PAX3-SIX2 muscle stem cell heterogeneity drives muscle-specific repair dynamics diversification

Its paralog, PAX3, a key regulator of embryonic myogenesis, is selectively expressed in a subset of adult MuSCs, with variable proportions across muscles. Here, using lineage tracing and muscle injury models, we show that PAX3-driven MuSC diversity underlies muscle-specific regeneration rates.

PAX3⁺ MuSCs exhibit enhanced proliferation and differentiation, supporting rapid repair, while PAX3 loss leads to proliferation arrest and cell death. Single-cell RNA-sequencing revealed that PAX3 regulates SIX2 expression, and that SIX2 modulates MuSC proliferation, with its loss impairing, and ectopic expression promoting, repair dynamics. PAX3/SIX2 expression correlates with distinct proliferative and differentiation behaviors, influencing regeneration in a muscle-type-dependent manner.