Journal Article

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

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

2018

Overview

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 (SOD G93A 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. Madaro et al. show that denervation induces accumulation of IL-6–STAT3-activated fibro-adipogenic progenitors without inflammation or muscle regeneration, leading to muscle atrophy and fibrosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/1 / 13/106 / 13/31 / 13/51 / 13/95 / 38 / 38/1 / 38/32 / 38/39 / 38/77 / 38/79 / 38/91 / 631/532/2118/2439 / 631/80/86 / 96 / Accumulation / Adipogenesis - drug effects / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Amyotrophic Lateral Sclerosis - pathology / Amyotrophic Lateral Sclerosis - prevention & control / Animal models / Animals / Atrophy / Biomedical and Life Sciences / Cancer Research / Cardiotoxins / Cell activation / Cell Biology / Cell Line / Coculture Techniques / Deactivation / Denervation / Denervation - methods / Developmental Biology / Disease Models, Animal / Fibrosis / Humans / Inactivation / Infiltration / Inflammation / Interleukin 6 / Interleukin-6 - antagonists & inhibitors / Interleukin-6 - genetics / Interleukin-6 - metabolism / Life Sciences / Macrophages / Male / Mice, Inbred C57BL / Mice, Transgenic / Muscles / Muscular Atrophy - genetics / Muscular Atrophy - metabolism / Muscular Atrophy - pathology / Muscular Atrophy - prevention & control / Muscular Atrophy, Spinal - genetics / Muscular Atrophy, Spinal - metabolism / Muscular Atrophy, Spinal - pathology / Muscular Atrophy, Spinal - prevention & control / Mutation / Myoblasts, Skeletal - drug effects / Myoblasts, Skeletal - metabolism / Myoblasts, Skeletal - pathology / Neuromuscular Agents - pharmacology / Neuromuscular diseases / Neuromuscular junctions / Pathogenesis / Quadriceps Muscle - drug effects / Quadriceps Muscle - innervation / Quadriceps Muscle - metabolism / Quadriceps Muscle - pathology / Regeneration / Rodents / Sciatic Nerve - surgery / Signal Transduction / Signaling / Spinal cord injuries / Spinal Cord Injuries - genetics / Spinal Cord Injuries - metabolism / Spinal Cord Injuries - pathology / Spinal Cord Injuries - prevention & control / Spinal muscular atrophy / Stat3 protein / STAT3 Transcription Factor - antagonists & inhibitors / STAT3 Transcription Factor - genetics / STAT3 Transcription Factor - metabolism / Stem cell transplantation / Stem Cells / Superoxide Dismutase-1 - genetics