title: Utrophin A is essential in mediating the functional adaptations of mdx mouse muscle following chronic AMPK activation.
abstract: 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.
authors.affiliation: Department of Cellular and Molecular Medicine, and Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Hasanen
authors.initials: H
authors.lastname: Al-Rewashdy
authors.affiliation: Department of Cellular and Molecular Medicine, and Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ljubicic
authors.affiliation: Department of Cellular and Molecular Medicine, and Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Lin
authors.affiliation: Department of Cellular and Molecular Medicine, and Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Renaud
authors.affiliation: Department of Cellular and Molecular Medicine, and Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada jasmin@uottawa.ca.
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Jasmin
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D049030:Dystroglycans / Q000235:genetics / Q000378:metabolism; D005260:Female; D060005:Genotyping Techniques; D018737:Hand Strength / Q000502:physiology; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics; D009210:Myofibrils / Q000502:physiology*; D010641:Phenotype; D012263:Ribonucleosides / Q000378:metabolism; D049411:Utrophin / Q000235:genetics* / Q000378:metabolism
chemical_list: D012263:Ribonucleosides; C483600:Utrn protein, mouse; D049411:Utrophin; D049030:Dystroglycans; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D055372:AMP-Activated Protein Kinases