Effect of genetic background on the dystrophic phenotype inmdxmice

Abstract

Genetic background significantly affects phenotype in multiple mouse models of human diseases, including muscular dystrophy. This phenotypic variability is partly attributed to genetic modifiers that regulate the disease process. Studies have demonstrated that introduction of the γ-sarcoglycan-null allele onto the DBA/2J background confers a more severe muscular dystrophy phenotype than the original strain, demonstrating the presence of genetic modifier loci in the DBA/2J background. To characterize the phenotype of dystrophin deficiency on the DBA/2J background, we created and phenotyped DBA/2J-congenic Dmdmdx mice (D2-mdx) and compared them with the original, C57BL/10ScSn-Dmdmdx (B10-mdx) model. These strains were compared with their respective control strains at multiple time points between 6 and 52 weeks of age. Skeletal and cardiac muscle function, inflammation, regeneration, histology and biochemistry were characterized. We found that D2-mdx mice showed significantly reduced skeletal muscle function as early as 7 weeks and reduced cardiac function by 28 weeks, suggesting that the disease phenotype is more severe than in B10-mdx mice. In addition, D2-mdx mice showed fewer central myonuclei and increased calcifications in the skeletal muscle, heart and diaphragm at 7 weeks, suggesting that their pathology is different from the B10-mdx mice. The new D2-mdx model with an earlier onset and more pronounced dystrophy phenotype may be useful for evaluating therapies that target cardiac and skeletal muscle function in dystrophin-deficient mice. Our data align the D2-mdx with Duchenne muscular dystrophy patients with the LTBP4 genetic modifier, making it one of the few instances of cross-species genetic modifiers of monogenic traits.

Impaired regenerative capacity and lower revertant fibre expansion in dystrophin-deficient mdx muscles on DBA/2 background

“…Coley et al ., have recently reported that mdx -DBA exhibits impaired skeletal and cardiac muscle functions at an earlier age than mdx -B1034. We also previously reported that compared to mdx -B10, mdx -DBA mice showed the greater decrease in skeletal muscle function and weight, and increased accumulation of fat and fibrosis, but did not show increased muscle degeneration29.…”

Intermittent glucocorticoid steroid dosing enhances muscle repair without eliciting muscle atrophy

“…However, there has been limited widespread uptake of weekly steroid regimens, so we investigated the effects of weekly and daily steroid dosing in an animal model of muscular dystrophy. These studies were conduced in 6-month-old mdx male mice on a DBA/2J background, since these mice bear a closer resemblance to human DMD pathology and specifically the age at which steroid dosing is often initiated (36). Mice were given prednisone and deflazacort i.p.…”

Recovery of respiratory function in mdx mice co‐treated with neutralizing interleukin‐6 receptor antibodies and urocortin‐2

“…There are several other mouse models of muscular dystrophy, for example D2‐ mdx (Coley et al . ) and mdx 4cv /mTR G2 (Yucel et al . 2018), which purportedly better recapitulate the human dystrophinopathies at least for limb and cardiac muscle.…”