Large-scale analysis of differential gene expression in the hindlimb muscles and diaphragm of mdx mouse

Abstract

The mdx mouse is an animal model for Duchenne muscular dystrophy (DMD), which is caused by the absence of dystrophin. Mdx limb muscles substantially compensate for the lack of dystrophin while the diaphragm is affected like DMD skeletal muscles. To understand better the complex cascade of molecular events leading to muscle degeneration and compensatory processes in mdx muscles, we analyzed alterations of gene expression in mdx hindlimb and diaphragm muscles as compared to their normal counterparts. The strategy was based on suppression subtractive hybridization followed by reverse Northern quantitative hybridization. Four subtracted/normalized libraries, containing cDNA clones up- or downregulated in mdx hindlimb muscles or diaphragm, were constructed and a total of 1536 cDNA clones were analyzed. Ninety-three cDNAs were found to be differentially expressed in mdx hindlimb muscles and/or diaphragm. They corresponded to 54 known genes and 39 novel cDNAs. The potential role of the known genes is discussed in the context of the mdx phenotype.

Comparative transcriptome analysis of muscular dystrophy models Largemyd, Dmdmdx/Largemyd and Dmdmdx: what makes them different?

“…Several transcriptome studies in Dmd mdx mouse were published in the last years, [12][13][14][15][16][17][18][19][20] but no studies in Large myd − / − nor in Dmd mdx /Large myd − / − were performed. 9 In Dmd mdx , similar data to the observed in our study were described by Boer et al 14 and Porter et al 17,21 Using an Affymetrix chip of about 12 000 genes/EST, Boer et al 14 identified 58 DEGs in Dmd mdx limb muscles, from which 49 were unregulated while only 9 were downregulated.…”

A change of heart: oxidative stress in governing muscle function?

“…More broadly, elevated oxidative stress could potentially contribute to the damage and weakness of respiratory and limb skeletal muscles, and possibly to the fibrosis observed in DMD. The mdx mouse, which carries a mutation in the dystrophin gene, is a commonly used model for human DMD (Disatnik et al 1998;Tkatchenko et al 2000;Hartel et al 2001). The diaphragm muscle in the mdx mouse is highly susceptible to oxidative stress and shows a disease progression similar to human DMD (Disatnik et al 1998;Tkatchenko et al 2000;Hartel et al 2001).…”

“…The mdx mouse, which carries a mutation in the dystrophin gene, is a commonly used model for human DMD (Disatnik et al 1998;Tkatchenko et al 2000;Hartel et al 2001). The diaphragm muscle in the mdx mouse is highly susceptible to oxidative stress and shows a disease progression similar to human DMD (Disatnik et al 1998;Tkatchenko et al 2000;Hartel et al 2001). The damage observed in dystrophic cardiomyopathy is mainly caused by abnormalities of Ca 2+ signalling, particularly in the early stages of disease (Jung et al 2007;Prosser et al 2011).…”

Proteomic profiling of animal models mimicking skeletal muscle disorders

“…It appears that the primary deficiency in the membrane cytoskeletal protein dystrophin causes a severe perturbation of the muscle proteome expression pattern including elements involved in nucleotide metabolism [58], cytosolic ion homeostasis [61], Ca 21 -cycling through the sarcoplasmic reticulum (SR) [60], and the stress response via small heat shock proteins [41]. These proteomic findings can now be correlated to large data sets from various global gene expression studies with dystrophin-deficient fibres [115][116][117][118][119][120][121]. Expression profiling suggests that cellular changes in dystrophin-deficient fibres are associated with altered developmental programming due to abnormal ion handling [115,116], a chronic inflammatory response [117,118], infiltration of connective tissue [118], an early delay in myofibre development [119] and a regeneration-inducing activation of signalling pathways involved in the proliferation and differentiation of satellite cells [120].…”