title: Arginine butyrate: a therapeutic candidate for Duchenne muscular dystrophy.
abstract: As a strategy to treat Duchenne muscular dystrophy, we used arginine butyrate, which combines two pharmacological activities: nitric oxide pathway activation, and histone deacetylase inhibition. Continuous intraperitoneal administration to dystrophin-deficient mdx mice resulted in a near 2-fold increase in utrophin (protein homologous to dystrophin) in skeletal muscle, heart, and brain, accompanied by an improvement of the dystrophic phenotype in both adult and newborn mice (45 and 70% decrease in creatine kinase level, respectively; 14% increase in tidal volume, 30% decrease in necrotic area in limb and 23% increase in isometric force). Intermittent administration, as performed in clinical trials, was then used to reduce the frequency of injections and to improve safety. This also enhanced utrophin level around 2-fold (EC50=284 mg/ml) and alleviated the dystrophic phenotype (inverted grid and grip test performance near to wild-type values, creatine kinase level decreased by 50%). Skin biopsies were used to monitor treatment efficacy, instead of invasive muscle biopsies, and this could be done a few days after the start of treatment. A 2-fold increase in utrophin expression was also shown in cultured human myotubes. In vivo and in vitro experiments demonstrated that the drug combination acts synergistically. Together, these data constitute a proof of principle of the beneficial effects of arginine butyrate on muscular dystrophy.
authors: Neurobiologie & Développement-Unité Propres de Recherche 3294, Centre National de la Recherche Scientifique, Institut de Neurobiologie Alfred Fessard-FRC2118, Gif sur Yvette, France.
authors: Sara
authors: S
authors: Vianello
authors: Hua
authors: H
authors: Yu
authors: Vincent
authors: V
authors: Voisin
authors: Hafedh
authors: H
authors: Haddad
authors: Xun
authors: X
authors: He
authors: Arthur S
authors: AS
authors: Foutz
authors: Catherine
authors: C
authors: Sebrié
authors: Brigitte
authors: B
authors: Gillet
authors: Morgane
authors: M
authors: Roulot
authors: Françoise
authors: F
authors: Fougerousse
authors: Caroline
authors: C
authors: Perronnet
authors: Cyrille
authors: C
authors: Vaillend
authors: Stefan
authors: S
authors: Matecki
authors: Diana
authors: D
authors: Escolar
authors: Laura
authors: L
authors: Bossi
authors: Maurice
authors: M
authors: Israël
authors: Sabine
authors: S
authors: de la Porte
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002087:Butyrates / Q000008:administration & dosage / Q000627:therapeutic use*; D002478:Cells, Cultured; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects; D049411:Utrophin / Q000235:genetics
chemical_list: D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; C483600:Utrn protein, mouse; D049411:Utrophin; C551344:utrophin B, mouse; D001120:Arginine; C033018:arginine butyrate
keywords: DMD; NO; histone deacetylase; mdx; pharmacology; treatment