Disruption Of Bioavailability Of Tgf-Beta In Collagen Vi-Related Muscular Dystrophy

Muscle extracellular matrix (ECM) plays a central role in muscle function by regulating mechanotransduction, growth factor bioavailability, and maintenance of tissue integrity. Collagen VI is a heterotrimeric, microfibrillar component of the muscle ECM. Mutations in the three major genes coding for collagen VI alpha chains cause congenital muscular dystrophy. To understand the underlying mechanisms of collagen VI-related dystrophies, we have generated and comprehensively characterized a new mouse model of the disease with homozygous inactivation of Col6a2 (Col6a2−/−). Col6a2−/− mice show histologic, functional (e.g. grip strength), and physiologic abnormalities (e.g. tetanic force) compared to wildtype and heterozygous controls. These findings mirror the histologic and functional changes in patients with collagen VI-related dystrophies, albeit milder in severity. Absence of collagen VI from the muscle ECM changes its morphology and alters the regulation of transforming growth factor β (TGFβ) pathway in human muscle biopsies and Col6a2−/− mouse muscle. Our data further suggests that absence of collagen VI disrupts the normal regulation of TGFβ, resulting in its increased steady-state activity while at the same time impairing its bioavailability. In conclusion, this study establishes and comprehensively characterizes a novel pre-clinical model for collagen VI-related dystrophies, proposes a direct mechanistic link between the primary genetic abnormality and the disease phenotype, and provides the basis for future mechanistic and pre-clinical interventional studies using TGFβ pathway modulation as a therapeutic approach.