Muscle function of SGCA- and SGCD-null mice was impaired and declined over time compared to wild type mice, with female SGCD-null mice outperforming males in hanging tests.
This study provides a comprehensive natural history dataset for LGMD2D and 2F mouse models, demonstrating progressive skeletal muscle impairment and the presence of cardiac fibrosis in SGCD-null mice, which will facilitate future pre-clinical therapeutic trials.
Limb-girdle muscular dystrophy types 2D and 2F (LGMD 2D and 2F) are autosomal recessive disorders caused by mutations in the alpha- and delta sarcoglycan genes, respectively, leading to severe muscle weakness and degeneration. The cause of the disease has been well characterized and a number of animal models are available for pre-clinical studies to test potential therapeutic interventions. To facilitate transition from drug discovery to clinical trials, standardized procedures and natural disease history data were collected for these mouse models. Implementing the TREAD-NMD standardized operating procedures, we here subjected LGMD2D (SGCA-null), LGMD2F (SGCD-null) and wild type (C57BL/6J) mice to five functional tests from the age of 4 to 32 weeks. To assess whether the functional test regime interfered with disease pathology, sedentary groups were taken along. Muscle physiology testing of tibialis anterior muscle was performed at the age of 34 weeks. Muscle histopathology and gene expression was analysed in skeletal muscles and heart. Muscle histopathology and gene expression was analysed in skeletal muscles and heart. Mice successfully accomplished the functional tests, which did not interfere with disease pathology. Muscle function of SGCA- and SGCD-null mice was impaired and declined over time. Interestingly, female SGCD-null mice outperformed males in the two and four limb hanging tests, which proved the most suitable non-invasive tests to assess muscle function. Muscle physiology testing of tibialis anterior muscle revealed lower specific force and higher susceptibility to eccentric-induced damage in LGMD mice. Analyzing muscle histopathology and gene expression, we identified the diaphragm as the most affected muscle in LGMD strains. Cardiac fibrosis was found in SGCD-null mice, being more severe in males than in females. Our study offers a comprehensive natural history dataset which will be useful to design standardized tests and future pre-clinical studies in LGMD2D and 2F mice.
Pasteuning-Vuhman et al. (Thu,) conducted a other in Limb-girdle muscular dystrophy types 2D and 2F (n=36). Functional test regime vs. Wild type mice and sedentary groups was evaluated on Muscle function (two and four limb hanging tests). Muscle function of SGCA- and SGCD-null mice was impaired and declined over time compared to wild type mice, with female SGCD-null mice outperforming males in hanging tests.