ABSTRACT
Duchenne muscular dystrophy (DMD) is a progressive and ultimately fatal skeletal muscle disease. Currently, the most effective therapy is the administration of a subclass of glucocorticoids, most notably deflazacort. Although deflazacort treatment can attenuate DMD progression, extend ambulation, and maintain muscle strength, the mechanism of its action remains unknown. Prior observations have shown that activation of a JNK1-mediated signal transduction cascade contributes to the progression of the DMD phenotype, in part by phosphorylation and inhibition of a calcineurin sensitive NF-ATc1 transcription factor. Here, we observed that deflazacort treatment restored myocyte viability in muscle cells with constitutive activation of JNK1 and in dystrophic mdx mice. However, deflazacort treatment did not alter JNK1 activity itself, but rather led to an increase in the activity of the calcineurin phosphatase and an up-regulation of NF-ATc1-dependent gene expression. The prophylactic effect of deflazacort treatment was associated with increased expression of NF-ATc1 target genes such as the dystrophin homologue utrophin. Moreover, the muscle sparing effects of deflazacort were completely abolished when used in conjunction with the calcineurin inhibitor cyclosporine. Collectively, these results show that deflazacort attenuates loss of dystrophic myofiber integrity by up-regulating the activity of the phosphatase calcineurin, which in turn negates JNK1 inhibition of NF-ATc1-mediated phosphorylation and nuclear exclusion of NF-ATc1.
Subject(s)
Calcineurin/metabolism , DNA-Binding Proteins/metabolism , Muscle Fibers, Skeletal/drug effects , Muscular Dystrophy, Duchenne/metabolism , Nuclear Proteins/metabolism , Pregnenediones/pharmacology , Transcription Factors/metabolism , Active Transport, Cell Nucleus , Animals , Cell Nucleus/metabolism , Enzyme Activation , Mice , Mice, Inbred mdx , Mitogen-Activated Protein Kinase 8/antagonists & inhibitors , Muscle Fibers, Skeletal/enzymology , Muscle Fibers, Skeletal/pathology , Muscle, Skeletal/drug effects , Muscle, Skeletal/pathology , Muscular Dystrophy, Duchenne/drug therapy , Muscular Dystrophy, Duchenne/pathology , NFATC Transcription Factors , Pregnenediones/therapeutic use , Signal Transduction/drug effects , Transcriptional Activation , Utrophin/metabolismABSTRACT
Muscular dystrophies are broadly classed as skeletal muscle disease entities of genetic origin. Accordingly, the development and application of gene therapy treatment modalities has focused on skeletal muscle gene replacement. Irrespective of this generalization, most forms of dystrophy are accompanied by progressive cardiomyopathy and cardiac involvement in muscular dystrophies is now recognized as an independent risk for patient morbidity. In this review, we summarize the available murine strains most suitable for modeling the dystrophic myocardium and discuss the use of adenoviral based vector systems as the preferred gene delivery vehicle for modulating dystrophic cardiomyopathy.
