Correction: 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.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.

Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy

“…At a young age, we find that prednisolone causes premature fibrosis and increased heart mass in mdx mice when vehicle controls show no signs of cardiomyopathy (Heier et al, 2013). In older mdx mice that naturally present with cardiomyopathy, we find that chronic prednisolone treatment increases heart fibrosis, increases blood pressure, and decreases heart function (Guerron et al, 2010; Heier et al, 2013; Uaesoontrachoon et al, 2014). We should note that there are differences in both heart function and blood pressure between the stages of mdx disease; in younger mdx here we saw no natural decrease in heart function and no natural blood pressure phenotype, whereas older mdx develop a cardiomyopathy with decreased heart function and a decrease in blood pressure (Spurney et al, 2009; Uaesoontrachoon et al, 2014).…”