| First Author | Reggio A | Year | 2020 |
| Journal | Cell Death Differ | Volume | 27 |
| Issue | 10 | Pages | 2921-2941 |
| PubMed ID | 32382110 | Mgi Jnum | J:350862 |
| Mgi Id | MGI:7627242 | Doi | 10.1038/s41418-020-0551-y |
| Citation | Reggio A, et al. (2020) Adipogenesis of skeletal muscle fibro/adipogenic progenitors is affected by the WNT5a/GSK3/beta-catenin axis. Cell Death Differ 27(10):2921-2941 |
| abstractText | Fibro/Adipogenic Progenitors (FAPs) are muscle-interstitial progenitors mediating pro-myogenic signals that are critical for muscle homeostasis and regeneration. In myopathies, the autocrine/paracrine constraints controlling FAP adipogenesis are released causing fat infiltrates. Here, by combining pharmacological screening, high-dimensional mass cytometry and in silico network modeling with the integration of single-cell/bulk RNA sequencing data, we highlighted the canonical WNT/GSK/beta-catenin signaling as a crucial pathway modulating FAP adipogenesis triggered by insulin signaling. Consistently, pharmacological blockade of GSK3, by the LY2090314 inhibitor, stabilizes beta-catenin and represses PPARgamma expression abrogating FAP adipogenesis ex vivo while limiting fatty degeneration in vivo. Furthermore, GSK3 inhibition improves the FAP pro-myogenic role by efficiently stimulating, via follistatin secretion, muscle satellite cell (MuSC) differentiation into mature myotubes. Combining, publicly available single-cell RNAseq datasets, we characterize FAPs as the main source of WNT ligands inferring their potential in mediating autocrine/paracrine responses in the muscle niche. Lastly, we identify WNT5a, whose expression is impaired in dystrophic FAPs, as a crucial WNT ligand able to restrain the detrimental adipogenic differentiation drift of these cells through the positive modulation of the beta-catenin signaling. |
