title: Functional and molecular effects of arginine butyrate and prednisone on muscle and heart in the mdx mouse model of Duchenne Muscular Dystrophy.
abstract: BACKGROUND
  The number of promising therapeutic interventions for Duchenne Muscular Dystrophy (DMD) is increasing rapidly. One of the proposed strategies is to use drugs that are known to act by multiple different mechanisms including inducing of homologous fetal form of adult genes, for example utrophin in place of dystrophin.
  
  
  RESULTS
  In this study, we have treated mdx mice with arginine butyrate, prednisone, or a combination of arginine butyrate and prednisone for 6 months, beginning at 3 months of age, and have comprehensively evaluated the functional, biochemical, histological, and molecular effects of the treatments in this DMD model. Arginine butyrate treatment improved grip strength and decreased fibrosis in the gastrocnemius muscle, but did not produce significant improvement in muscle and cardiac histology, heart function, behavioral measurements, or serum creatine kinase levels. In contrast, 6 months of chronic continuous prednisone treatment resulted in deterioration in functional, histological, and biochemical measures. Arginine butyrate-treated mice gene expression profiling experiments revealed that several genes that control cell proliferation, growth and differentiation are differentially expressed consistent with its histone deacetylase inhibitory activity when compared to control (saline-treated) mdx mice. Prednisone and combination treated groups showed alterations in the expression of genes that control fibrosis, inflammation, myogenesis and atrophy.
  
  
  CONCLUSIONS
  These data indicate that 6 months treatment with arginine butyrate can produce modest beneficial effects on dystrophic pathology in mdx mice by reducing fibrosis and promoting muscle function while chronic continuous treatment with prednisone showed deleterious effects to skeletal and cardiac muscle. Our results clearly indicate the usefulness of multiple assays systems to monitor both beneficial and toxic effects of drugs with broad range of in vivo activity.
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
authors.forename: Alfredo D
authors.initials: AD
authors.lastname: Guerron
authors.forename: Rashmi
authors.initials: R
authors.lastname: Rawat
authors.forename: Arpana
authors.initials: A
authors.lastname: Sali
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Spurney
authors.forename: Emidio
authors.initials: E
authors.lastname: Pistilli
authors.forename: Hee-Jae
authors.initials: HJ
authors.lastname: Cha
authors.forename: Gouri S
authors.initials: GS
authors.lastname: Pandey
authors.forename: Ramkishore
authors.initials: R
authors.lastname: Gernapudi
authors.forename: Dwight
authors.initials: D
authors.lastname: Francia
authors.forename: Viken
authors.initials: V
authors.lastname: Farajian
authors.forename: Diana M
authors.initials: DM
authors.lastname: Escolar
authors.forename: Laura
authors.initials: L
authors.lastname: Bossi
authors.forename: Magali
authors.initials: M
authors.lastname: Becker
authors.forename: Patricia
authors.initials: P
authors.lastname: Zerr
authors.forename: Sabine
authors.initials: S
authors.lastname: de la Porte
authors.forename: Heather
authors.initials: H
authors.lastname: Gordish-Dressman
authors.forename: Terence
authors.initials: T
authors.lastname: Partridge
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D051379:Mice; D018101:Mice, Inbred mdx; D009132:Muscles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D011241:Prednisone / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D049411:Utrophin / Q000378:metabolism
chemical_list: D002087:Butyrates; D012333:RNA, Messenger; D049411:Utrophin; D001120:Arginine; C033018:arginine butyrate; D011241:Prednisone