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

Alexis Osseni (), Aymeric Ravel-Chapuis, Edwige Belotti, Isabella Scionti, Yann-Gaël Gangloff, Vincent Moncollin, Laetitia Mazelin, Remi Mounier, Pascal Leblanc, Bernard J. Jasmin () and Laurent Schaeffer ()
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Alexis Osseni: CNRS UMR 5261, INSERM U 1315, Université 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
Laurent Schaeffer: CNRS UMR 5261, INSERM U 1315, Université de Lyon

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34831-3

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