PMID- 26494902
OWN - NLM
STAT- MEDLINE
DCOM- 20160923
LR  - 20181113
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 25
IP  - 1
DP  - 2016 Jan 1
TI  - Combinatorial therapeutic activation with heparin and AICAR stimulates additive 
      effects on utrophin A expression in dystrophic muscles.
PG  - 24-43
LID - 10.1093/hmg/ddv444 [doi]
AB  - Upregulation of utrophin A is an attractive therapeutic strategy for treating 
      Duchenne muscular dystrophy (DMD). Over the years, several studies revealed that 
      utrophin A is regulated by multiple transcriptional and post-transcriptional 
      mechanisms, and that pharmacological modulation of these pathways stimulates 
      utrophin A expression in dystrophic muscle. In particular, we recently showed 
      that activation of p38 signaling causes an increase in the levels of utrophin A 
      mRNAs and protein by decreasing the functional availability of the destabilizing 
      RNA-binding protein called K-homology splicing regulatory protein, thereby 
      resulting in increases in the stability of existing mRNAs. Here, we treated 
      6-week-old mdx mice for 4 weeks with the clinically used anticoagulant drug 
      heparin known to activate p38 mitogen-activated protein kinase, and determined 
      the impact of this pharmacological intervention on the dystrophic phenotype. Our 
      results show that heparin treatment of mdx mice caused a significant  approximately 1.5- to 
      3-fold increase in utrophin A expression in diaphragm, extensor digitorum longus 
      and tibialis anterior (TA) muscles. In agreement with these findings, 
      heparin-treated diaphragm and TA muscle fibers showed an accumulation of utrophin 
      A and beta-dystroglycan along their sarcolemma and displayed improved morphology and 
      structural integrity. Moreover, combinatorial drug treatment using both heparin 
      and 5-amino-4-imidazolecarboxamide riboside (AICAR), the latter targeting 5' 
      adenosine monophosphate-activated protein kinase and the transcriptional 
      activation of utrophin A, caused an additive effect on utrophin A expression in 
      dystrophic muscle. These findings establish that heparin is a relevant 
      therapeutic agent for treating DMD, and illustrate that combinatorial treatment 
      of heparin with AICAR may serve as an effective strategy to further increase 
      utrophin A expression in dystrophic muscle via activation of distinct signaling 
      pathways.
CI  - (c) The Author 2015. Published by Oxford University Press. All rights reserved. For 
      Permissions, please email: journals.permissions@oup.com.
FAU - Peladeau, Christine
AU  - Peladeau C
AD  - Department of Cellular and Molecular Medicine and Centre for Neuromuscular 
      Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
FAU - Ahmed, Aatika
AU  - Ahmed A
AD  - Department of Cellular and Molecular Medicine and Centre for Neuromuscular 
      Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
FAU - Amirouche, Adel
AU  - Amirouche A
AD  - Department of Cellular and Molecular Medicine and Centre for Neuromuscular 
      Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
FAU - Crawford Parks, Tara E
AU  - Crawford Parks TE
AD  - Department of Cellular and Molecular Medicine and Centre for Neuromuscular 
      Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
FAU - Bronicki, Lucas M
AU  - Bronicki LM
AD  - Department of Cellular and Molecular Medicine and Centre for Neuromuscular 
      Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
FAU - Ljubicic, Vladimir
AU  - Ljubicic V
AD  - Department of Cellular and Molecular Medicine and Centre for Neuromuscular 
      Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
FAU - Renaud, Jean-Marc
AU  - Renaud JM
AD  - Department of Cellular and Molecular Medicine and Centre for Neuromuscular 
      Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
FAU - Jasmin, Bernard J
AU  - Jasmin BJ
AD  - Department of Cellular and Molecular Medicine and Centre for Neuromuscular 
      Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada 
      jasmin@uottawa.ca.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151022
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Ribonucleotides)
RN  - 0 (Utrn protein, mouse)
RN  - 0 (Utrophin)
RN  - 360-97-4 (Aminoimidazole Carboxamide)
RN  - 9005-49-6 (Heparin)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - F0X88YW0YK (AICA ribonucleotide)
SB  - IM
MH  - Aminoimidazole Carboxamide/*analogs & derivatives/therapeutic use
MH  - Animals
MH  - Cell Line
MH  - Drug Therapy, Combination
MH  - Heparin/*therapeutic use
MH  - Mice
MH  - Mice, Inbred mdx
MH  - Muscle, Skeletal/drug effects/metabolism/pathology
MH  - Muscular Dystrophy, Duchenne/*drug therapy
MH  - Ribonucleotides/*therapeutic use
MH  - Signal Transduction/drug effects
MH  - Up-Regulation/drug effects
MH  - Utrophin/*biosynthesis/genetics
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
PMC - PMC4690489
EDAT- 2015/10/24 06:00
MHDA- 2016/09/24 06:00
PMCR- 2017/01/01
CRDT- 2015/10/24 06:00
PHST- 2015/06/02 00:00 [received]
PHST- 2015/10/19 00:00 [accepted]
PHST- 2015/10/24 06:00 [entrez]
PHST- 2015/10/24 06:00 [pubmed]
PHST- 2016/09/24 06:00 [medline]
PHST- 2017/01/01 00:00 [pmc-release]
AID - ddv444 [pii]
AID - 10.1093/hmg/ddv444 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2016 Jan 1;25(1):24-43. doi: 10.1093/hmg/ddv444. Epub 2015 Oct 22.