P.1.9 Repeated cardiotoxin treatment progresses muscle phenotype in Collagen VI deficient mice

Abstract

Collagen VI-related myopathies are inherited muscle disorders characterized clinically by muscle weakness and pathologically by fiber size variation and enhanced fibrosis. These disorders show broad spectrum of clinical presentation from severe Ullrich congenital muscular dystrophy (UCMD) to milder Bethlem myopathy (BM), both of which and both are caused by mutations in one of Col6A1–3 genes, In mice, collagen VI deficiency has been reported to reveal remarkable phenotypes in some organs such as bones, cartilages and adipose tissues, however their skeletal muscle presents a milder phenotype as that in BM. We have generated collagen VI-deficient mice and observed their muscle pathology chronologically. Along aging, distal muscles showed fiber size variation remarkably but only milder moderate fibrosis. Since collagen VI is produced in interstitial mesenchymal cells, we hypothesized if activation of mesenchymal cells contributes the muscle pathological phenotypes in collagen VI-deficient mice. We injected cardiotoxin (CTX) to TA muscles of collagen VI-deficient mice repeatedly to induce muscle necrosis and regeneration-mediated activation of mesenchymal cells artificially. After CTX injections, myofibers were well regenerated even with multiple CTX treatment, and along the number of CTX injections, muscle weakness, myofiber atrophy and interstitial fibrosis were progressed as observed in UCMD. The finding suggests that dysregulation of interstitial mesenchymal cells may be associated with the pathogenesis of collagen VI-related myopathies.