Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice
Payam Mohassel, … , Daniel B. Rifkin, Carsten G. Bönnemann
Payam Mohassel, … , Daniel B. Rifkin, Carsten G. Bönnemann
Published May 1, 2025
Citation Information: J Clin Invest. 2025;135(9):e173354. https://doi.org/10.1172/JCI173354.
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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

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Figure 3

Col6a2–/– muscle has reduced contractile force and is susceptible to lengthening contraction injury.

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Col6a2–/– muscle has reduced contractile force and is susceptible to le...
(A) Representative tracing of total tetanic force measurement in isolated EDL muscle. (B and C) Maximal twitch force (B) and total tetanic force (C) are markedly reduced in 10-week-old Col6a2–/– mouse EDL muscle. (D) The difference in force generation was negligible after normalization to functional cross-sectional area (i.e., specific force). (B–D) Error bars indicate SEM. Statistical comparisons were performed by 2-way ANOVA and Tukey’s adjustment for multiple comparisons. (E) Representative tracing of force measurement in isolated EDL muscle after eccentric contraction. (F) Tetanic force declined precipitously after repeated eccentric contractions in Col6a2–/– EDL muscle. The decline was more prominent in male animals (n = 5 male, 5 female for WT and Col6a2+/–, and n = 8 male, 5 female for Col6a2–/–). Statistical analysis was performed using linear mixed models and Bonferroni adjustment for multiple comparisons. (G) Muscle cryosections stained with fluorescent wheat germ agglutinin (green) and DAPI (blue) after downhill running and systemic administration of Evans blue dye (EBD). Red fibers (EBD positive) represent those with damaged sarcolemma. Scale bars: 50 μm. (H) Quantification of EBD-positive fibers normalized to muscle area. For statistical comparisons, ordinary 1-way ANOVA was performed at baseline (no differences) and after downhill running with Bonferroni’s adjustment for multiple comparisons. WT, n = 13 (7 male, 6 female); Col6a2+/–, n = 9 (4 male, 5 female); Col6a2–/–, n = 13 (6 male, 7 female). Error bars in all panels represent SEM.