Abstract
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.
Highlights
Muscular dystrophies are a group of inherited, heterogeneous muscle disorders characterized by progressive muscle weakness and degeneration
Limbgirdle muscular dystrophy (LGMD) is the most heterogeneous collection of muscular dystrophies with over 30 LGMD subtypes identified according to their genetic defects with autosomal dominantly and recessively inherited LGMDs subgrouped as LGMD1 and LGMD2, respectively
The traverse times and numbers of paw slips were lower at baseline and increased over time in LGMD mice compared to wild type mice
Summary
Muscular dystrophies are a group of inherited, heterogeneous muscle disorders characterized by progressive muscle weakness and degeneration. Sarcoglycanopathies are one of the more common forms of autosomal recessive LGMD and comprise four subtypes: LGMD2C, -D, -E and -F. They are caused by mutations in the genes coding for the muscle-specific transmembrane sarcoglycan proteins α-, β-, γ-, and δ-sarcoglycan. The DGC is a large complex of membrane-associated proteins that further consists of dystrophin, the dystroglycans (α and β), sarcospan, the syntrophins (α1, β1, β2, γ1- and γ2) and α-dystrobrevin [2]. This complex physically links the intracellular cytoskeleton to the extracellular matrix. The loss of this structural connection, for instance due to mutations in one of the sarcoglycans, makes muscle fibers more susceptible to damage during muscle contraction [2,3,4,5]
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