PMID- 37285284
OWN - NLM
STAT- MEDLINE
DCOM- 20230609
LR  - 20230710
IS  - 2050-084X (Electronic)
IS  - 2050-084X (Linking)
VI  - 12
DP  - 2023 Jun 7
TI  - Inhibition of type I PRMTs reforms muscle stem cell identity enhancing their 
      therapeutic capacity.
LID - 10.7554/eLife.84570 [doi]
LID - RP84570
AB  - In skeletal muscle, muscle stem cells (MuSC) are the main cells responsible for 
      regeneration upon injury. In diseased skeletal muscle, it would be 
      therapeutically advantageous to replace defective MuSCs, or rejuvenate them with 
      drugs to enhance their self-renewal and ensure long-term regenerative potential. 
      One limitation of the replacement approach has been the inability to efficiently 
      expand MuSCs ex vivo, while maintaining their stemness and engraftment abilities. 
      Herein, we show that inhibition of type I protein arginine methyltransferases 
      (PRMTs) with MS023 increases the proliferative capacity of ex vivo cultured 
      MuSCs. Single cell RNA sequencing (scRNAseq) of ex vivo cultured MuSCs revealed 
      the emergence of subpopulations in MS023-treated cells which are defined by 
      elevated Pax7 expression and markers of MuSC quiescence, both features of 
      enhanced self-renewal. Furthermore, the scRNAseq identified MS023-specific 
      subpopulations to be metabolically altered with upregulated glycolysis and 
      oxidative phosphorylation (OxPhos). Transplantation of MuSCs treated with MS023 
      had a better ability to repopulate the MuSC niche and contributed efficiently to 
      muscle regeneration following injury. Interestingly, the preclinical mouse model 
      of Duchenne muscular dystrophy had increased grip strength with MS023 treatment. 
      Our findings show that inhibition of type I PRMTs increased the proliferation 
      capabilities of MuSCs with altered cellular metabolism, while maintaining their 
      stem-like properties such as self-renewal and engraftment potential.
CI  - (c) 2023, Dominici et al.
FAU - Dominici, Claudia
AU  - Dominici C
AD  - Segal Cancer Center, Lady Davis Institute for Medical Research, McGill 
      University, Montreal, Canada.
AD  - Departments of Human Genetics, McGill University, Montreal, Canada.
FAU - Villarreal, Oscar D
AU  - Villarreal OD
AD  - Segal Cancer Center, Lady Davis Institute for Medical Research, McGill 
      University, Montreal, Canada.
FAU - Dort, Junio
AU  - Dort J
AD  - CHU Sainte-Justine Research Center, Universite de Montreal, Montreal, Canada.
FAU - Heckel, Emilie
AU  - Heckel E
AD  - CHU Sainte-Justine Research Center, Universite de Montreal, Montreal, Canada.
FAU - Wang, Yu Chang
AU  - Wang YC
AD  - Genome Quebec Innovation Centre, Montreal, Canada.
FAU - Ragoussis, Ioannis
AU  - Ragoussis I
AD  - Genome Quebec Innovation Centre, Montreal, Canada.
FAU - Joyal, Jean-Sebastien
AU  - Joyal JS
AD  - CHU Sainte-Justine Research Center, Universite de Montreal, Montreal, Canada.
FAU - Dumont, Nicolas
AU  - Dumont N
AD  - CHU Sainte-Justine Research Center, Universite de Montreal, Montreal, Canada.
FAU - Richard, Stephane
AU  - Richard S
AUID- ORCID: 0000-0003-2665-4806
AD  - Segal Cancer Center, Lady Davis Institute for Medical Research, McGill 
      University, Montreal, Canada.
AD  - Departments of Human Genetics, McGill University, Montreal, Canada.
AD  - Gerald Bronfman, Department of Oncology, McGill University, Montreal, Canada.
AD  - Departments of Medicine, McGill University, Montreal, Canada.
AD  - Departments of Biochemistry, McGill University, Montreal, Canada.
LA  - eng
SI  - GEO/GSM5972491
SI  - GEO/GSM5972492
SI  - GEO/GSM5972493
SI  - GEO/GSM5972494
GR  - FDN-154303/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230607
PL  - England
TA  - Elife
JT  - eLife
JID - 101579614
RN  - EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
SB  - IM
UOF - doi: 10.1101/2023.01.03.522550
UOF - doi: 10.7554/eLife.84570.1
UOF - doi: 10.7554/eLife.84570.2
MH  - Animals
MH  - Mice
MH  - Muscle, Skeletal/metabolism
MH  - *Satellite Cells, Skeletal Muscle/metabolism
MH  - Cells, Cultured
MH  - *Muscular Dystrophy, Duchenne/therapy/metabolism
MH  - Protein-Arginine N-Methyltransferases/metabolism
PMC - PMC10328524
OTO - NOTNLM
OT  - MS023
OT  - arginine methylation
OT  - duchenne muscular dystrophy
OT  - mouse
OT  - muscle stem cell
OT  - regenerative medicine
OT  - skeletal muscle
OT  - stem cells
OT  - type I PRMT
COIS- CD, OV, JD, EH, YW, IR, JJ, ND, SR No competing interests declared
EDAT- 2023/06/07 19:42
MHDA- 2023/06/09 06:42
PMCR- 2023/06/07
CRDT- 2023/06/07 12:53
PHST- 2023/06/09 06:42 [medline]
PHST- 2023/06/07 19:42 [pubmed]
PHST- 2023/06/07 12:53 [entrez]
PHST- 2023/06/07 00:00 [pmc-release]
AID - 84570 [pii]
AID - 10.7554/eLife.84570 [doi]
PST - epublish
SO  - Elife. 2023 Jun 7;12:RP84570. doi: 10.7554/eLife.84570.