GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE302nnn/GSE302292/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE302292GEOGSEfalsePAX3-SIX2 muscle stem cell heterogeneity drives muscle-specific repair dynamics diversificationThe human body contains around 640 distinct muscles, each capable of regeneration following injury through the action of muscle-specific stem cells (MuSCs) that express the transcription factor PAX7. Its paralog, PAX3, a master regulator of embryonic myogenesis, is selectively expressed in a subset of adult quiescent MuSCs. The proportion of PAX3⁺ MuSCs varies across muscles. By combining lineage tracing and skeletal muscle injury, we demonstrate that PAX3 drives MuSC diversity and muscle-specific regeneration rates. PAX3-expressing MuSCs display enhanced proliferation and differentiation capacities, enabling a faster response following injury, whereas loss of PAX3 leads to proliferation arrest and cell death. Single-cell RNA-sequencing analyses revealed the specific expression of Six2 in PAX3+ MuSCs. We show that PAX3 is required for SIX2 expression, and loss of SIX2 in MuSCs reduces proliferation and differentiation rates. Conversely, ectopic Six2 expression promotes a faster response in PAX3- MuSCs. With this work, we establish that PAX3/SIX2 expression correlates with distinct MuSCs behavior, influencing regeneration rates in a muscle-type-dependent context. Our findings highlight a previously unrecognized layer of regulation in MuSCs behaviour and muscle repair and suggest that PAX3-SIX2 heterogeneity could be leveraged for targeted therapeutic strategies in muscle-wasting diseases.2026/08/11GSE302292GSM9101314GSM910131519057302292Mus musculus