title: Treatment with the cysteine precursor l-2-oxothiazolidine-4-carboxylate (OTC) implicates taurine deficiency in severity of dystropathology in mdx mice.
abstract: Oxidative stress has been implicated in the pathology of the lethal skeletal muscle disease Duchenne muscular dystrophy (DMD), and various antioxidants have been investigated as a potential therapy. Recently, treatment of the mdx mouse model for DMD with the antioxidant and cysteine and glutathione (GSH) precursor n-acetylcysteine (NAC) was shown to decrease protein thiol oxidation and improve muscle pathology and ex vivo muscle strength. This study further investigates the mechanism for the benefits of NAC on dystrophic muscle by administering l-2-oxothiazolidine-4-carboxylate (OTC) which also upregulates intracellular cysteine and GSH, but does not directly function as an antioxidant. We observed that OTC, like NAC, decreases protein thiol oxidation, decreases pathology and increases strength, suggesting that the both NAC and OTC function via increasing cysteine and GSH content of dystrophic muscle. We demonstrate that mdx muscle is not deficient in either cysteine or GSH and that these are not increased by OTC treatment. However, we show that dystrophic muscle of 12 week old mdx mice is deficient in taurine, a by-product of disposal of excess cysteine, a deficiency that is ameliorated by OTC treatment. These data suggest that in dystrophic muscles, apart from the strong association of increased oxidative stress and protein thiol oxidation with dystropathology, another major issue is an insufficiency in taurine that can be corrected by increasing the availability of cysteine. This study provides new insight into the molecular mechanism underlying the benefits of NAC in muscular dystrophy and supports the use of OTC as an alternative drug for potential clinical applications to DMD.
authors.affiliation: School of Anatomy, Physiology and Human Biology, The University of Western Australia, Perth, Western Australia, Australia. jessica.terrill@uwa.edu.au
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Terrill
authors.forename: Amber
authors.initials: A
authors.lastname: Boyatzis
authors.forename: Miranda D
authors.initials: MD
authors.lastname: Grounds
authors.forename: Peter G
authors.initials: PG
authors.lastname: Arthur
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011761:Pyrrolidonecarboxylic Acid / Q000494:pharmacology*; D013654:Taurine / Q000172:deficiency* / Q000378:metabolism; D053778:Thiazolidines / Q000494:pharmacology*
chemical_list: D053778:Thiazolidines; D013654:Taurine; D011761:Pyrrolidonecarboxylic Acid; D000111:Acetylcysteine; C029536:2-oxothiazolidine-4-carboxylic acid
keywords: -2-oxothiazolidine-4-carboxylate; 2-[6-(4-aminophenoxy)-3-oxo-3H-xanthen-9-yl]benzoic acid; 2-mercaptoethanol; 2ME; 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; 5,5′-dithiobis-(2-nitrobenzoic acid); ACN; APF; BODIPY FL-N-(2-aminoethyl) maleimide; CK; CS; CTAB; DMD; DTNB; Duchenne muscular dystrophy; EGTA; FLM; GSH; GSSG; HEPES; MPO; N-ethylmaleimide; NEM; OPA; OTCl; Oxidative stress; PBS; ROS; SDS; SDS-PAGE; TCA; TCEP; TNF; Taurine; Texas Red C2-maleimide; Texas red; acetonitrile; citrate synthase; creatine kinase; ethylene glycol tetraacetic acid; glutathione; hexadecyltrimethylammonium bromide; l-2-Oxothiazolidine-4-carboxylate; mdx mice; myeloperoxidase, N-acetylcysteine; o-phthalaldehyde; oxidized glutathione; phosphate buffered saline; reactive oxygen species; sodium dodecyl sulphate; sodium dodecyl sulphate polyacrylamide gel electrophoresis; trichloroacetic acid; tris(2-carboxyethyl)phosphine; tumor necrosis factor