Titolo: Mechanistic insights on the molecular signals underlying Collagen VI functions in muscle and tendon: a step forward for COL6-related myopathies

Codice Progetto: 2022MXH3JY

Responsabile scientifico per il DMM: Prof. Paolo Bonaldo
Coordinatore: Università degli Studi di PADOVA - Prof. Paolo Bonaldo

Partner-Unità di ricerca: Consiglio Nazionale delle Ricerche - Università degli Studi di BOLOGNA  

Bando: PRIN 2022 - Decreto Direttoriale n. 104 del 02-02-2022
Durata: 28/09/2023 - 27/09/2025 (24 mesi)

Finanziamento progetto: € 251.019,00 - CUP C53D23003130006

 

Abstract del progetto

In skeletal muscles, the three-dimensional organization of the extracellular matrix (ECM) not only guarantees transmission of mechanical forces, but also triggers signaling cues finely regulating the homeostasis of muscle and tendon cells. One key player is collagen VI (COL6), a distinctive ECM protein which regulates a range of cell activities and whose mutations are causative for COL6-related myopathies (COL6-RM). Insights in the pathomolecular mechanisms of COL6-RM were provided by COL6-deficient mice, allowing to throw light on the defects triggered by COL6 deficiency in myofibers, satellite cells (SCs) and tenocytes. Our past work in mice and patients showed that COL6 deficiency has a remarkable impact on mitochondrial function and autophagy, as well as on SC self-renewal. On the other hand, the multitasking nature of COL6 implies that further work is needed to get a more comprehensive knowledge of pathomolecular defects and address some key open questions. Although it is clear that COL6 exerts a critical role in regulating SC quiescence, the receptor(s) and effectors transducing these effects remain unknown. Furthermore, as COL6 regulates tendon homeostasis, it is crucial to understand how COL6 deficiency impacts on tendons. This project aims at filling some major knowledge gaps in COL6-RM, by focusing on two mechanisms emerging from our recent work, represented by the COL6/ANTXR2 axis and the mechanosensing complex of primary cilium (PC). ANTXR2 is a cell surface protein involved in ECM turnover by triggering COL6 endocytosis and sharing some features of mechanotransducers. PC is a specialized cell surface structure acting as a sensor for transducing extracellular signals within cells. Our preliminary data strongly support a role for these mediators in transducing COL6 signals within SCs and tenocytes. Therefore, in this project we will study ANTXR2 in SCs and investigate relevant mechanotransduction and signaling pathways in COL6- and ANTXR2-deficient SCs. We will generate a conditional knockout mouse with SC-specific ablation of ANTXR2 and characterize its phenotypic features under basal and regenerating conditions. In parallel, we will study the contribution of PC in mediating COL6 signals in tenocytes and myogenic cells, as well as their response to mechanical stress, and characterize the impact of COL6 defects on PC-related activities, including cell motility and autophagy. To get further insights on the role of these mechanisms in the etiology of COL6-RM, one part of the project will be devoted to studies in tissue samples and cultured cells from patients with different COL6 mutations, and the contribution of ANTXR2 and PC in ECM remodeling will be investigated. The achievement of the project will allow the identification of molecular players mediating COL6 signals in the muscle-tendon unit and provide better knowledge on mechanisms underlying COL6-RM, with identification of potential novel targets for therapy.