Denervation-activated STAT3-IL6 signaling in fibro-adipogenic progenitors promotes myofibers atrophy and fibrosis

Nat Cell Biol, 2018 · DOI: 10.1038/s41556-018-0151-y · Published: August 1, 2018

Regenerative Medicine Neurology Genetics

Simple Explanation

Fibro-Adipogenic Progenitors (FAPs) typically help repair muscles after injury by working with inflammatory and muscle stem cells. However, denervation, or nerve disconnection, causes FAPs to accumulate without proper muscle regeneration. These abnormally activated FAPs produce elevated levels of IL6, leading to muscle atrophy and fibrosis. Similar FAPs were found in mouse models of spinal cord injury, SMA, ALS and in muscles of ALS patients. Blocking the STAT3-IL6 pathway in these FAPs reduced muscle atrophy and fibrosis in denervation and ALS mouse models, highlighting FAPs' role in neuromuscular diseases.

Study Duration

Not specified

Participants

ALS patients and mouse models

Evidence Level

Level not specified, basic research study

Key Findings

1
Denervation leads to the accumulation of FAPs in skeletal muscles, without a corresponding increase in macrophages or muscle stem cells.
2
FAPs from denervated muscles exhibit elevated STAT3 activation and IL6 secretion, promoting muscle atrophy and fibrosis.
3
Inhibition of STAT3-IL6 signaling in FAPs effectively counters muscle atrophy and fibrosis in mouse models of denervation and ALS.

Research Summary

This study reveals a previously unappreciated function of FAPs as a source of pro-atrophic and pro-fibrotic signals in denervated muscles, particularly due to the aberrant activation of IL6-STAT3 signaling. The accumulation of FAPs with aberrant IL6-STAT3 activation is observed in conditions of acute traumatic damage of NMJs (e.g. spinal cord injury) and/or progressive denervation, within physiological (aging) or pathological (e.g. Spinal Muscle Atrophy — SMA; Amyotrophic Lateral Sclerosis - ALS) conditions. Targeting IL6-STAT3 signaling in DEN FAPs with FDA-approved drugs could potentially counter muscle atrophy and fibrosis in acute denervation or during ALS progression.

Practical Implications

Therapeutic Target

Targeting IL6-STAT3 signaling in FAPs could be a therapeutic strategy for treating muscle atrophy and fibrosis associated with denervation and neuromuscular disorders.

Understanding FAP Function

This research enhances our understanding of the diverse roles of FAPs in muscle homeostasis, highlighting their potential contribution to disease pathogenesis.

Clinical Relevance

The identification of FAPs with aberrant IL6-STAT3 activation in ALS patients suggests a potential biomarker for disease progression and therapeutic response.

Study Limitations

1
The precise mechanism of FAP activation in denervated muscles remains unknown.
2
The study primarily focuses on mouse models, and further investigation is needed to validate these findings in human patients.
3
The long-term effects of IL6-STAT3 inhibition on muscle function and overall health require further evaluation.

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