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Series GSE208360 Query DataSets for GSE208360
Status Public on May 05, 2023
Title Clearance of defective muscle stem cells by senolytics reduces the expression of senescence-associated secretory phenotype and restores myogenesis in myotonic dystrophy type 1
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary 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.
Overall design Myoblasts were extracted from muscle biopsies provided by 3 different DM1 patients and 3 different age and sex-matched healthy individuals. After expansion in vitro, cells were purified by Fluorescence-activated cell sorting (FACS) based on the expression of the myogenic marker CD56, pooled together and analized using scRNA-seq.
Contributor(s) Conte TC, Duran-Bishop G, Orfi Z, Mokhtari I, Deprez A, Roussel M, Côté I, Pellerito O, Maggiorani D, Benabdallah B, Leclerc S, Feulner L, Mathieu J, Gagnon C, Andelfinger G, Beauséjour C, McGraw S, Duchesne E, Dumont NA
Citation(s) 37468473
Submission date Jul 18, 2022
Last update date Sep 12, 2023
Contact name Mohan Malleshaiah
Organization name Montreal Clinical Research Institute (IRCM)
Department stem cells and cellular reprogramming
Lab Dr. Malleshaiah
Street address 110 Pine Avenue West
City Montreal
State/province Quebec
ZIP/Postal code H2W 1R7
Country Canada
Platforms (1)
GPL20301 Illumina HiSeq 4000 (Homo sapiens)
Samples (2)
GSM6341891 Muscle, control,3 samples pooled, scRNA-seq
GSM6341892 Muscle, patient,3 samples pooled, scRNA-seq
BioProject PRJNA859683

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Supplementary file Size Download File type/resource
GSE208360_Merge_RDS.rds.gz 755.9 Mb (ftp)(http) RDS
GSE208360_RAW.tar 272.2 Mb (http)(custom) TAR (of MTX, RDS, TSV)
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Raw data are available in SRA
Processed data provided as supplementary file
Processed data are available on Series record

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