FAPs orchestrate ANTXR2-mediated fine-tuning of collagen VI to ensure skeletal muscle function

Tissue function relies on the ECM, which surrounds cells and provides structural and biochemical support. Maintaining ECM homeostasis requires a tightly regulated balance between deposition and degradation of its components, and disruption of this equilibrium can lead to disease. Here, we examined the role of anthrax toxin receptor 2 (ANTXR2/CMG2), an ECM turnover receptor whose loss-of-function mutations cause hyaline fibromatosis syndrome (HFS), a multisystem connective tissue disorder. We show that ANTXR2 is expressed predominantly by fibro-adipogenic progenitors (FAPs) and mediates internalization of the major ECM component collagen VI (COL6). ANTXR2-null (Antxr2^−/−) mice exhibit premature COL6 accumulation within intramuscular connective tissue, leading to tissue stiffening and progressive, maladaptive muscle hypertrophy with impaired locomotion and myopathic features. Using Antxr2^−/−::Col6a1^−/− double-knockout mice, we demonstrate that these phenotypes are COL6-dependent, highlighting the essential role of ANTXR2-mediated COL6 remodeling in preserving ECM homeostasis and skeletal muscle function and establishing a mechanistic basis for muscle pathology in HFS.