title: The mdx Mutation in the 129/Sv Background Results in a Milder Phenotype: Transcriptome Comparative Analysis Searching for the Protective Factors.
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.
authors.affiliation: Laboratory of Muscle Proteins and Comparative Histopathology, Human Genome and Stem-cell Research Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Priscila Clara
authors.initials: PC
authors.lastname: Calyjur
authors.affiliation: Laboratory of Muscle Proteins and Comparative Histopathology, Human Genome and Stem-cell Research Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Camila de Freitas
authors.initials: Cde F
authors.lastname: Almeida
authors.affiliation: Laboratory of Muscle Proteins and Comparative Histopathology, Human Genome and Stem-cell Research Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Danielle
authors.initials: D
authors.lastname: Ayub-Guerrieri
authors.affiliation: Laboratory of Muscle Proteins and Comparative Histopathology, Human Genome and Stem-cell Research Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Antonio Fernando
authors.initials: AF
authors.lastname: Ribeiro
authors.affiliation: Laboratory of Muscle Proteins and Comparative Histopathology, Human Genome and Stem-cell Research Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Stephanie de Alcântara
authors.initials: Sde A
authors.lastname: Fernandes
authors.affiliation: Laboratory of Muscle Proteins and Comparative Histopathology, Human Genome and Stem-cell Research Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Renata
authors.initials: R
authors.lastname: Ishiba
authors.affiliation: Laboratory of Muscle Proteins and Comparative Histopathology, Human Genome and Stem-cell Research Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Andre Luis Fernandes Dos
authors.initials: AL
authors.lastname: Santos
authors.affiliation: Laboratory of Muscle Proteins and Comparative Histopathology, Human Genome and Stem-cell Research Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Paula
authors.initials: P
authors.lastname: Onofre-Oliveira
authors.affiliation: Laboratory of Muscle Proteins and Comparative Histopathology, Human Genome and Stem-cell Research Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Mariz
authors.initials: M
authors.lastname: Vainzof
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D010641:Phenotype; D065840:Protective Factors; D059467:Transcriptome