Functional and Molecular Effects of Arginine Butyrate and Prednisone on Muscle and Heart in the mdx Mouse Model of Duchenne Muscular Dystrophy

被引：39

作者：

Guerron, Alfredo D. ^{[1
]}

Rawat, Rashmi ^{[1
]}

Sali, Arpana ^{[1
]}

Spurney, Christopher F. ^{[2
]}

Pistilli, Emidio ^{[3
]}

Cha, Hee-Jae ^{[4
]}

Pandey, Gouri S. ^{[1
]}

Gernapudi, Ramkishore ^{[1
]}

Francia, Dwight ^{[1
]}

Farajian, Viken ^{[1
]}

Escolar, Diana M. ^{[1
]}

Bossi, Laura ^{[5
]}

Becker, Magali ^{[5
]}

Zerr, Patricia ^{[5
]}

de la Porte, Sabine

Gordish-Dressman, Heather ^{[1
]}

Partridge, Terence ^{[1
]}

Hoffman, Eric P. ^{[1
]}

Nagaraju, Kanneboyina ^{[1
]}

机构：

[1] George Washington Univ, Sch Med & Hlth Sci, Dept Integrat Syst Biol, Childrens Natl Med Ctr,Ctr Genet Med Res, Washington, DC 20052 USA

[2] Childrens Natl Med Ctr, Div Cardiol, Washington, DC 20010 USA

[3] Univ Penn, Pennsylvania Muscle Inst, Philadelphia, PA 19104 USA

[4] Kosin Univ, Coll Med, Dept Parasitol & Genet, Pusan, South Korea

[5] Transgene SA, Illkirch Graffenstaden, France

来源：

PLOS ONE | 2010年 / 5卷 / 06期

基金：

美国国家卫生研究院;

关键词：

GLUCOCORTICOID TREATMENT; MICE; STRENGTH; IMPROVES; CELLS; DEFLAZACORT; EXPRESSION; DIAPHRAGM; PERSISTENT; FIBROSIS;

D O I：

10.1371/journal.pone.0011220

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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. Methodology/Principal Findings: 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/Significance: 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.

引用

页数：12

共 33 条

[1] Deflazacort increases laminin expression and myogenic repair, and induces early persistent functional gain in mdx mouse muscular dystrophy [J].