Inhibition of fatty acid oxidation enables heart regeneration in adult mice

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 () and Thomas Braun ()
Additional contact information
Xiang Li: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research
Fan Wu: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research
Stefan Günther: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research
Mario Looso: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research
Carsten Kuenne: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research
Ting Zhang: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research
Marion Wiesnet: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research
Stephan Klatt: Goethe-University
Sven Zukunft: Goethe-University
Ingrid Fleming: Goethe-University
Gernot Poschet: Heidelberg University
Astrid Wietelmann: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research
Ann Atzberger: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research
Michael Potente: Max Planck Institute for Heart and Lung Research
Xuejun Yuan: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research
Thomas Braun: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research

Nature, 2023, vol. 622, issue 7983, 619-626

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41586-023-06585-5

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