HMGB1-RAGE regulates muscle satellite cell homeostasis through p38-MAPK- and myogenin-dependent repression of Pax7 transcription.

Expression of the paired-box 7 (PAX7) transcription factor is regulated during both myoblast proliferation and differentiation: high levels of PAX7 compromise myogenic differentiation because of excess and prolonged proliferation, whereas low levels of PAX7 result in precocious differentiation. We showed that myogenin repressed Pax7 transcription in differentiating myoblasts by binding to specific recognition sites in the Pax7 promoter, and that high-mobility group box 1 (HMGB1)-receptor for advanced glycation end-products (RAGE) signaling was required for myogenin induction and myogenin-dependent repression of Pax7 transcription. In addition, PAX7 negatively and myogenin positively regulated RAGE expression. RAGE, a multiligand receptor of the immunoglobulin superfamily, was not expressed in adult skeletal muscles, and was transiently expressed in activated, proliferating and differentiating satellite cells (SCs) in injured muscles. Compared with wild-type muscles, Rage(-/-) muscles exhibited increased numbers of basal SCs that were further increased in injured Rage(-/-) muscles following elevated myoblast asymmetric division; complete regeneration of injured Rage(-/-) muscles was found to be delayed by ~1 week. Thus, RAGE signaling physiologically repressed Pax7 transcription in SCs by upregulating myogenin, thereby accelerating muscle regeneration and limiting SC self-renewal.