3 research outputs found
Natural disease history of mouse models for limb girdle muscular dystrophy types 2D and 2F
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 miceFunctional Genomics of Muscle, Nerve and Brain Disorder
Evaluation of 2 '-Deoxy-2 '-fluoro Antisense Oligonucleotides for Exon Skipping in Duchenne Muscular Dystrophy
Functional Genomics of Muscle, Nerve and Brain Disorder
Natural disease history of mouse models for limb girdle muscular dystrophy types 2D and 2F
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</p