Denervation-activated STAT3–IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis

Luca Madaro, Magda Passafaro, David Sala, Usue Etxaniz, Francesca Lugarini, Daisy Proietti, Maria Vittoria Alfonsi, Chiara Nicoletti, Sole Gatto, Marco De Bardi, Ricardo Rojas-García, Lorenzo Giordani, Sara Marinelli, Vittoria Pagliarini, Claudio Sette, Alessandra Sacco, Pier Lorenzo Puri

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Abstract

Fibro-adipogenic progenitors (FAPs) are typically activated in response to muscle injury, and establish functional interactions with inflammatory and muscle stem cells (MuSCs) to promote muscle repair. We found that denervation causes progressive accumulation of FAPs, without concomitant infiltration of macrophages and MuSC-mediated regeneration. Denervation-activated FAPs exhibited persistent STAT3 activation and secreted elevated levels of IL-6, which promoted muscle atrophy and fibrosis. FAPs with aberrant activation of STAT3–IL-6 signalling were also found in mouse models of spinal cord injury, spinal muscular atrophy, amyotrophic lateral sclerosis (ALS) and in muscles of ALS patients. Inactivation of STAT3–IL-6 signalling in FAPs effectively countered muscle atrophy and fibrosis in mouse models of acute denervation and ALS (SODG93A mice). Activation of pathogenic FAPs following loss of integrity of neuromuscular junctions further illustrates the functional versatility of FAPs in response to homeostatic perturbations and suggests their potential contribution to the pathogenesis of neuromuscular diseases.

Original languageEnglish
Pages (from-to)917-927
Number of pages11
JournalNature Cell Biology
Volume20
Issue number8
DOIs
Publication statusPublished - Aug 1 2018

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Madaro, L., Passafaro, M., Sala, D., Etxaniz, U., Lugarini, F., Proietti, D., Alfonsi, M. V., Nicoletti, C., Gatto, S., De Bardi, M., Rojas-García, R., Giordani, L., Marinelli, S., Pagliarini, V., Sette, C., Sacco, A., & Puri, P. L. (2018). Denervation-activated STAT3–IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis. Nature Cell Biology, 20(8), 917-927. https://doi.org/10.1038/s41556-018-0151-y