Abstract
Merosin deficient congenital muscular dystrophy 1A (MDC1A) is a very rare autosomal recessive disorder caused by mutations in the LAMA2 gene leading to severe and progressive muscle weakness and atrophy. Although over 350 causative mutations have been identified for MDC1A, no treatment is yet available. There are many therapeutic approaches in development, but the lack of natural history data of the mouse model and standardized outcome measures makes it difficult to transit these pre-clinical findings to clinical trials. Therefore, in the present study, we collected natural history data and assessed pre-clinical outcome measures for the dy2J/dy2J mouse model using standardized operating procedures available from the TREAT-NMD Alliance. Wild type and dy2J/dy2J mice were subjected to five different functional tests from the age of four to 32 weeks. Non-tested control groups were taken along to assess whether the functional test regime interfered with muscle pathology. Respiratory function, body weights and creatine kinase levels were recorded. Lastly, skeletal muscles were collected for further histopathological and gene expression analyses. Muscle function of dy2J/dy2J mice was severely impaired at four weeks of age and all mice lost the ability to use their hind limbs. Moreover, respiratory function was altered in dy2J/dy2J mice. Interestingly, the respiration rate was decreased and declined with age, whereas the respiration amplitude was increased in dy2J/dy2J mice when compared to wild type mice. Creatine kinase levels were comparable to wild type mice. Muscle histopathology and gene expression analysis revealed that there was a specific regional distribution pattern of muscle damage in dy2J/dy2J mice. Gastrocnemius appeared to be the most severely affected muscle with a high proportion of atrophic fibers, increased fibrosis and inflammation. By contrast, triceps was affected moderately and diaphragm only mildly. Our study presents a complete natural history dataset which can be used in setting up standardized studies in dy2J/dy2J mice.
Highlights
Wild type and dy mouse model of laminin α2 deficient (2J)/dy2J mice were subjected to a functional test regime from four to 32 weeks of age and body weights were recorded
Dy2J/dy2J mice were significantly lighter than gender-matched wild type mice (Fig 2A)
To assess muscle strength and function, the four limb grip strength test was used revealing significantly lower grip strength in dy 2J/dy2J compared to wild type mice (Fig 2B)
Summary
The dy 2J/dy2J (B6.WK-Lama2dy-2J/J) mice were purchased from Jackson Laboratory (strain 000524) (10) and bred in the Experimental Animal Facility of the Leiden University Medical Center. The mice were received on a C57BL/6J background and could be compared to C57BL/6J wild type mice. They were kept in individually ventilated cages with 12 hours of light/dark cycles at 20.5 ̊C and had ad libitum access to standard RM3 chow (SDS, Essex, UK) and water. Animal Experiment Committee (Dierexperimentencommissie) of the Leiden University Medical Center approved all performed experiments. Efforts were made to minimize the burden and distress
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