Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice
Payam Mohassel, Hailey Hearn, Jachinta Rooney, Yaqun Zou, Kory Johnson, Gina Norato, Matthew A. Nalls, Pomi Yun, Tracy Ogata, Sarah Silverstein, David A. Sleboda, Thomas J. Roberts, Daniel B. Rifkin, Carsten G. Bönnemann
Payam Mohassel, Hailey Hearn, Jachinta Rooney, Yaqun Zou, Kory Johnson, Gina Norato, Matthew A. Nalls, Pomi Yun, Tracy Ogata, Sarah Silverstein, David A. Sleboda, Thomas J. Roberts, Daniel B. Rifkin, Carsten G. Bönnemann
View: Text | PDF
Research Article Genetics Muscle biology

Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice

Abstract

Collagen VI–related disorders (COL6-RDs) are a group of rare muscular dystrophies caused by pathogenic variants in collagen VI genes (COL6A1, COL6A2, and COL6A3). Collagen type VI is a heterotrimeric, microfibrillar component of the muscle extracellular matrix (ECM), predominantly secreted by resident fibroadipogenic precursor cells in skeletal muscle. The absence or mislocalization of collagen VI in the ECM underlies the noncell-autonomous dysfunction and dystrophic changes in skeletal muscle with a yet elusive direct mechanistic link between the ECM and myofiber dysfunction. Here, we conducted a comprehensive natural history and outcome study in a mouse model of COL6-RDs (Col6a2–/– mice) using standardized (TREAT-NMD) functional, histological, and physiological parameters. Notably, we identify a conspicuous dysregulation of the TGF-β pathway early in the disease process and propose that the collagen VI–deficient matrix is not capable of regulating the dynamic TGF-β bioavailability both at baseline and in response to muscle injury. Thus, we propose a new mechanism for pathogenesis of the disease that links the ECM regulation of TGF-β with downstream skeletal muscle abnormalities, paving the way for the development and validation of therapeutics that target this pathway.

Authors

Payam Mohassel, Hailey Hearn, Jachinta Rooney, Yaqun Zou, Kory Johnson, Gina Norato, Matthew A. Nalls, Pomi Yun, Tracy Ogata, Sarah Silverstein, David A. Sleboda, Thomas J. Roberts, Daniel B. Rifkin, Carsten G. Bönnemann

×

Figure 4

Col6a2–/– muscle ECM is fibrotic, has abnormal morphology, and shows altered passive mechanical properties.

Options: View larger image (or click on image) Download as PowerPoint
Col6a2–/– muscle ECM is fibrotic, has abnormal morphology, and shows al...
(A) Representative image of Sirius red stain shows increased fibrillar collagen content (collagen I and collagen III) in Col6a2–/– mouse muscle. Scale bars: 500 μm. (B) Quantification of the Sirius red stain (collagen area) in gastrocnemius muscle sections shows marked increase in fibrillar collagen in mice 10 weeks of age or older. (C) Scanning electron microscope images of decellularized lateral gastrocnemius muscle of WT and Col6a2–/– mouse show altered ECM morphology, increased thickness, and variability of fibrillar collagen most notably in the endomysium (arrows). Myonuclear impressions on the endomysium are noted in the top and middle panels. P, perimysium; E, endomysium. (D) Schematic of A.V. Hill viscoelastic mechanical model of skeletal muscle. The right panel shows the force tracing of isolated EDL muscle after passive stretch. The different components of the model are calculated from different portions of the stress-relaxation protocol as indicated. S, series elastic element; P, parallel elastic element; D, damping; A, active contractile element. (E) Quantification of passive mechanical properties of isolated EDL muscle in 60-week-old animals shows a marked increase in series modulus of elasticity and damping coefficient, but not the parallel elastic element, in Col6a2–/– mice. Statistical comparisons were performed by 2-way ANOVA and Tukey’s adjustment for multiple comparisons. Error bars represent SEM.