Skeletal muscle is a highly adaptable tissue that relies on a pool of resident muscle stem cells to maintain homeostasis, regenerate after injury, and respond to environmental stress. These muscle stem cells, also known as satellite cells, exhibit significant heterogeneity, with distinct subpopulations playing specialized roles in muscle repair. A key determinant of this functional diversity is Pax3, a transcription factor with a key roles in embryonic muscle development. The presentation will explore the role of Pax3 in driving heterogeneity during development and in the adaptive response to muscle injury. Using a combination of genetic models, lineage tracing, and single-cell RNA sequencing, we have identified distinct Pax3-dependent regulatory networks that govern Pax3 function during development. In addition, we have explored the role of Pax3 in adult muscle stem cell. Loss of Pax3 leads to impaired muscle satellite activation, reduced regenerative capacity, and disrupted muscle repair. These findings not only shed light on the mechanisms underlying muscle stem cell heterogeneity but also provide insights into the evolutionary regulation of muscle stem cells and potential therapeutic strategies for muscle-wasting disorders. Understanding the molecular circuits that control adult stem cell behavior will be essential for developing regenerative medicine approaches aimed at enhancing muscle repair in aging and disease.

Frédéric Relaix is invited by Pascal Maire.