Defective collagen VI-NG2 axis impairs pericyte balance between proliferation and quiescence in COLVI-related myopathies.

Collagen VI-related myopathies (COLVI-RMs) are rare genetic disorders caused by impaired assembly and secretion of COLVI, a key extracellular matrix (ECM) protein. COLVI deficiency alters ECM architecture and biomechanics, leading to progressive muscle fiber damage and connective tissue abnormalities. While pericytes are emerging as key players in muscle regeneration due to their myogenic potential, their role in COLVI-RMs remains unclear. This study investigates pericyte involvement in COLVI-RMs, focusing on the interaction between COLVI and neural/glial antigen 2 (NG2), a proteoglycan expressed on pericyte membranes. Muscle biopsies from COLVI-RMs patients revealed abnormal pericyte distribution, reduced vessel coverage, and thickened capillary basement membranes. In vitro, healthy pericytes formed a dense COLVI network, while COLVI-RM-derived pericytes displayed a disrupted matrix and impaired cell-ECM interaction. Proximity ligation assays demonstrated a significant reduction in COLVI-NG2 binding in COLVI-RM pericytes, correlating with altered balance between proliferative and quiescent states. In turn, defects in signaling pathways related to proliferation (Akt/mTOR and Wnt/β-catenin pathways) and quiescence (N-cadherin, Notch3, FOXO3A) were identified, revealing a marked quiescent state. In vitro inhibition of the COLVI-NG2 binding in healthy pericytes reproduced these pathological features, underscoring the functional relevance of this molecular axis. Taken together, the data here reported revealed an unexpected role of NG2-COLVI binding on pericytes status. It follows that the impairment of functional binding between NG2 and COLVI could have important consequences on the pericytes myogenic potential in COLVI-RMs, and consequently on the muscle regeneration. Finally, targeting defective pericytes could provide potential therapeutic strategies for these debilitating diseases.