Early skeletal muscle pathology and disease progress in the dy 3K /dy 3K mouse model of congenital muscular dystrophy with laminin α2 chain-deficiency

Deficiency of laminin α2 chain leads to a severe form of congenital muscular dystrophy (LAMA2-CMD), and dystrophic symptoms progress rapidly in early childhood. Currently, there is no treatment for this detrimental disorder. Development of therapies is largely hindered by lack of understanding of mechanisms involved in the disease initiation and progress, both in patients but also in mouse models that are commonly used in the preclinical setup. Here, we unveil the first pathogenic events and characterise the disease development in a mouse model for LAMA2-CMD (dy /dy ), by analysing muscles at perinatal, neonatal and postnatal stages. We found that apoptotic muscle fibres were present as early as postnatal day 1. Other typical dystrophic hallmarks (muscle degeneration, inflammation, and extensive production of the extracellular matrix proteins) were clearly evident already at postnatal day 4, and the highest degree of muscle deterioration was reached by day 7. Interestingly, the severe phenotype of limb muscles partially recovered on days 14 and 21, despite worsening of the general condition of the dy /dy mouse by that age. We found that masticatory muscles were severely affected in dy /dy mice and this may be an underlying cause of their malnutrition, which contributes to death around day 21. We also showed that several signalling pathways were affected already in 1-day-old dy /dy muscle. Therapeutic tests in the dy /dy mouse model should therefore be initiated shortly after birth, but should also take into account timing and correlation between regenerative and pathogenic events.