Denervation Drives YAP/TAZ Activation in Muscular Fibro/Adipogenic Progenitors
Gallardo, Felipe S.
Pontificia Universidad Catolica de Chile
Cordova-Casanova, Adriana
Pontificia Universidad Catolica de Chile
Bock-Pereda, Alexia
Pontificia Universidad Catolica de Chile
Ravasio, Andrea
Pontificia Universidad Catolica de Chile
Casar, Juan Carlos
Pontificia Universidad Catolica de Chile
Brandan, Enrique
Pontificia Universidad Catolica de Chile
Journal
International Journal of Molecular Sciences
ISSN
1661-6596
1422-0067
Open Access
gold
Volume
24
Loss of motoneuron innervation (denervation) is a hallmark of neurodegeneration and aging of the skeletal muscle. Denervation induces fibrosis, a response attributed to the activation and expansion of resident fibro/adipogenic progenitors (FAPs), i.e., multipotent stromal cells with myofibroblast potential. Using in vivo and in silico approaches, we revealed FAPs as a novel cell population that activates the transcriptional coregulators YAP/TAZ in response to skeletal muscle denervation. Here, we found that denervation induces the expression and transcriptional activity of YAP/TAZ in whole muscle lysates. Using the Pdgfra(H2B:EGFP/+) transgenic reporter mice to trace FAPs, we demonstrated that denervation leads to increased YAP expression that accumulates within FAPs nuclei. Consistently, re-analysis of published single-nucleus RNA sequencing (snRNA-seq) data indicates that FAPs from denervated muscles have a higher YAP/TAZ signature level than control FAPs. Thus, our work provides the foundations to address the functional role of YAP/TAZ in FAPs in a neurogenic pathological context, which could be applied to develop novel therapeutic approaches for the treatment of muscle disorders triggered by motoneuron degeneration.