Antxr2-mediated fine-tuning of Collagen VI ensures skeletal muscle function

Bonaldo, P.; Metti, S.; bracq, l.; Signor, M.; Facchinello, N.; Gambarotto, L.; Nogara, L.; Pigato, G.; Abrami, L.; Kunz, B.; Duc, J.; Sabatelli, P.; De Acutis, A.; Fortunato, G. M.; Vozzi, G.; Braghetta, P.; Blaauw, B.; van der Goot, F. G.

doi:10.1101/2025.09.11.675515

bioRxiv · 10.1101/2025.09.11.675515

Antxr2-mediated fine-tuning of Collagen VI ensures skeletal muscle function

Bonaldo, P.·Metti, S.·bracq, l.·Signor, M.·Facchinello, N.·Gambarotto, L.·Nogara, L.·Pigato, G.·Abrami, L.·Kunz, B.·Duc, J.·Sabatelli, P.·De Acutis, A.·Fortunato, G. M.·Vozzi, G.·Braghetta, P.·Blaauw, B.·van der Goot, F. G.

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Abstract

Tissue function relies on the extracellular matrix (ECM) that surrounds cells, providing structural and biochemical support. The complex ECM composition depends on an adequately tuned balance between the deposition and degradation of each of its components. Disequilibrium may cause disease, as observed for Collagen VI (COL6), for which mutations lead to muscular dystrophy. Here, we investigated the role of Anthrax Toxin Receptor 2 (ANTXR2/CMG2), a receptor that controls the turnover of COL6, in skeletal muscle. We show that ANTXR2 is mostly expressed by fibro-adipogenic precursors and that its deficiency in ANTXR2 null (Antxr2-/-) mice leads to a premature and irregular COL6 accumulation in intramuscular connective tissue. This results in tissue stiffening and gradual, non-functional muscle hypertrophy, marked by impaired locomotion and myopathic signs. Our findings further indicate that COL6 accretion drives these alterations, as revealed by Antxr2-/-::Col6a1-/- double knockout mice, highlighting the essential role of ANTXR2-mediated COL6 remodeling in maintaining ECM homeostasis and muscle functionality. SIGNIFICANCE STATEMENTRemodelling of the extracellular matrix (ECM) was long thought to rely almost exclusively on extracellular proteases. Increasing evidence, however, indicates that some ECM components may undergo intracellular degradation following receptor-mediated endocytosis, as we have found for Collagen VI (COL6). Here, we identify the COL6 receptor ANTXR2 as a critical regulator of ECM turnover in skeletal muscle.. When ANTXR2 is absent, COL6 builds up, followed by the accumulation of fibrillar collagens, without changes in gene expression. These alterations in muscle ECM lead to increased stiffness, myofiber defects and impaired locomotor activity. Our findings establish ANTXR2 as a key regulator in ECM remodelling, offering new insights into potential treatments for conditions associated with defective ECM remodeling, such as aging and congenital muscular dystrophies.

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Bonaldo, P., Metti, S., bracq, l., Signor, M., Facchinello, N., Gambarotto, L., Nogara, L., Pigato, G., Abrami, L., Kunz, B., Duc, J., Sabatelli, P., De Acutis, A., Fortunato, G. M., Vozzi, G., Braghetta, P., Blaauw, B., van der Goot, F. G.. 2025-09-19. Antxr2-mediated fine-tuning of Collagen VI ensures skeletal muscle function. https://doi.org/10.1101/2025.09.11.675515

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