Skeletal muscle fibro-adipogenic progenitors of dystrophic mice are insensitive to NOTCH-dependent regulation of adipogenesis

Abstract

Fibro adipogenic progenitors (FAPs) promote satellite cell differentiation in adult skeletal muscle regeneration. However, in pathological conditions, FAPs are responsible for fibrosis and fat 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. Nonetheless, factors released by hematopoietic cells restore the sensitivity to NOTCH adipogenic inhibition. An unbiased mass spectrometry-based proteomic analysis of FAPs from muscles of wild type and mdx mice, revealed that the synergistic cooperation between NOTCH and inflammatory signals controls FAP differentiation. These results offer a basis for rationalizing the pathological outcomes of fat infiltrations in skeletal muscle and may suggest new therapeutic strategies to mitigate the detrimental effects of fatty depositions in muscles of dystrophic patients.\n\nHighlightsO_LISingle-cell mass cytometry reveals that wt and mdx FAPs are in different cell states.\nC_LIO_LIActivation of the NOTCH signaling pathway negatively regulates adipogenesis of wt but not mdx FAPs.\nC_LIO_LIDeep proteomics suggests a mechanism explaining the different sensitivity of mdx- FAPs to NOTCH.\nC_LIO_LITNF-a stimulation restores the anti-adipogenic effect of NOTCH in mdx FAPs.\nC_LI