Inhibition of fatty acid oxidation enables heart regeneration in adult mice

Li, Xiang; Wu, Fan; Guenther, Stefan; Looso, Mario; Kuenne, Carsten; Zhang, Ting; Wiesnet, Marion; Klatt, Stephan; Zukunft, Sven; Fleming, Ingrid; Poschet, Gernot; Wietelmann, Astrid; Atzberger, Ann; Potente, Michael; Yuan, Xuejun; Braun, Thomas

doi:10.1038/s41586-023-06585-5

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Inhibition of fatty acid oxidation enables heart regeneration in adult mice

MPS-Authors

/persons/resource/persons228662

Li, Xiang
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224104

Wu, Fan
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224128

Guenther, Stefan
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224384

Looso, Mario
Bioinformatics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224382

Kuenne, Carsten
Bioinformatics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224108

Zhang, Ting
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons248847

Wiesnet, Marion
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224397

Wietelmann, Astrid
Small Animal Magnetic Resonance Imaging, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons228786

Atzberger, Ann
Facs Service, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224364

Potente, Michael
Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224106

Yuan, Xuejun
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224052

Braun, Thomas
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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引用

Li, X., Wu, F., Guenther, S., Looso, M., Kuenne, C., Zhang, T., Wiesnet, M., Klatt, S., Zukunft, S., Fleming, I., Poschet, G., Wietelmann, A., Atzberger, A., Potente, M., Yuan, X., & Braun, T. (2023). Inhibition of fatty acid oxidation enables heart regeneration in adult mice. NATURE. doi:10.1038/s41586-023-06585-5.

引用: https://hdl.handle.net/21.11116/0000-000D-E7E2-F

要旨

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 alpha-ketoglutarate in Cpt1b-mutant cardiomyocytes, leading to activation of the alpha-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.
Inhibition of the fatty acid oxidation metabolic pathway through inactivation of Cpt1b enhances cardiomyocyte survival and proliferation and allows heart regeneration in adult mice.