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Adv."],"published-print":{"date-parts":[[2026,9,18]]},"abstract":"<jats:p>\n                    The 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-pos 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\n                    <jats:italic toggle=\"yes\">Six2<\/jats:italic>\n                    in PAX3-pos MuSCs. We show that PAX3 is required for SIX2 expression, and loss of SIX2 in MuSCs reduces proliferation and differentiation rates. Conversely, ectopic\n                    <jats:italic toggle=\"yes\">Six2<\/jats:italic>\n                    expression promotes proliferation of PAX3-neg MuSCs by directly activating cell cycle pathways. 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 MuSC behaviour and muscle repair and suggest that PAX3-SIX2 heterogeneity could be leveraged for targeted therapeutic strategies in muscle-wasting diseases.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aed0880","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T18:02:56Z","timestamp":1789581776000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["PAX3-SIX2 muscle stem cell heterogeneity drives muscle-specific repair dynamics diversification"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5585-4232","authenticated-orcid":true,"given":"Virginia","family":"Zoglio","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris-Est Cr\u00e9teil, INSERM, U955 IMRB, F-94010 Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Chebouti","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Est Cr\u00e9teil, INSERM, U955 IMRB, F-94010 Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fayez","family":"Issa","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Est Cr\u00e9teil, INSERM, U955 IMRB, F-94010 Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Th\u00e9o","family":"Massard","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Est Cr\u00e9teil, INSERM, U955 IMRB, F-94010 Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Polin","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Est Cr\u00e9teil, INSERM, U955 IMRB, F-94010 Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Manin","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Est Cr\u00e9teil, INSERM, U955 IMRB, F-94010 Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7795-0029","authenticated-orcid":true,"given":"Pascal","family":"Maire","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris Cit\u00e9, Institut Cochin, INSERM, CNRS, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0457-1410","authenticated-orcid":true,"given":"Dawon","family":"Choi","sequence":"additional","affiliation":[{"name":"Division of Life Science, Center for Stem Cell Research, HKUST-Nan Fung Life Sciences Joint Laboratory, State Key Laboratory of Nervous System Disorders, Daniel and Mayce Yu Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5954-3284","authenticated-orcid":true,"given":"Indigo T.C.","family":"Chan","sequence":"additional","affiliation":[{"name":"Division of Life Science, Center for Stem Cell Research, HKUST-Nan Fung Life Sciences Joint Laboratory, State Key Laboratory of Nervous System Disorders, Daniel and Mayce Yu Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0796-5406","authenticated-orcid":true,"given":"Tom H.","family":"Cheung","sequence":"additional","affiliation":[{"name":"Division of Life Science, Center for Stem Cell Research, HKUST-Nan Fung Life Sciences Joint Laboratory, State Key Laboratory of Nervous System Disorders, Daniel and Mayce Yu Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China."},{"name":"Hong Kong Center for Neurodegenerative Diseases, InnoHK, Hong Kong, China."},{"name":"Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, Shenzhen-Hong Kong Institute of Brain Science, HKUST, Shenzhen Research Institute, Shenzhen, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5497-5669","authenticated-orcid":true,"given":"Joana Esteves","family":"de Lima","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Est Cr\u00e9teil, INSERM, U955 IMRB, F-94010 Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1270-1472","authenticated-orcid":true,"given":"Frederic","family":"Relaix","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Est Cr\u00e9teil, INSERM, U955 IMRB, F-94010 Cr\u00e9teil, France."},{"name":"\u00c9cole nationale v\u00e9t\u00e9rinaire d\u2019Alfort, U955 IMRB, 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