1. Fibro-adipogenic progenitors of dystrophic mice are insensitive to NOTCH regulation of adipogenesis.
- Author
-
Marinkovic M, Fuoco C, Sacco F, Cerquone Perpetuini A, Giuliani G, Micarelli E, Pavlidou T, Petrilli LL, Reggio A, Riccio F, Spada F, Vumbaca S, Zuccotti A, Castagnoli L, Mann M, Gargioli C, and Cesareni G
- Subjects
- Adipocytes cytology, Adipocytes metabolism, Animals, Biomarkers, Disease Susceptibility, Fibrosis, Mice, Mice, Inbred mdx, Models, Biological, Muscle Fibers, Skeletal cytology, Muscle Fibers, Skeletal metabolism, Phenotype, Proteomics methods, Regeneration, Signal Transduction, Single-Cell Analysis, Adipogenesis, Cell Differentiation, Receptors, Notch metabolism, Satellite Cells, Skeletal Muscle cytology, Satellite Cells, Skeletal Muscle metabolism, Stem Cells cytology, Stem Cells metabolism
- Abstract
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., (© 2019 Marinkovic et al.)
- Published
- 2019
- Full Text
- View/download PDF