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LSD1 inhibition circumvents glucocorticoid-induced muscle wasting of male mice

Author

Listed:
  • Qingshuang Cai

    (IGBMC UMR 7104- UMR-S 1258)

  • Rajesh Sahu

    (IGBMC UMR 7104- UMR-S 1258)

  • Vanessa Ueberschlag-Pitiot

    (IGBMC UMR 7104- UMR-S 1258)

  • Sirine Souali-Crespo

    (IGBMC UMR 7104- UMR-S 1258)

  • Céline Charvet

    (IGBMC UMR 7104- UMR-S 1258)

  • Ilyes Silem

    (IGBMC UMR 7104- UMR-S 1258)

  • Félicie Cottard

    (IGBMC UMR 7104- UMR-S 1258)

  • Tao Ye

    (IGBMC UMR 7104- UMR-S 1258)

  • Fatima Taleb

    (IGBMC UMR 7104- UMR-S 1258)

  • Eric Metzger

    (Klinikum der Albert-Ludwigs-Universität Freiburg)

  • Roland Schuele

    (Klinikum der Albert-Ludwigs-Universität Freiburg)

  • Isabelle M. L. Billas

    (IGBMC UMR 7104- UMR-S 1258)

  • Gilles Laverny

    (IGBMC UMR 7104- UMR-S 1258)

  • Daniel Metzger

    (IGBMC UMR 7104- UMR-S 1258)

  • Delphine Duteil

    (IGBMC UMR 7104- UMR-S 1258)

Abstract

Synthetic glucocorticoids (GC), such as dexamethasone, are extensively used to treat chronic inflammation and autoimmune disorders. However, long-term treatments are limited by various side effects, including muscle atrophy. GC activities are mediated by the glucocorticoid receptor (GR), that regulates target gene expression in various tissues in association with cell-specific co-regulators. Here we show that GR and the lysine-specific demethylase 1 (LSD1) interact in myofibers of male mice, and that LSD1 connects GR-bound enhancers with NRF1-associated promoters to stimulate target gene expression. In addition, we unravel that LSD1 demethylase activity is required for triggering starvation- and dexamethasone-induced skeletal muscle proteolysis in collaboration with GR. Importantly, inhibition of LSD1 circumvents muscle wasting induced by pharmacological levels of dexamethasone, without affecting their anti-inflammatory activities. Thus, our findings provide mechanistic insights into the muscle-specific GC activities, and highlight the therapeutic potential of targeting GR co-regulators to limit corticotherapy-induced side effects.

Suggested Citation

  • Qingshuang Cai & Rajesh Sahu & Vanessa Ueberschlag-Pitiot & Sirine Souali-Crespo & Céline Charvet & Ilyes Silem & Félicie Cottard & Tao Ye & Fatima Taleb & Eric Metzger & Roland Schuele & Isabelle M. , 2024. "LSD1 inhibition circumvents glucocorticoid-induced muscle wasting of male mice," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47846-9
    DOI: 10.1038/s41467-024-47846-9
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    References listed on IDEAS

    as
    1. Delphine Duteil & Eric Metzger & Dominica Willmann & Panagiota Karagianni & Nicolaus Friedrichs & Holger Greschik & Thomas Günther & Reinhard Buettner & Iannis Talianidis & Daniel Metzger & Roland Sch, 2014. "LSD1 promotes oxidative metabolism of white adipose tissue," Nature Communications, Nature, vol. 5(1), pages 1-14, September.
    2. Dongmei Zhu & Stefanie Hölz & Eric Metzger & Mihael Pavlovic & Anett Jandausch & Cordula Jilg & Petra Galgoczy & Corinna Herz & Markus Moser & Daniel Metzger & Thomas Günther & Sebastian J. Arnold & R, 2014. "Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells," Nature Communications, Nature, vol. 5(1), pages 1-14, May.
    3. Eric Metzger & Melanie Wissmann & Na Yin & Judith M. Müller & Robert Schneider & Antoine H. F. M. Peters & Thomas Günther & Reinhard Buettner & Roland Schüle, 2005. "LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription," Nature, Nature, vol. 437(7057), pages 436-439, September.
    4. Milica Tosic & Anita Allen & Dominica Willmann & Christoph Lepper & Johnny Kim & Delphine Duteil & Roland Schüle, 2018. "Lsd1 regulates skeletal muscle regeneration and directs the fate of satellite cells," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    5. Ramachandran Prakasam & Angela Bonadiman & Roberta Andreotti & Emanuela Zuccaro & Davide Dalfovo & Caterina Marchioretti & Debasmita Tripathy & Gianluca Petris & Eric N. Anderson & Alice Migazzi & Lau, 2023. "LSD1/PRMT6-targeting gene therapy to attenuate androgen receptor toxic gain-of-function ameliorates spinobulbar muscular atrophy phenotypes in flies and mice," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
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