title: Nitric oxide signalling pathway in Duchenne muscular dystrophy mice: up-regulation of L-arginine transporters.
abstract: DMD (Duchenne muscular dystrophy) is an incurable rapidly worsening neuromuscular degenerative disease caused by the absence of dystrophin. In skeletal muscle a lack of dystrophin disrupts the recruitment of neuronal NOS (nitric oxide synthase) to the sarcolemma thus affecting NO (nitric oxide) production. Utrophin is a dystrophin homologue, the expression of which is greatly up-regulated in the sarcolemma of dystrophin-negative fibres from mdx mice, a mouse model of DMD. Although cardiomyopathy is an important cause of death, little is known about the NO signalling pathway in the cardiac muscle of DMD patients. Thus we used cardiomyocytes and hearts from two month-old mdx and mdx:utrophin-/- (double knockout) mice (mdx:utr) to study key steps in NO signalling: L-arginine transporters, NOS and sGC (soluble guanylyl cyclase). nNOS did not co-localize with dystrophin or utrophin to the cardiomyocyte membrane. Despite this nNOS activity was markedly decreased in both mdx and mdx:utr mice, whereas nNOS expression was only decreased in mdx:utr mouse hearts, suggesting that utrophin up-regulation in cardiomyocytes maintains nNOS levels, but not function. sGC protein levels and activity remained at control levels. Unexpectedly, L-arginine transporter expression and function were significantly increased, suggesting a novel biochemical compensatory mechanism of the NO pathway and a potential entry site for therapeutics.
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, U.S.A.
authors.forename: Jayalakshmi
authors.initials: J
authors.lastname: Ramachandran
authors.forename: Joel S
authors.initials: JS
authors.lastname: Schneider
authors.forename: Pierre-Antoine
authors.initials: PA
authors.lastname: Crassous
authors.forename: Ruifang
authors.initials: R
authors.lastname: Zheng
authors.forename: James P
authors.initials: JP
authors.lastname: Gonzalez
authors.forename: Lai-Hua
authors.initials: LH
authors.lastname: Xie
authors.forename: Annie
authors.initials: A
authors.lastname: Beuve
authors.forename: Diego
authors.initials: D
authors.lastname: Fraidenraich
authors.forename: R Daniel
authors.initials: RD
authors.lastname: Peluffo
mesh_terms: D026905:Amino Acid Transport Systems; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D027201:Cationic Amino Acid Transporter 1 / Q000096:biosynthesis* / Q000235:genetics; D027202:Cationic Amino Acid Transporter 2 / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics*; D049411:Utrophin / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics
chemical_list: D026905:Amino Acid Transport Systems; D027201:Cationic Amino Acid Transporter 1; D027202:Cationic Amino Acid Transporter 2; C420826:Slc7a1 protein, mouse; D049411:Utrophin; D009569:Nitric Oxide; D001120:Arginine; D052248:Nitric Oxide Synthase Type I