Nature Communications (Jul 2023)

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,
  • Nicolas A. Dumont

DOI
https://doi.org/10.1038/s41467-023-39663-3
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 17

Abstract

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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.