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Clearance of defective muscle stem cells by senolytics reduces the expression of senescence-associated secretory phenotype and restores myogenesis in myotonic dystrophy type 1

Conte Talita C., Duran-Bishop Gilberto, Orfi Zakaria, Mokhtari Inès, Deprez Alyson, Roussel Marie-Pier, Côté Isabelle, Pellerito Ornella, Maggiorani Damien, Benabdallah Basma, Leclerc Severine, Feulner Lara, Mathieu Jean, Gagnon Cynthia, Andelfinger Gregor, Beauséjour Christian, McGraw Serge, Duchesne Élise et Dumont Nicolas A.. (2022). Clearance of defective muscle stem cells by senolytics reduces the expression of senescence-associated secretory phenotype and restores myogenesis in myotonic dystrophy type 1. bioRxiv, e497227.

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URL officielle: https://doi.org/10.1101/2022.06.22.497227

Résumé

Muscle weakness and atrophy are clinical hallmarks of myotonic dystrophy type 1 (DM1). Muscle stem cells, which contribute to skeletal muscle growth and repair, are also affected in this disease. However, the molecular mechanisms leading to this defective activity and the impact on the disease severity are still elusive. Here, we explored through an unbiased approach the molecular signature leading to myogenic cell defects in DM1. Single cell RNAseq data revealed the presence of a specific subset of DM1 myogenic cells expressing a senescence signature, characterized by the high expression of genes related to senescence-associated secretory phenotype (SASP). This profile was confirmed using different senescence markers in vitro and in situ. Accumulation of intranuclear RNA foci in senescent cells, suggest that RNA-mediated toxicity contribute to senescence induction. High expression of IL-6, a prominent SASP cytokine, in the serum of DM1 patients was identified as a biomarker correlating with muscle weakness and functional capacity limitations. Drug screening revealed that the BCL-XL inhibitor (A1155463), a senolytic drug, can specifically target senescent DM1 myoblasts to induce their apoptosis and reduce their SASP. Removal of senescent cells re-established the myogenic function of the non-senescent DM1 myoblasts, which displayed improved proliferation and differentiation capacity in vitro; and enhanced engraftment following transplantation in vivo. Altogether this study presents a well-defined senescent molecular signature in DM1 untangling part of the pathological mechanisms observed in the disease; additionally, we demonstrate the therapeutic potential of targeting these defective cells with senolytics to restore myogenesis.

Type de document:Article publié dans une revue avec comité d'évaluation
Pages:e497227
Version évaluée par les pairs:Non
Date:2022
Identifiant unique:10.1101/2022.06.22.497227
Sujets:Sciences de la santé
Sciences de la santé > Sciences de l'activité physique et réadaptation > Physiothérapie
Sciences de la santé > Sciences médicales
Département, module, service et unité de recherche:Départements et modules > Département des sciences de la santé > Unité d'enseignement en physiothérapie
Mots-clés:DM1, myotonic distrophy type 1, muscle weakness, skeletal muscle, muscle stem cells, myogenic cell defects, myogenesis, senolytics, dystrophie myotonique de type 1, faiblesse musculaire, muscle squelettique, cellules souches musculaires, anomalies des cellules myogéniques, myogenèse, sénolytiques.
Déposé le:19 janv. 2023 21:03
Dernière modification:19 janv. 2023 21:03
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