Skeletal Muscle Satellite Cells Co-Opt the Tenogenic GeneScleraxisto 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 we show thatScxexpression is not detectable in adult muscle stem cells (also known as satellite cells, SCs) during quiescence.Scxexpression begins in activated SCs and continues throughout regenerative myogenesis after injury. By SC-specificScxgene inactivation (ScxcKO), we show thatScxfunction 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 ScxcKO, and are not overlapping withScx-target genes identified in tendon development. Together with a recent finding of a subpopulation ofScx-expressing connective tissue fibroblasts with myogenic potential during early embryogenesis, we propose that regenerative and developmental myogenesis co-opt theScxgene via different mechanisms.