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 8

Decreased Ltbp4–TGF-β binding does not alter the Col6a2–/– mouse muscle phenotype.

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Decreased Ltbp4–TGF-β binding does not alter the Col6a2–/– mouse muscle ...
(A) Double-homozygous Ltbp4hom/Col6a2–/– mice have weight similar to that of Col6a2–/– mice and are smaller and lighter than WT and Ltbp4het and Ltbp4hom littermates. (B) H&E staining of tibialis anterior muscle of double-homozygous Ltbp4hom/Col6a2–/– mice shows dystrophic features similar to those in Col6a2–/– mice (25 weeks old). Scale bars: 50 μm. (C) Although Ltbp4hom/Col6a2–/– mice have slightly higher forelimb grip strength compared with Col6a2–/– mice, it remains markedly lower than that of WT Ltbp4het and Ltbp4hom littermates. (D) Physiological parameters in isolated EDL muscle of 25-week-old Ltbp4hom/Col6a2–/– mice were unchanged in comparison with Col6a2–/– mice. For C and D, statistical comparisons were performed by 2-way ANOVA and Tukey’s adjustment for multiple comparisons. ****P < 0.0001. (E) After repeated eccentric contractions, tetanic force declined precipitously in isolated double-homozygous Ltbp4hom/Col6a2–/– and Col6a2–/– EDL muscles, more prominently in male animals compared with female animals. Statistical analysis was performed using linear mixed models and Bonferroni adjustment for multiple comparisons. Error bars represent SEM.