Muscle stem cells produce a protective Fibrillin-1 matrix to prevent precocious activation.

Multiple biological mechanisms have been uncovered to regulate muscle stem cell quiescence, including inhibition of differentiation, adhesion-dependent anchoring, and translational control, which can be broadly classified as intrinsic or extrinsic properties. Here, we identify the matrix glycoprotein Fibrillin-1 (Fbn1) as a Notch-regulated, cell-autonomous effector, essential for maintaining quiescence in muscle stem cells. Known for its causal role in Marfan syndrome (MFS), a connective tissue disorder that also presents with skeletal muscle atrophy, Fbn1 emerges as a critical niche component that protects stem cells from aberrant growth factor signalling. We demonstrate that targeted deletion of Fbn1 in muscle stem cells leads to dose-dependent quiescence defects, characterized by loss of cellular projections, depletion of the stem cell pool, and decline in long-term muscle function. Consistently, human MFS muscle biopsies show abnormally activated satellite cells, implicating stem cell imbalance in the development of MFS-associated myopathy. Mechanistically, the loss of Fbn1 upregulates TGFβ signalling, and pharmacological inhibition of this pathway, using the Angiotensin Receptor blocker losartan, restores the cellular and physiological defects of mutant muscles. These findings reveal a new quiescence-preserving mechanism through extracellular matrix-mediated shielding from mitogenic signals, and position stem cell dysfunction as a driver of MFS myopathy.