Authors
Virginia Zoglio, Sarah Chebouti, Fayez Issa, Théo Massard, Benjamin Polin, Sylvie Manin, Pascal Maire, Dawon Choi, Indigo T C Chan, Tom H Cheung, Joana Esteves de Lima, Frederic Relaix
Published in
Science advances. Volume 12. Issue 38. Pages eaed0880. Sep 18, 2026. Epub Sep 16, 2026.
Abstract
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 Six2 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 Six2 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.
PMID:
42748246
Bibliographic data and abstract were imported from PubMed on 17 Sep 2026.
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