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

Abstract

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, our work positions FBN1 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 progressive decline in 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 TGF{beta} 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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=159 SRC="FIGDIR/small/666604v1_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@1895e71org.highwire.dtl.DTLVardef@1974e87org.highwire.dtl.DTLVardef@a49979org.highwire.dtl.DTLVardef@5813c9_HPS_FORMAT_FIGEXP M_FIG C_FIG Model of Fibrillin-1 protective barrier in quiescent satellite cells.Satellite cells produce Fibrillin-1 (FBN1) to establish a localized extracellular matrix barrier that limits exposure to mitogenic signals. Mechanistically, FBN1 expression is induced by Notch signalling and serves to sequester latent TGF{beta} complexes in an inactive form, thereby preventing their activation within the immediate niche. This barrier is spatially restricted beneath the basal lamina and remains functionally independent from the abundant interstitial FBN1 produced by fibro-adipogenic progenitors (FAPs). The model describes a self-contained, satellite cell-derived ECM system that maintains quiescence by insulating the cells from activating cues.