Abstract
The mdx mouse is a good genetic and molecular murine model for Duchenne Muscular Dystrophy (DMD), a progressive and devastating muscle disease. However, this model is inappropriate for testing new therapies due to its mild phenotype. Here, we transferred the mdx mutation to the 129/Sv strain with the aim to create a more severe model for DMD. Unexpectedly, functional analysis of the first three generations of mdx129 showed a progressive amelioration of the phenotype, associated to less connective tissue replacement, and more regeneration than the original mdxC57BL. Transcriptome comparative analysis was performed to identify what is protecting this new model from the dystrophic characteristics. The mdxC57BL presents three times more differentially expressed genes (DEGs) than the mdx129 (371 and 137 DEGs respectively). However, both models present more overexpressed genes than underexpressed, indicating that the dystrophic and regenerative alterations are associated with the activation rather than repression of genes. As to functional categories, the DEGs of both mdx models showed a predominance of immune system genes. Excluding this category, the mdx129 model showed a decreased participation of the endo/exocytic pathway and homeostasis categories, and an increased participation of the extracellular matrix and enzymatic activity categories. Spp1 gene overexpression was the most significant DEG exclusively expressed in the mdx129 strain. This was confirmed through relative mRNA analysis and osteopontin protein quantification. The amount of the 66 kDa band of the protein, representing the post-translational product of the gene, was about 4,8 times higher on western blotting. Spp1 is a known DMD prognostic biomarker, and our data indicate that its upregulation can benefit phenotype. Modeling the expression of the DEGs involved in the mdx mutation with a benign course should be tested as a possible therapeutic target for the dystrophic process.
Highlights
Neuromuscular disorders are a heterogeneous group of genetic diseases, causing progressive loss of motor ability
Duchenne muscular dystrophy (DMD) is the most common and severe human muscular dystrophy, affecting 1 in 3500 male births. It is caused by mutations in the dystrophin gene which result in the absence of this important sarcolemmal protein and consequent muscle degeneration
In the grip strength test, first generation of mdx129 (F1) animals were stronger than mdxC57BL mice, but the results were only significant at 30 days, three and four months
Summary
Neuromuscular disorders are a heterogeneous group of genetic diseases, causing progressive loss of motor ability. More than 30 genetically defined forms are recognized and in the last decade mutations in several genes have been reported that result in deficiency or loss of function of different important muscle proteins. Duchenne muscular dystrophy (DMD) is the most common and severe human muscular dystrophy, affecting 1 in 3500 male births. It is caused by mutations in the dystrophin gene which result in the absence of this important sarcolemmal protein and consequent muscle degeneration. The clinical course of DMD is severe and progressive, starting with muscle weakness at the age of five and loss of ambulation around 12 years; without special care, death occurs due to respiratory failure or cardiomyopathy in the late teens [1]. There is no effective cure for patients suffering from this type of dystrophy
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