The D2-mdx mouse for Duchenne muscular dystrophy is more severely affected than the classic BL10-mdx model due to dysfunctional Anxa6 and Ltbp4 genes, which are associated with impaired regeneration and fibrosis, respectively. Detailed knowledge of the natural disease history is incomplete or lacking for the D2-mdx model. We characterized the natural disease history of the D2-mdx and BL10-mdx models in a cross-sectional study conducted at two independent laboratories (Leiden University Medical Center and University of Bari), which allowed direct comparisons between study sites. At both laboratories, six groups were included, each containing n=8-10 D2-mdx, BL10-mdx, DBA/2J and C57BL/10ScSnJ males. Starting at the age of 4 weeks, forelimb grip strength and body weight were assessed monthly. Prior to euthanasia, heart function was evaluated with echocardiography or MRI and levels of creatine kinase and lactate dehydrogenase were measured. Mice were sacrificed at either 2 (only LUMC), 4, 8, 12, 28 or 52 weeks of age to assess muscle pathology with histological and molecular analyses. There was substantial agreement in results between study sites. Forelimb grip strength of D2-mdx males was impaired compared to BL10-mdx and both wild type strains. While serum biomarker levels were elevated in D2-mdx mice, they were lower than those observed in BL10-mdx mice. D2-mdx mice developed cardiomyopathy at an earlier age (28-week time point) than BL10-mdx mice. Histological and molecular examinations of the gastrocnemius, diaphragm, and heart indicated that muscle pathology in D2-mdx mice was more severe than in BL10-mdx mice, showing greater tissue damage, collagen deposition, and the presence of tissue calcifications, which were absent in the other experimental groups. However, severity of histopathological hallmarks significantly ameliorated with age in the D2-mdx strain. These findings will be instrumental in designing future pre-clinical studies involving D2-mdx mice.
Natural history study of the D2-mdx mouse for Duchenne muscular dystrophy: a comparison across two independent study sites
Brigida Boccanegra;Paola Mantuano;Antonietta Mele;Ornella Cappellari;Lisamaura Tulimiero;Annamaria De Luca
2025-01-01
Abstract
The D2-mdx mouse for Duchenne muscular dystrophy is more severely affected than the classic BL10-mdx model due to dysfunctional Anxa6 and Ltbp4 genes, which are associated with impaired regeneration and fibrosis, respectively. Detailed knowledge of the natural disease history is incomplete or lacking for the D2-mdx model. We characterized the natural disease history of the D2-mdx and BL10-mdx models in a cross-sectional study conducted at two independent laboratories (Leiden University Medical Center and University of Bari), which allowed direct comparisons between study sites. At both laboratories, six groups were included, each containing n=8-10 D2-mdx, BL10-mdx, DBA/2J and C57BL/10ScSnJ males. Starting at the age of 4 weeks, forelimb grip strength and body weight were assessed monthly. Prior to euthanasia, heart function was evaluated with echocardiography or MRI and levels of creatine kinase and lactate dehydrogenase were measured. Mice were sacrificed at either 2 (only LUMC), 4, 8, 12, 28 or 52 weeks of age to assess muscle pathology with histological and molecular analyses. There was substantial agreement in results between study sites. Forelimb grip strength of D2-mdx males was impaired compared to BL10-mdx and both wild type strains. While serum biomarker levels were elevated in D2-mdx mice, they were lower than those observed in BL10-mdx mice. D2-mdx mice developed cardiomyopathy at an earlier age (28-week time point) than BL10-mdx mice. Histological and molecular examinations of the gastrocnemius, diaphragm, and heart indicated that muscle pathology in D2-mdx mice was more severe than in BL10-mdx mice, showing greater tissue damage, collagen deposition, and the presence of tissue calcifications, which were absent in the other experimental groups. However, severity of histopathological hallmarks significantly ameliorated with age in the D2-mdx strain. These findings will be instrumental in designing future pre-clinical studies involving D2-mdx mice.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
