Mouse skeletal muscle satellite cells co-opt the tenogenic gene Scleraxis to instruct regeneration

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 Scx expression is not detectable in adult muscle stem cells (also known as satellite cells, SCs) during quiescence. Scx expression begins in activated SCs and continues throughout regenerative myogenesis after injury. By SC-specific Scx gene inactivation (Scx cKO), we show that Scx 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 Scx cKO and are not overlapping with Scx-target genes identified in tendon development. Together with a recent finding of a subpopulation of Scx-expressing connective tissue fibroblasts with myogenic potential during early embryogenesis, we propose that regenerative and developmental myogenesis co-opt the Scx gene via different mechanisms.