Adipogenesis of skeletal muscle fibro/adipogenic progenitors is affected by the WNT5a/GSK3/β-catenin axis

Abstract

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/β-catenin signaling as a crucial pathway modulating FAP adipogenesis triggered by insulin signaling. Consistently, pharmacological blockade of GSK3, by the LY2090314 inhibitor, stabilizes β-catenin and represses PPARγ 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 β-catenin signaling.

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Fig. 1: GSK inhibitors affect the differentiation potential of FAPs.
Fig. 2: LY2090314 restricts FAP adipogenesis ex vivo while limiting fatty degeneration in vivo.
Fig. 3: β-catenin degradation marks FAPs undergoing adipogenesis.
Fig. 4: GSK3 inhibition promotes MuSC self-renewal and boosts the promyogenic ability of FAPs.
Fig. 5: FAPs are the main source of Wnt ligands in the muscle stem cell niche.
Fig. 6: Wnt5a expression is impaired in mdx FAPs.
Fig. 7: Wnt5a restrains FAP adipogenesis by activating the canonical β-catenin signaling.

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Acknowledgements

This work has been supported by the European Research Council (ERC) (grant N°. 322749) and by the Foundation AIRC for Research on Cancer (AIRC) (grant N°. 14135), and partly supported by the AIRC Investigator Grant (IG 2013) to G.C.; A Reggio was supported by Fondazione Umberto Veronesi. The PKIS library was supplied by GlaxoSmithKline, LLC, and the Structural Genomic Consortium under an open access Material Transfer and Trust Agreement: http://www.sgc-unc.org. This work was made possible at IRBM by the CNCCS s.c.a.r.l. initiative.

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Reggio, A., Rosina, M., Palma, A. et al. Adipogenesis of skeletal muscle fibro/adipogenic progenitors is affected by the WNT5a/GSK3/β-catenin axis. Cell Death Differ (2020). https://doi.org/10.1038/s41418-020-0551-y

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