LOX inhibition (BAPN treatment) attenuates satellite cell differentiation

Integration of extracellular matrix (ECM)-derived cues into transcriptional programs is essential primarily in rapidly morphing environments such as regenerating tissues. Here we demonstrate that Lysyl oxidase (Lox), known for its ECM modifying activities, primarily collagen crosslinking and fibronectin matrix assembly, also directly regulates transcription factor (TF) localization. Using genetic and pharmacological strategies, we highlight a novel intracellular role for Lox in myogenic progenitors essential for muscle regeneration. We show that Lox interacts with, and directly oxidizes, Vestigial-Like 3 (Vgll3), a transcriptional co-activator acting with Mef2 and TEF TFs. This enzymatic activity is required for Vgll3 cytoplasmic to nuclear translocation in regulation of myogenic differentiation. Our work highlights a novel mechanism for TF sub-cellular localization and suggests a mechanism for integrating ECM organization with transcriptional output during myogenic differentiation. Modulating this integration mechanism could affect the balance between ECM organization and cell differentiation and serve as a basis for novel therapeutic strategies targeting fibrotic pathologies.