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Inhibition of fatty acid oxidation enables heart regeneration in adult mice

Postnatal maturation of cardiomyocytes is characterized by a metabolic switch from glycolysis to fatty acid oxidation, chromatin reconfiguration and exit from the cell cycle, instating a barrier for adult heart regeneration1,2. Here, to explore whether metabolic reprogramming can overcome this barri...

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Main Authors: Li, Xiang (Author) , Wu, Fan (Author) , Günther, Stefan (Author) , Looso, Mario (Author) , Kuenne, Carsten (Author) , Zhang, Ting (Author) , Wiesnet, Marion (Author) , Klatt, Stephan (Author) , Zukunft, Sven (Author) , Fleming, Ingrid (Author) , Poschet, Gernot (Author) , Wietelmann, Astrid (Author) , Atzberger, Ann (Author) , Potente, Michael (Author) , Yuan, Xuejun (Author) , Braun, Thomas (Author)
Format: Article (Journal)
Language:English
Published: 27 September 2023
In: Nature
Year: 2023, Volume: 622, Issue: 7983, Pages: 619-626, [20], 1-5
ISSN:1476-4687
DOI:10.1038/s41586-023-06585-5
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41586-023-06585-5
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41586-023-06585-5
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Author Notes:Xiang Li, Fan Wu, Stefan Günther, Mario Looso, Carsten Kuenne, Ting Zhang, Marion Wiesnet, Stephan Klatt, Sven Zukunft, Ingrid Fleming, Gernot Poschet, Astrid Wietelmann, Ann Atzberger, Michael Potente, Xuejun Yuan & Thomas Braun
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Summary:Postnatal maturation of cardiomyocytes is characterized by a metabolic switch from glycolysis to fatty acid oxidation, chromatin reconfiguration and exit from the cell cycle, instating a barrier for adult heart regeneration1,2. Here, to explore whether metabolic reprogramming can overcome this barrier and enable heart regeneration, we abrogate fatty acid oxidation in cardiomyocytes by inactivation of Cpt1b. We find that disablement of fatty acid oxidation in cardiomyocytes improves resistance to hypoxia and stimulates cardiomyocyte proliferation, allowing heart regeneration after ischaemia-reperfusion injury. Metabolic studies reveal profound changes in energy metabolism and accumulation of α-ketoglutarate in Cpt1b-mutant cardiomyocytes, leading to activation of the α-ketoglutarate-dependent lysine demethylase KDM5 (ref. 3). Activated KDM5 demethylates broad H3K4me3 domains in genes that drive cardiomyocyte maturation, lowering their transcription levels and shifting cardiomyocytes into a less mature state, thereby promoting proliferation. We conclude that metabolic maturation shapes the epigenetic landscape of cardiomyocytes, creating a roadblock for further cell divisions. Reversal of this process allows repair of damaged hearts.
Item Description:Gesehen am 23.02.2024
Physical Description:Online Resource
ISSN:1476-4687
DOI:10.1038/s41586-023-06585-5

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