Functional and molecular effects of arginine butyrate and prednisone on muscle and heart in the mdx mouse model of Duchenne Muscular Dystrophy.
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.
Guerron
Alfredo D
AD
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.
Rawat
Rashmi
R
Sali
Arpana
A
Spurney
Christopher F
CF
Pistilli
Emidio
E
Cha
Hee-Jae
HJ
Pandey
Gouri S
GS
Gernapudi
Ramkishore
R
Francia
Dwight
D
Farajian
Viken
V
Escolar
Diana M
DM
Bossi
Laura
L
Becker
Magali
M
Zerr
Patricia
P
de la Porte
Sabine
S
Gordish-Dressman
Heather
H
Partridge
Terence
T
Hoffman
Eric P
EP
Nagaraju
Kanneboyina
K
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
D002087:Butyrates; D012333:RNA, Messenger; D049411:Utrophin; D001120:Arginine; C033018:arginine butyrate; D011241:Prednisone