Matrix remodeling plays an etiological role in driving laminin-α2 deficient pathology

Laminin-α2 (gene: LAMA2 ) is a key protein in the basement membrane of muscle and Schwann cells. A complete lack of this protein results in LAMA2-related congenital muscular dystrophy (LAMA2-RD), a severe muscle disease characterized by progressive muscle weakness, respiratory insufficiency, failure to thrive and shortened life span. One key signature of this disease is early onset of fibrosis coupled with poor muscle growth. We previously showed that TGF-β and its activator, integrin-αV, are elevated in dystrophic fibers of Dy ^W mice, a mouse model of LAMA2-RD. Other than activating TGF-β, integrin-αV is also known to facilitate the transdifferentiation of various cell types to myofibroblasts. In this study we present evidence for transcriptional dysregulation of genes driving myofibroblast transdifferentiation and extracellular matrix (ECM) remodelling during the early development of Dy ^W mice that is also reflected in muscle biopsies from young LAMA2-RD patients. We hypothesize that the early ECM remodelling, seen in both Dy ^W mice and LAMA2-RD children, may explain the congenital onset of fibrosis with poor muscle growth seen in the disease.