TY - JOUR
T1 - Denervation-activated STAT3–IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis
AU - Madaro, Luca
AU - Passafaro, Magda
AU - Sala, David
AU - Etxaniz, Usue
AU - Lugarini, Francesca
AU - Proietti, Daisy
AU - Alfonsi, Maria Vittoria
AU - Nicoletti, Chiara
AU - Gatto, Sole
AU - De Bardi, Marco
AU - Rojas-García, Ricardo
AU - Giordani, Lorenzo
AU - Marinelli, Sara
AU - Pagliarini, Vittoria
AU - Sette, Claudio
AU - Sacco, Alessandra
AU - Puri, Pier Lorenzo
PY - 2018
Y1 - 2018
N2 - 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 (SODG93Amice). 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.
AB - 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 (SODG93Amice). 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.
KW - Cell Biology
KW - Cell Biology
UR - http://hdl.handle.net/10807/126410
UR - http://www.nature.com/ncb/index.html
U2 - 10.1038/s41556-018-0151-y
DO - 10.1038/s41556-018-0151-y
M3 - Article
SN - 1465-7392
VL - 20
SP - 917
EP - 927
JO - Nature Cell Biology
JF - Nature Cell Biology
ER -