Cited by 310Muscle Physiology and DisordersNeurogenetic and Muscular Disorders ResearchCardiac Fibrosis and Remodeling

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

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Madaro, Luca, Passafaro, Magda, Sala, David, Etxaniz, Usue, Lugarini, Francesca, Proietti, Daisy, Alfonsi, Maria Vittoria, Nicoletti, Chiara, Gatto, Sole, De Bardi, Marco, Rojas-García, Ricardo, Giordani, Lorenzo, Marinelli, Sara, Pagliarini, Vittoria, Sette, Claudio, Sacco, Alessandra, Puri, Pier Lorenzo·2018·Nature Cell Biology

DOI 10.1038/s41556-018-0151-yPMC PMC6145844

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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 (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.

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Authors: 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.
Affiliations: Fondazione Santa Lucia (IT)
University of Rome Tor Vergata (IT)
Sanford Burnham Prebys Medical Discovery Institute (US)
Centre National de la Recherche Scientifique (FR)
National Research Council (IT)
Università Cattolica del Sacro Cuore (IT)
ORCID: Madaro, Luca
Passafaro, Magda
Etxaniz, Usue
Proietti, Daisy
Alfonsi, Maria Vittoria
Nicoletti, Chiara
Gatto, Sole
Giordani, Lorenzo
Marinelli, Sara
Pagliarini, Vittoria
Sette, Claudio
Sacco, Alessandra
Puri, Pier Lorenzo
Venue: Nature Cell Biology
Publisher: Springer Science and Business Media LLC
Published: 2018-07-26
Volume: 20
Issue: 8
Pages: 917-927
ISSN: 1465-7392 (ISSN-L)
1476-4679
DOI: 10.1038/s41556-018-0151-y
PMC: PMC6145844
OpenAlex: W2883365705
Cited by: 310
References: 41
Citations by year: 2026: 40 · 2025: 37 · 2024: 57 · 2023: 36 · 2022: 43 · 2021: 41 · 2020: 36 · 2019: 18 · 2018: 2
FWCI: 8.62
Type: journal article
Language: en
Update notices: correction (2024-02-07)
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature Cell Biology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
HAL (submittedVersion, cc-by)
IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
Funders: Medical University of South Carolina
National Institutes of Health
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR052779, R01AR064873, P30AR061303, R01AR056712)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Health Sciences › Medicine › Genetics (clinical) › Neurogenetic and Muscular Disorders Research
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords: fibro-adipogenic progenitors, denervation, muscle atrophy, muscle fibrosis, amyotrophic lateral sclerosis, spinal cord injury, spinal muscular atrophy, muscle regeneration, muscle stem cells, neuromuscular disorders
MeSH terms: Superoxide Dismutase-1, Interleukin-6 Inhibitors, Amyotrophic Lateral Sclerosis, Animals, Cell Line, Denervation, Disease Models, Animal, Fibrosis, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Muscular Atrophy, Muscular Atrophy, Spinal, Mutation, Neuromuscular Agents, Sciatic Nerve, Spinal Cord Injuries, Signal Transduction, Interleukin-6, Coculture Techniques, Myoblasts, Skeletal, Adipogenesis, STAT3 Transcription Factor, Quadriceps Muscle, Cardiotoxins

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

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