Arginine butyrate: a therapeutic candidate for Duchenne muscular dystrophy.

Sara Vianello (1, 2) , Hua Yu (1) , Vincent Voisin (1) , Hafedh Haddad (1) , Xun He (1) , Arthur S. Foutz (1) , Catherine Sebrié (3) , Brigitte Gillet (3) , Morgane Roulot (1) , Françoise Fougerousse (4) , Caroline Perronnet (5) , Cyrille Vaillend (5) , Stefan Matecki (6, 7) , Diana Escolar (8) , Laura Bossi , Maurice Israël (1) , Sabine de La Porte (2, 1)

1 INAF - Institut de Neurobiologie Alfred Fessard
2 N&eD - Neurobiologie et Développement
3 ICSN - Institut de Chimie des Substances Naturelles
4 Généthon
5 CNPS - Centre de Neurosciences Paris-Sud
6 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
7 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
8 Johns Hopkins School of Medicine

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.

Domaines: Neurosciences [q-bio.NC]

Sara Vianello, Hua Yu, Vincent Voisin, Hafedh Haddad, Xun He, et al.. Arginine butyrate: a therapeutic candidate for Duchenne muscular dystrophy.. FASEB Journal, 2013, 27 (6), pp.2256-69. ⟨10.1096/fj.12-215723⟩. ⟨hal-00850330⟩