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Pharmacological inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by downregulating TGF-β via Smad3 acetylation

Author

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  • Alexis Osseni

    (CNRS UMR 5261, INSERM U 1315, Université de Lyon
    Centre de Biotechnologie Cellulaire, Hospices Civils de Lyon)

  • Aymeric Ravel-Chapuis

    (Faculty of Medicine, 451 Smyth Road, University of Ottawa)

  • Edwige Belotti

    (CNRS UMR 5261, INSERM U 1315, Université de Lyon)

  • Isabella Scionti

    (CNRS UMR 5261, INSERM U 1315, Université de Lyon)

  • Yann-Gaël Gangloff

    (CNRS UMR 5261, INSERM U 1315, Université de Lyon)

  • Vincent Moncollin

    (CNRS UMR 5261, INSERM U 1315, Université de Lyon)

  • Laetitia Mazelin

    (CNRS UMR 5261, INSERM U 1315, Université de Lyon)

  • Remi Mounier

    (CNRS UMR 5261, INSERM U 1315, Université de Lyon)

  • Pascal Leblanc

    (CNRS UMR 5261, INSERM U 1315, Université de Lyon)

  • Bernard J. Jasmin

    (Faculty of Medicine, 451 Smyth Road, University of Ottawa
    University of Ottawa)

  • Laurent Schaeffer

    (CNRS UMR 5261, INSERM U 1315, Université de Lyon
    Centre de Biotechnologie Cellulaire, Hospices Civils de Lyon)

Abstract

The absence of dystrophin in Duchenne muscular dystrophy disrupts the dystrophin-associated glycoprotein complex resulting in skeletal muscle fiber fragility and atrophy, associated with fibrosis as well as microtubule and neuromuscular junction disorganization. The specific, non-conventional cytoplasmic histone deacetylase 6 (HDAC6) was recently shown to regulate acetylcholine receptor distribution and muscle atrophy. Here, we report that administration of the HDAC6 selective inhibitor tubastatin A to the Duchenne muscular dystrophy, mdx mouse model increases muscle strength, improves microtubule, neuromuscular junction, and dystrophin-associated glycoprotein complex organization, and reduces muscle atrophy and fibrosis. Interestingly, we found that the beneficial effects of HDAC6 inhibition involve the downregulation of transforming growth factor beta signaling. By increasing Smad3 acetylation in the cytoplasm, HDAC6 inhibition reduces Smad2/3 phosphorylation, nuclear translocation, and transcriptional activity. These findings provide in vivo evidence that Smad3 is a new target of HDAC6 and implicate HDAC6 as a potential therapeutic target in Duchenne muscular dystrophy.

Suggested Citation

  • Alexis Osseni & Aymeric Ravel-Chapuis & Edwige Belotti & Isabella Scionti & Yann-Gaël Gangloff & Vincent Moncollin & Laetitia Mazelin & Remi Mounier & Pascal Leblanc & Bernard J. Jasmin & Laurent Scha, 2022. "Pharmacological inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by downregulating TGF-β via Smad3 acetylation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34831-3
    DOI: 10.1038/s41467-022-34831-3
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    References listed on IDEAS

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    1. Masatoshi Nomura & En Li, 1998. "Smad2 role in mesoderm formation, left–right patterning and craniofacial development," Nature, Nature, vol. 393(6687), pages 786-790, June.
    2. Rik Derynck & Ying E. Zhang, 2003. "Smad-dependent and Smad-independent pathways in TGF-β family signalling," Nature, Nature, vol. 425(6958), pages 577-584, October.
    3. Wenting Guo & Maximilian Naujock & Laura Fumagalli & Tijs Vandoorne & Pieter Baatsen & Ruben Boon & Laura Ordovás & Abdulsamie Patel & Marc Welters & Thomas Vanwelden & Natasja Geens & Tine Tricot & V, 2017. "HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
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    1. Caroline Dour & Maria Chatzifrangkeskou & Coline Macquart & Maria M. Magiera & Cécile Peccate & Charlène Jouve & Laura Virtanen & Tiina Heliö & Katriina Aalto-Setälä & Silvia Crasto & Bruno Cadot & Dé, 2022. "Actin-microtubule cytoskeletal interplay mediated by MRTF-A/SRF signaling promotes dilated cardiomyopathy caused by LMNA mutations," Nature Communications, Nature, vol. 13(1), pages 1-21, December.

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