Adipogenesis of Skeletal Muscle Fibro/Adipogenic Progenitors is Controlled by the WNT5a/GSK3/β-Catenin Axis

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, in silico network modelling with the integration of single-cell/bulk RNA sequencing data, we highlighted the canonical WNT/GSK/β-catenin signaling as a crucial pathway controlling FAP adipogenesis. In particular, pharmacological blockade of GSK3, by using LY2090314, stabilizes β-catenin and represses PPARγ expression abrogating FAP adipogenesis ex vivo while limiting fatty degeneration in vivo. We also characterize FAPs as the main source of Wnt ligands that entertain autocrine/paracrine responses in the muscle niche. WNT5a, whose expression is impaired in dystrophic FAPs, is sufficient to restrain the detrimental adipogenic differentiation drift of these cells. Overall, we propose that the modulation of the WNT pathway, either by targeting GSK3 or by restoring autocrine WNT5a signaling in FAPs, might be a strategy to counteract intramuscular fat infiltrations in myopathies.