Chondrolectin regulates the sublaminar localization and regenerative function of muscle satellite cells in mice

Abstract

Skeletal muscle satellite cells (SCs) reside between the myofiber sarcolemma and basal lamina, where extracellular matrix (ECM) interactions are essential for their maintenance and regenerative function. Here, we identify chondrolectin (CHODL), a type I transmembrane protein with a C-type lectin domain, as a critical regulator of SC biology. Single-cell RNA-seq analysis reveals that Chodl is highly enriched in quiescent SCs but downregulated in proliferating myoblasts. Using conditional knockout models, we show that deletion of Chodl in embryonic myoblasts (ChodlMKO) or adult SCs (ChodlPKO) does not affect muscle development but markedly impairs regeneration in both young and aged mice. Chodl-deficient SCs exhibit reduced self-renewal, diminish proliferation, and impair differentiation, leading to defective myofiber repair. In silico network perturbation further predicts disruption of ECM-ligand interactions and Notch signaling, consistent with our observation that a significant fraction of SCs in ChodlPKOmice localize outside the basal lamina and undergo precocious activation. Together, these findings establish CHODL as a key determinant of SC niche localization and regenerative function, uncovering a previously unrecognized mechanism linking ECM interactions to muscle stem cell maintenance and repair.