ANTXR2 as a key player in Collagen VI signaling in muscle stem cells: new therapeutic perspectives for COL6-related myopathies.

Prof. Gisou van der Goot, EPFL Lausanne


In skeletal muscles, the three-dimensional organization of the extracellular matrix (ECM) guarantees
transmission of mechanical forces, but it also triggers signaling cues that finely regulate the homeostasis of satellite
cells (SCs), the muscle stem cells, essential for muscle regeneration. One key player is collagen VI (COL6), a
distinctive ECM protein which regulates a wide range of cellular activities and whose mutations are causative for
COL6-related myopathies, a group of rare inherited muscle diseases characterized by early onset muscle weakness
and connective tissue involvement, for which no cure is available.
While COL6 plays a critical role in SC function, the underlying mechanisms are poorly understood. COL6 has
been shown to be a key component of the SC niche, where it regulates SC quiescence and self-renewal. The
receptor(s) and effectors transducing these signals are however unknown. Gene expression analysis revealed that,
among known COL6 cell surface interactors, anthrax toxin receptor 2 (ANTXR2) is expressed by quiescent SCs
and is the most downregulated gene upon exit of SCs from dormancy, mimicking the behavior displayed by COL6
genes. The present project aims at dissecting the precise role of the ANTXR2/COL6 axis in SCs to
understanding the mechanisms linking COL6 deficiency to SC impairment.
ANTXR2 is a cell surface protein with an established role in binding Anthrax toxin, but whose physiological
functions are poorly understood. Our recent studies showed that ANTXR2 plays a distinct role in ECM turnover by
triggering COL6 endocytosis and intracellular degradation, that it is involved in mitotic spindle orientation during
asymmetric cell division and that it shares some key features of mechanotransducers. The hypothesis we propose
to test is that ANTXR2 acts as a stemness factor and that alterations of its signaling lead to abnormal SCs
activation. We will generate a conditional knockout mouse with SC-specific ablation of ANTXR2 and characterize
its phenotypic features under basal and regenerating conditions. To get further insights into the role of the
ANTRX2/COL6 axis in the etiology of COL6-RM, we will also analyze expression of ANTXR2 and its downstream
effectors in human primary myogenic cells and fibroblasts derived from control donors and from patients affected
by COL6-related myopathies. Finally, we will test whether forced ANTXR2 activation can modulate myogenic
differentiation and prevent abnormal activation of COL6-deficient muscle stem cells. This project will lead to the
identification of new molecular players mediating COL6 signaling in muscle stem cells and provide better
knowledge of the mechanisms underlying COL6-related myopathies, thus allowing the identification of novel
therapeutic targets. The project will be carried by Samuel Metti, trained in the Bonaldo laboratory, expert in COL6,
during his postdoctoral stay in my lab. The combined expertise of the two labs, in COL6 and ANTXR2 respectively,
offers a unique opportunity for the success of this project.