of mTOR signaling impaired RPE regeneration, while activation of mTOR signaling benefited RPE recovery, suggesting mTOR signaling was required and sufficient for RPE regeneration post-ablation in zebrafish. We further identified an interesting crosstalk between mTOR signaling and microglia/macrophages during RPE regeneration that mTOR acts as an upstream regulator of microglia/macrophage infiltration to the injury site while microglia/macrophage, in turn, rainenforce mTOR activity.
2022-03-01 | GSE174538 | GEO
Project description:An outstanding mystery in biology is why some species, such as the axolotl, can regenerate tissues whereas mammals cannot1. Here, we demonstrate that rapid activation of protein synthesis is a unique feature of the injury response critical for limb regeneration in the axolotl (Ambystoma mexicanum). By applying polysome sequencing, we identify hundreds of transcripts, including antioxidants and ribosome components that are selectively activated at the level of translation from pre-existing messenger RNAs in response to injury. By contrast, protein synthesis is not activated in response to non-regenerative digit amputation in the mouse. We identify the mTORC1 pathway as a key upstream signal that mediates tissue regeneration and translational control in the axolotl. We discover unique expansions in mTOR protein sequence among urodele amphibians. By engineering an axolotl mTOR (axmTOR) in human cells, we show that these changes create a hypersensitive kinase that allows axolotls to maintain this pathway in a highly labile state primed for rapid activation. This change renders axolotl mTOR more sensitive to nutrient sensing, and inhibition of amino acid transport is sufficient to inhibit tissue regeneration. Together, these findings highlight the unanticipated impact of the translatome on orchestrating the early steps of wound healing in a highly regenerative species and provide a missing link in our understanding of vertebrate regenerative potential.
2023-05-08 | GSE185593 | GEO
Project description:To investigate the functional and mechanistic roles of mTOR in zebrafish larvae fin regeneration, we firstly examined the spatiotemporal expression of mTOR in larvae fin and established a mTOR knockout (mTOR-KO) transgenic fish line using CRISPER / Cas9 gene editing technology. Moreover, mTOR was essential for the activation of macrophages, which is a key factor in maintaining the regenerative repair process. We also demonstrated that mTOR knockdown attenuated the proliferative capacity of bud embryo cell during the regenerative phase, while cell apoptosis was not affected. RNA-sequence analysis showed changes in mitochondrial function and dnm1l was identified as the main regulatory factor during the fin regeneration stage. We further suggested that mTOR may promote mitochondrial fission to support bud embryo cell regeneration via CaM-mTOR-dnm1l axis.
2023-10-13 | GSE242949 | GEO