PMID- 25324540
OWN - NLM
STAT- MEDLINE
DCOM- 20151116
LR  - 20220309
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Linking)
VI  - 24
IP  - 5
DP  - 2015 Mar 1
TI  - Utrophin A is essential in mediating the functional adaptations of mdx mouse 
      muscle following chronic AMPK activation.
PG  - 1243-55
LID - 10.1093/hmg/ddu535 [doi]
AB  - Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin along 
      muscle fibers. An attractive therapeutic avenue for DMD consists in the 
      upregulation of utrophin A, a protein with high sequence identity and functional 
      redundancy with dystrophin. Recent work has shown that pharmacological 
      interventions that induce a muscle fiber shift toward a slower, more oxidative 
      phenotype with increased expression of utrophin A confer morphological and 
      functional improvements in mdx mice. Whether such improvements result from the 
      increased expression of utrophin A per se or are linked to other beneficial 
      adaptations associated with the slow, oxidative phenotype remain to be 
      established. To address this central issue, we capitalized on the use of double 
      knockout (dKO) mice, which are mdx mice also deficient in utrophin. We first 
      compared expression of signaling molecules and markers of the slow, oxidative 
      phenotype in muscles of mdx versus dKO mice and found that both strains exhibit 
      similar phenotypes. Chronic activation of 5' adenosine monophosphate-activated 
      protein kinase with 5-amino-4-imidazolecarboxamide riboside (AICAR) resulted in 
      expression of a slower, more oxidative phenotype in both mdx and dKO mice. In mdx 
      mice, this fiber type shift was accompanied by clear functional improvements that 
      included reductions in central nucleation, IgM sarcoplasmic penetration and 
      sarcolemmal damage resulting from eccentric contractions, as well as in increased 
      grip strength. These important morphological and functional adaptations were not 
      seen in AICAR-treated dKO mice. Our findings show the central role of utrophin A 
      in mediating the functional benefits associated with expression of a slower, more 
      oxidative phenotype in dystrophic animals.
CI  - (c) The Author 2014. Published by Oxford University Press. All rights reserved. For 
      Permissions, please email: journals.permissions@oup.com.
FAU - Al-Rewashdy, Hasanen
AU  - Al-Rewashdy H
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 - Lin, Wei
AU  - Lin W
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
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141016
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Ribonucleosides)
RN  - 0 (Utrn protein, mouse)
RN  - 0 (Utrophin)
RN  - 146888-27-9 (Dystroglycans)
RN  - 360-97-4 (Aminoimidazole Carboxamide)
RN  - 53IEF47846 (acadesine)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/genetics/*metabolism
MH  - Aminoimidazole Carboxamide/analogs & derivatives/metabolism
MH  - Animals
MH  - Disease Models, Animal
MH  - Dystroglycans/genetics/metabolism
MH  - Female
MH  - Genotyping Techniques
MH  - Hand Strength/physiology
MH  - Male
MH  - Mice
MH  - Mice, Inbred mdx
MH  - Mice, Knockout
MH  - Muscular Dystrophy, Duchenne/genetics
MH  - Myofibrils/*physiology
MH  - Phenotype
MH  - Ribonucleosides/metabolism
MH  - Utrophin/*genetics/metabolism
EDAT- 2014/10/18 06:00
MHDA- 2015/11/17 06:00
CRDT- 2014/10/18 06:00
PHST- 2014/10/18 06:00 [entrez]
PHST- 2014/10/18 06:00 [pubmed]
PHST- 2015/11/17 06:00 [medline]
AID - ddu535 [pii]
AID - 10.1093/hmg/ddu535 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2015 Mar 1;24(5):1243-55. doi: 10.1093/hmg/ddu535. Epub 2014 Oct 
      16.