Natural disease history of mouse models for limb girdle muscular dystrophy types 2D and 2F

PLoS One. 2017 Aug 10;12(8):e0182704. doi: 10.1371/journal.pone.0182704. eCollection 2017.


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.

MeSH terms

  • Animals
  • Collagen / metabolism
  • Female
  • Lipid Metabolism
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscular Dystrophies, Limb-Girdle / metabolism*
  • Muscular Dystrophies, Limb-Girdle / pathology
  • Muscular Dystrophy, Animal / metabolism*
  • Muscular Dystrophy, Animal / pathology
  • Myostatin / genetics
  • Myostatin / metabolism
  • Signal Transduction
  • Transcriptome
  • Transforming Growth Factor beta / metabolism


  • Mstn protein, mouse
  • Myostatin
  • Transforming Growth Factor beta
  • Collagen

Grant support

This work was supported by grants from ZonMw (Project 113302001) received by A. Aartsma-Rus, NeurOmics (FP7, Agreement 2012-305121) received by Prof. dr. A. Aartsma-Rus and AFM, 20251, dr. M. van Putten. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.