Fibro-adipogenic progenitors of dystrophic mice are insensitive to NOTCH regulation of adipogenesis

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Milica Marinkovic, Claudia Fuoco, Francesca Sacco, Andrea Cerquone Perpetuini, Giulio Giuliani, Elisa Micarelli, Theodora Pavlidou, Lucia Lisa Petrilli, Alessio Reggio, Federica Riccio, Filomena Spada, Simone Vumbaca, Alessandro Zuccotti, Luisa Castagnoli, Matthias Mann, Cesare Gargioli, Gianni Cesareni

Fibro-adipogenic progenitors (FAPs) promote satellite cell differentiation in adult skeletal muscle regeneration. However, in pathological conditions, FAPs are responsible for fibrosis and fatty infiltrations. Here we show that the NOTCH pathway negatively modulates FAP differentiation both in vitro and in vivo. However, FAPs isolated from young dystrophin-deficient mdx mice are insensitive to this control mechanism. An unbiased mass spectrometry-based proteomic analysis of FAPs from muscles of wild-type and mdx mice suggested that the synergistic cooperation between NOTCH and inflammatory signals controls FAP differentiation. Remarkably, we demonstrated that factors released by hematopoietic cells restore the sensitivity to NOTCH adipogenic inhibition in mdx FAPs. These results offer a basis for rationalizing pathological ectopic fat infiltrations in skeletal muscle and may suggest new therapeutic strategies to mitigate the detrimental effects of fat depositions in muscles of dystrophic patients.

Original languageEnglish
JournalLife Science Alliance
Issue number3
Publication statusPublished - Jun 2019
Externally publishedYes

Bibliographical note

© 2019 Marinkovic et al.

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