PMID- 21659335
OWN - NLM
STAT- MEDLINE
DCOM- 20120112
LR  - 20171116
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Linking)
VI  - 20
IP  - 17
DP  - 2011 Sep 1
TI  - Chronic AMPK activation evokes the slow, oxidative myogenic program and triggers 
      beneficial adaptations in mdx mouse skeletal muscle.
PG  - 3478-93
LID - 10.1093/hmg/ddr265 [doi]
AB  - A therapeutic approach for Duchenne muscular dystrophy (DMD) is to up-regulate 
      utrophin in skeletal muscle in an effort to compensate for the lack of 
      dystrophin. We previously hypothesized that promotion of the slow, oxidative 
      myogenic program, which triggers utrophin up-regulation, can attenuate the 
      dystrophic pathology in mdx animals. Since treatment of healthy mice with the 
      AMP-activated protein kinase (AMPK) activator 
      5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) enhances oxidative 
      capacity and elicits a fast-to-slow fiber-type transition, we evaluated the 
      effects of chronic AMPK stimulation on skeletal muscle phenotype and utrophin 
      expression in mdx mice. Daily AICAR administration (500 mg/kg/day, 30 days) of 
      5-7-week-old mdx animals induced an elevation in mitochondrial cytochrome c 
      oxidase enzyme activity, an increase in myosin heavy-chain type IIa-positive 
      fibers and slower twitch contraction kinetics in the fast, glycolytic extensor 
      digitorum longus muscle. Utrophin expression was significantly enhanced in 
      response to AICAR, which occurred coincident with an elevated beta-dystroglycan 
      expression along the sarcolemma. These adaptations were associated with an 
      increase in sarcolemmal structural integrity under basal conditions, as well as 
      during damaging eccentric contractions ex vivo. Notably, peroxisome 
      proliferator-activated receptor gamma co-activator-1alpha (PGC-1alpha) and silent information 
      regulator two ortholog 1 protein contents were significantly higher in muscle 
      from mdx mice compared with wild-type littermates and AICAR further increased 
      PGC-1alpha expression. Our data show that AICAR-evoked muscle plasticity results in 
      beneficial phenotypic adaptations in mdx mice and suggest that the contextually 
      novel application of this compound for muscular dystrophy warrants further study.
FAU - Ljubicic, Vladimir
AU  - Ljubicic V
AD  - Department of Cellular and Molecular Medicine, Faculty of Medicine, Centre for 
      Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
FAU - Miura, Pedro
AU  - Miura P
FAU - Burt, Matthew
AU  - Burt M
FAU - Boudreault, Louise
AU  - Boudreault L
FAU - Khogali, Shiemaa
AU  - Khogali S
FAU - Lunde, John A
AU  - Lunde JA
FAU - Renaud, Jean-Marc
AU  - Renaud JM
FAU - Jasmin, Bernard J
AU  - Jasmin BJ
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110609
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (PPAR gamma)
RN  - 0 (Ribonucleotides)
RN  - 146888-27-9 (Dystroglycans)
RN  - 360-97-4 (Aminoimidazole Carboxamide)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - F0X88YW0YK (AICA ribonucleotide)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Aminoimidazole Carboxamide/*analogs & derivatives/pharmacology
MH  - Animals
MH  - Cell Line
MH  - Dystroglycans/genetics/metabolism
MH  - Mice
MH  - Mice, Inbred mdx
MH  - Muscle, Skeletal/*drug effects/*metabolism
MH  - PPAR gamma/genetics/metabolism
MH  - Ribonucleotides/*pharmacology
MH  - Sarcolemma/genetics/metabolism
EDAT- 2011/06/11 06:00
MHDA- 2012/01/13 06:00
CRDT- 2011/06/11 06:00
PHST- 2011/06/11 06:00 [entrez]
PHST- 2011/06/11 06:00 [pubmed]
PHST- 2012/01/13 06:00 [medline]
AID - ddr265 [pii]
AID - 10.1093/hmg/ddr265 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2011 Sep 1;20(17):3478-93. doi: 10.1093/hmg/ddr265. Epub 2011 Jun 
      9.