Low doses of arginine butyrate derivatives improve dystrophic phenotype and restore membrane integrity in DMD models. - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue FASEB Journal Année : 2014

Low doses of arginine butyrate derivatives improve dystrophic phenotype and restore membrane integrity in DMD models.

Résumé

: A new approach to treating Duchenne muscular dystrophy was investigated by using the ester or amide covalent association of arginine [nitric oxide (NO) pathway] and butyrate [histone deacetylase (HDAC) inhibition] in mdx mice and patient myotubes. Two prodrugs were synthesized, and the beneficial effects on dystrophic phenotype were studied. Nerve excitability abnormalities detected in saline-treated mice were almost totally rescued in animals treated at low doses (50-100 mg/kg/d). Force and fatigue resistance were improved ≈60% and 3.5-fold, respectively, and the percentage of necrosis in heart sections was reduced ≈90% in the treated mice. A decrease of >50% in serum creatine kinase indicated an overall improvement in the muscles. Restoration of membrane integrity was studied directly by measuring the reduction (≈74%) of Evans blue incorporation in the limb muscles of the treated animals, the increase in utrophin level, and the normalization of lipid composition of the heart. In cultures of human myotubes (primary cells and cell line), both prodrugs and HDAC inhibitors increased by 2- to 4-fold the utrophin level, which was correctly localized at the membrane. β-Dystroglycan and embryonic myosin protein levels were also increased. Finally, a 50% reduction in the number of spontaneous Ca(2+) spikes was observed after treatment with NO synthase substrate and HDAC inhibitors. Overall, the beneficial effects were obtained with doses 10 (in vivo) and 5 (in vitro) times lower than those of the salt formulation. Altogether, these data constitute proof of principle of the beneficial effects of low doses of arginine butyrate derivatives on muscular dystrophy, enhancing the NO pathway and inhibiting HDAC.-Vianello, S., Consolaro, F., Bich, C., Cancela, J.-M., Roulot, M., Lanchec, E., Touboul, D., Brunelle, A., Israël, M., Benoit, E., de la Porte, S. Low doses of arginine butyrate derivatives improve dystrophic phenotype and restore membrane integrity in DMD models.

Domaines

Chimie organique
Fichier non déposé

Dates et versions

hal-01003300 , version 1 (10-06-2014)

Identifiants

Citer

Sara Vianello, Francesca Consolaro, Claudia Bich, José-Manuel Cancela, Morgane Roulot, et al.. Low doses of arginine butyrate derivatives improve dystrophic phenotype and restore membrane integrity in DMD models.. FASEB Journal, 2014, 28 (6), pp.2603-2619. ⟨10.1096/fj.13-244798⟩. ⟨hal-01003300⟩
125 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More