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 1

Col6a2–/– mice develop early postnatal muscle atrophy and weakness.

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Col6a2–/– mice develop early postnatal muscle atrophy and weakness. (A)...
(A) Schematic representation of the Col6a2 knockout allele. The LacZ sequence is not expressed but is used in the genotyping strategy. (B) Immunofluorescence staining of frozen gastrocnemius muscle shows complete absence of collagen VI from the muscle ECM in Col6a2–/– mice. Scale bars: 25 μm. (C) Col6a2–/– mice weigh less than WT and Col6a2+/– littermates. (D) Male and female Col6a2–/– mice have smaller muscles compared with WT and Col6a2+/– littermates. (E) Male and female Col6a2–/– mice have markedly reduced forelimb grip strength compared with WT and Col6a2+/– littermates. (F) Col6a2–/– mice have an increased probability of falling in the hanging wire test (10 weeks old). Statistical comparisons in F were performed using Cox proportional hazard model. Genotype is significantly related to the hazard of falling (log-rank test = 17.9, df = 2; P < 0.001), with the following pairwise differences: WT vs. Col6a2–/–, HR = 0.12 (95% CI: 0.03–0.57), P = 0.02; Col6a2+/– vs. Col6a2–/–, HR = 0.15 (95% CI: 0.05–0.50), P = 0.006; Col6a2+/– vs. WT, HR = 1.25 (95% CI: 0.23–6.84), P = 1.0. M, male; F, female. For all other panels, error bars indicate SEM, and statistical comparisons were performed by 2-way ANOVA with Tukey’s adjustment for multiple comparisons. ****P < 0.0001.