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Inhibition of fatty acid oxidation enables heart regeneration in adult mice

Author

Listed:
  • 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
    Helmholtz Association of German Research Centres
    Charité-Universitätsmedizin Berlin)

  • Xuejun Yuan

    (Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research
    Instituto de Investigacion en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society)

  • Thomas Braun

    (Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research
    Instituto de Investigacion en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society)

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.

Suggested Citation

  • 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 & M, 2023. "Inhibition of fatty acid oxidation enables heart regeneration in adult mice," Nature, Nature, vol. 622(7983), pages 619-626, October.
  • Handle: RePEc:nat:nature:v:622:y:2023:i:7983:d:10.1038_s41586-023-06585-5
    DOI: 10.1038/s41586-023-06585-5
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    Cited by:

    1. Yamei Liu & Shuya Wang & Jiaxiong Zhang & Quan Sun & Yi Xiao & Jing Chen & Meilian Yao & Guogang Zhang & Qun Huang & Tianjiao Zhao & Qiong Huang & Xiaojing Shi & Can Feng & Kelong Ai & Yongping Bai, 2024. "Reprogramming the myocardial infarction microenvironment with melanin-based composite nanomedicines in mice," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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