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

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.

• Authors: 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
• Journal: Nature cell biology (Nat Cell Biol) Vol. 20 Issue 8 Pg. 917-927 (08 2018) ISSN: 1476-4679 [Electronic] England
• PMID: 30050118 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotoxins
• IL6 protein, human
• Interleukin-6
• Neuromuscular Agents
• SOD1 protein, human
• STAT3 Transcription Factor
• STAT3 protein, human
• Stat3 protein, mouse
• interleukin-6, mouse
• Superoxide Dismutase-1

Topics

• Adipogenesis (drug effects)
• Amyotrophic Lateral Sclerosis (genetics, metabolism, pathology, prevention & control)
• Animals
• Cardiotoxins
• Cell Line
• Coculture Techniques
• Denervation (methods)
• Disease Models, Animal
• Fibrosis
• Humans
• Interleukin-6 (antagonists & inhibitors, genetics, metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Transgenic
• Muscular Atrophy (genetics, metabolism, pathology, prevention & control)
• Muscular Atrophy, Spinal (genetics, metabolism, pathology, prevention & control)
• Mutation
• Myoblasts, Skeletal (drug effects, metabolism, pathology)
• Neuromuscular Agents (pharmacology)
• Quadriceps Muscle (drug effects, innervation, metabolism, pathology)
• STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Sciatic Nerve (surgery)
• Signal Transduction
• Spinal Cord Injuries (genetics, metabolism, pathology, prevention & control)
• Superoxide Dismutase-1 (genetics)