Clearance of defective muscle stem cells by senolytics restores myogenesis in myotonic dystrophy type 1

Talita C. Conte, Gilberto Duran-Bishop, Zakaria Orfi, Inès Mokhtari, Alyson Deprez, Isabelle Côté, Thomas Molina, Tae-Yeon Kim, Lydia Tellier, Marie-Pier Roussel, Damien Maggiorani, Basma Benabdallah, Severine Leclerc, Lara Feulner, Ornella Pellerito, Jean Mathieu, Gregor Andelfinger, Cynthia Gagnon, Christian Beauséjour, Serge McGraw, Elise Duchesne () and Nicolas A. Dumont ()
Additional contact information
Talita C. Conte: CHU Sainte-Justine Research Center
Gilberto Duran-Bishop: CHU Sainte-Justine Research Center
Zakaria Orfi: CHU Sainte-Justine Research Center
Inès Mokhtari: CHU Sainte-Justine Research Center
Alyson Deprez: CHU Sainte-Justine Research Center
Isabelle Côté: Saguenay-Lac-St-Jean Integrated University Health and Social Services Center
Thomas Molina: CHU Sainte-Justine Research Center
Tae-Yeon Kim: CHU Sainte-Justine Research Center
Lydia Tellier: CHU Sainte-Justine Research Center
Marie-Pier Roussel: Saguenay-Lac-St-Jean Integrated University Health and Social Services Center
Damien Maggiorani: CHU Sainte-Justine Research Center
Basma Benabdallah: CHU Sainte-Justine Research Center
Severine Leclerc: CHU Sainte-Justine Research Center
Lara Feulner: CHU Sainte-Justine Research Center
Ornella Pellerito: CHU Sainte-Justine Research Center
Jean Mathieu: Saguenay-Lac-St-Jean Integrated University Health and Social Services Center
Gregor Andelfinger: CHU Sainte-Justine Research Center
Cynthia Gagnon: Saguenay-Lac-St-Jean Integrated University Health and Social Services Center
Christian Beauséjour: CHU Sainte-Justine Research Center
Serge McGraw: CHU Sainte-Justine Research Center
Elise Duchesne: Université du Québec à Chicoutimi
Nicolas A. Dumont: CHU Sainte-Justine Research Center

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Muscle stem cells, the engine of muscle repair, are affected in myotonic dystrophy type 1 (DM1); however, the underlying molecular mechanism and the impact on the disease severity are still elusive. Here, we show using patients’ samples that muscle stem cells/myoblasts exhibit signs of cellular senescence in vitro and in situ. Single cell RNAseq uncovers a subset of senescent myoblasts expressing high levels of genes related to the senescence-associated secretory phenotype (SASP). We show that the levels of interleukin-6, a prominent SASP cytokine, in the serum of DM1 patients correlate with muscle weakness and functional capacity limitations. Drug screening revealed that the senolytic BCL-XL inhibitor (A1155463) can specifically remove senescent DM1 myoblasts by inducing their apoptosis. Clearance of senescent cells reduced the expression of SASP, which rescued the proliferation and differentiation capacity of DM1 myoblasts in vitro and enhanced their engraftment following transplantation in vivo. Altogether, this study identifies the pathogenic mechanism associated with muscle stem cell defects in DM1 and opens a therapeutic avenue that targets these defective cells to restore myogenesis.

Date: 2023
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DOI: 10.1038/s41467-023-39663-3

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