Cross-Sectional Study Into Age-Related Pathology Of Mouse Models For Limb Girdle Muscular Dystrophy Types 2d And 2f

Limb girdle muscular dystrophy (LGMD) types 2D and 2F are caused by mutations in the genes encoding for alpha- and delta-sarcoglycan, respectively, leading to progressive muscle weakness. Mouse models exist for LGMD2D (Sgca(-/-)) and 2F (Sgcd(-/-)). In a previous natural history study, we described the pathology in these mice at 34 weeks of age. However, the development of muscle pathology at younger ages has not been fully characterised yet. We therefore performed a study into age-related changes in muscle function and pathology by examining mice at different ages. From 4 weeks of age onwards, male mice were subjected to functional tests and sacrificed at respectively 8, 16 or 24 weeks of age. Muscle histopathology and expression of genes involved in muscle pathology were analysed for several skeletal muscles, while miRNA levels were assessed in serum. In addition, for Sgcd(-/-) mice heart pathology was assessed. Muscle function showed a gradual decline in both Sgca(-/-) and Sgcd(-/-) mice. Respiratory function was also impaired at all examined timepoints. Already at 8 weeks of age, muscle pathology was prominent, and fibrotic, inflammatory and regenerative markers were elevated, which remained relatively constant with age. In addition, Sgcd(-/-) mice showed signs of cardiomyopathy from 16 weeks of age onwards. These results indicate that Sgca(-/-) and Sgcd(-/-) are relevant disease models for LGMD2D and 2F.