Restorative macrophage-derived RNAseT2 stimulates muscle stem cell fusion via an SLK/N-WASP/actin bundling dependent axis
Muscle stem cells (MuSCs) fuse to form myofibers to repair skeletal muscle after injury. Within the regenerative MuSC niche, restorative macrophages stimulate MuSC fusion, although the molecular mechanisms involved are largely unknown. Here, we show that restorative macrophages secrete ribonuclease T2 (RNAseT2) to stimulate MuSC fusion. RNAseT2 enters MuSCs via the mannose receptor and induces the formation of actin bundles in MuSCs, enabling cell/cell fusion. Mechanistically, RNAseT2 binds to Ste20-like kinase (SLK), which itself triggers the phosphorylation-mediated activation of N-WASP, through Paxillin phosphorylation, allowing actin bundling necessary for MuSC fusion. In vivo, overexpressing RNAseT2 in regenerating muscle increases fusion in newly formed myofibers in mouse and zebrafish while macrophages deficient for RNAseT2 gene lead to fusion defect and smaller myofibers. This study reveals a new function for the highly conserved RNAseT2 and provides a new molecular mechanism by which restorative macrophages support MuSC fusion during muscle repair.
Authors
- Odile Boespflug‐Tanguy (ORCID: https://orcid.org/0000-0003-2389-1232)
- Katharina Ternka (ORCID: https://orcid.org/0000-0003-3773-4625)
- Antonio Moretta (ORCID: https://orcid.org/0000-0001-7506-6440)
- Bénédicte Chazaud (ORCID: https://orcid.org/0000-0002-1262-502X)
- Rémi Mounier (ORCID: https://orcid.org/0000-0003-3464-3322)
- Robert Knight (ORCID: https://orcid.org/0000-0001-9920-836X)
- Matthias Kettwig (ORCID: https://orcid.org/0000-0003-4804-7716)
- Michèle Weiss‐Gayet
- Gaëtan Juban (ORCID: https://orcid.org/0000-0002-5845-9223)
- Annie Adrait (ORCID: https://orcid.org/0000-0002-1565-2859)
- Yohann Couté (ORCID: https://orcid.org/0000-0003-3896-6196)
- Marie‐Catherine Le Bihan
- Oded Shoseyov (ORCID: https://orcid.org/0000-0003-3340-9921)
- Francesco Acquati (ORCID: https://orcid.org/0000-0002-9537-400X)
- Jules Guillemaud
- Emméran Le Moal
- Christelle Gobet
- Camilla Farnetani
Institutions
- Université Claude Bernard Lyon 1 (FR)
- University of Insubria (IT)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Délégation Paris 7 (FR)
- King's College London (GB)
- Hebrew University of Jerusalem (IL)
- Université Paris Cité (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Smith Institute (GB)
- CEA Grenoble (FR)
- Chr. Hansen (Denmark) (DK)
- Sorbonne Paris Cité (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Universitätsmedizin Göttingen (DE)
- Direction de la Recherche Technologique (FR)
- Institut NeuroMyoGène (FR)
- Hôpital Robert-Debré (FR)
- NeuroDiderot (FR)
- University of Göttingen (DE)
- Université Grenoble Alpes (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-04-14
- DOI
- https://doi.org/10.1038/s41467-026-71990-z
- Primary Topic
- Muscle Physiology and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Agence Nationale de la Recherche
- Fondation pour la Recherche Médicale
- AFM-Téléthon
- Biotechnology and Biological Sciences Research Council