PMID- 33864373
OWN - NLM
STAT- MEDLINE
DCOM- 20220307
LR  - 20220307
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 30
IP  - 12
DP  - 2021 Jun 9
TI  - Modeling muscle regeneration in RNA toxicity mice.
PG  - 1111-1130
LID - 10.1093/hmg/ddab108 [doi]
AB  - RNA toxicity underlies the pathogenesis of disorders such as myotonic dystrophy 
      type 1 (DM1). Muscular dystrophy is a key element of the pathology of DM1. The 
      means by which RNA toxicity causes muscular dystrophy in DM1 is unclear. Here, we 
      have used the DM200 mouse model of RNA toxicity due to the expression of a mutant 
      DMPK 3'UTR mRNA to model the effects of RNA toxicity on muscle regeneration. 
      Using a BaCl2-induced damage model, we find that RNA toxicity leads to decreased 
      expression of PAX7, and decreased numbers of satellite cells, the stem cells of 
      adult skeletal muscle (also known as MuSCs). This is associated with a delay in 
      regenerative response, a lack of muscle fiber maturation and an inability to 
      maintain a normal number of satellite cells. Repeated muscle damage also elicited 
      key aspects of muscular dystrophy, including fat droplet deposition and increased 
      fibrosis, and the results represent one of the first times to model these classic 
      markers of dystrophic changes in the skeletal muscles of a mouse model of RNA 
      toxicity. Using a ligand-conjugated antisense (LICA) oligonucleotide ASO 
      targeting DMPK sequences for the first time in a mouse model of RNA toxicity in 
      DM1, we find that treatment with IONIS 877864, which targets the DMPK 3'UTR mRNA, 
      is efficacious in correcting the defects in regenerative response and the 
      reductions in satellite cell numbers caused by RNA toxicity. These results 
      demonstrate the possibilities for therapeutic interventions to mitigate the 
      muscular dystrophy associated with RNA toxicity in DM1.
CI  - (c) The Author(s) 2021. Published by Oxford University Press. All rights reserved. 
      For Permissions, please email: journals.permissions@oup.com.
FAU - Yadava, Ramesh S
AU  - Yadava RS
AD  - Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
FAU - Mandal, Mahua
AU  - Mandal M
AD  - Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
FAU - Giese, Jack M
AU  - Giese JM
AD  - Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
FAU - Rigo, Frank
AU  - Rigo F
AD  - Ionis Pharmaceuticals Inc., Carlsbad, CA 90210, USA.
FAU - Bennett, C Frank
AU  - Bennett CF
AD  - Ionis Pharmaceuticals Inc., Carlsbad, CA 90210, USA.
FAU - Mahadevan, Mani S
AU  - Mahadevan MS
AD  - Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
LA  - eng
GR  - R01 AR071170/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (DMPK protein, mouse)
RN  - 0 (Oligonucleotides, Antisense)
RN  - 0 (RNA, Messenger)
RN  - 63231-63-0 (RNA)
RN  - EC 2.7.11.1 (Myotonin-Protein Kinase)
SB  - IM
MH  - Animals
MH  - Disease Models, Animal
MH  - Humans
MH  - Mice
MH  - Muscle Development/*genetics
MH  - Muscle, Skeletal/growth & development/metabolism/pathology
MH  - Myotonic Dystrophy/*genetics/pathology
MH  - Myotonin-Protein Kinase/antagonists & inhibitors/*genetics
MH  - Oligonucleotides, Antisense/*pharmacology
MH  - RNA/*genetics/toxicity
MH  - RNA, Messenger/genetics
MH  - Regeneration/genetics
PMC - PMC8188403
EDAT- 2021/04/18 06:00
MHDA- 2022/03/08 06:00
PMCR- 2021/04/16
CRDT- 2021/04/17 08:33
PHST- 2021/03/23 00:00 [received]
PHST- 2021/04/08 00:00 [revised]
PHST- 2021/04/09 00:00 [accepted]
PHST- 2021/04/18 06:00 [pubmed]
PHST- 2022/03/08 06:00 [medline]
PHST- 2021/04/17 08:33 [entrez]
PHST- 2021/04/16 00:00 [pmc-release]
AID - 6230870 [pii]
AID - ddab108 [pii]
AID - 10.1093/hmg/ddab108 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2021 Jun 9;30(12):1111-1130. doi: 10.1093/hmg/ddab108.