Mouse skeletal muscle satellite cells co-opt the tenogenic gene <i>Scleraxis</i> to instruct regeneration.

Abstract

Skeletal muscles connect bones and tendons for locomotion and posture. Understanding the regenerative processes of muscle, bone, and tendon is of importance to basic research and clinical applications. Despite their interconnections, distinct transcription factors have been reported to orchestrate each tissue's developmental and regenerative processes. Here, using adult mouse skeletal muscles, we show that <i>Scx</i> expression is not detectable in adult muscle stem cells (also known as satellite cells, SCs) during quiescence. <i>Scx</i> expression begins in activated SCs and continues throughout regenerative myogenesis after injury. By SC-specific <i>Scx</i> gene inactivation (<i>Scx</i> cKO), we show that <i>Scx</i> function is required for SC expansion/renewal and robust new myofiber formation after injury. We combined single-cell RNA sequencing and CUT&RUN to identify direct Scx target genes during muscle regeneration. These target genes help explain the muscle regeneration defects of <i>Scx</i> cKO and are not overlapping with <i>Scx</i>-target genes identified in tendon development. Together with a recent finding of a subpopulation of <i>Scx</i>-expressing connective tissue fibroblasts with myogenic potential during early embryogenesis, we propose that regenerative and developmental myogenesis co-opt the <i>Scx</i> gene via different mechanisms.