Collagen type VI regulates TGFß bioavailability in skeletal muscle

Collagen VI-related disorders (COL6-RDs) are a group of rare muscular dystrophies caused by pathogenic variants in collagen VI genes. ¬¬Collagen type VI is a heterotrimeric, microfibrillar component of the muscle extracellular matrix (ECM), predominantly secreted by resident fibroadipogenic precursor cells in skeletal muscle. Collagen VI absence or mislocalization in the skeletal muscle ECM underlies the non-cell autonomous dystrophic changes and dysfunction in skeletal muscle in COL6-RDs with an as of yet elusive direct mechanistic link between the ECM and myofiber dysfunction. Here, we derive a novel mouse model of COL6-RD, Col6a2-/- mice, and conduct a comprehensive natural history study in male and female animals aged to 60 weeks of age. Col6a2-/- mice have a normal lifespan but develop muscle weakness based on standardized behavioral tests (grip and hanging wire test), muscle atrophy with histologic hallmarks of muscular dystrophy, and reduced muscle force prodcution on physiologic parameters. We also report a robust dysregulation of TGFß pathway early in the disease process and thus propose a new mechanism for pathogenesis of the disease that links the ECM regulation of TGFß with downstream skeletal muscle abnormalities, paving the way for developing therapeutics that target this pathway. Overall design: Thirty-two samples representing quadricep muscle from male and female mice representing wildtype (WT) and Col6a2 -/- at two different age groups (5 weeks and 25 weeks old).