MST1/2 regulates fibro/adipogenic progenitor fate decisions in skeletal muscle regeneration
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Updated: Jun 29, 2025
Identification, Isolation, and Characterization of Fibro-Adipogenic Progenitors FAPs and Myogenic Progenitors MPs in Skeletal Muscle in the Rat
Published on: June 9, 2021
Kezhi Wang1, Jingjing Yang1, Yina An1
1College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
Abstract:
Defective skeletal muscle regeneration is often accompanied by fibrosis. Fibroblast/adipose progenitors (FAPs) are important in these processes, however, the regulation of FAP fate decisions is unclear. Here, using inducible conditional knockout mice, we show that blocking mammalian Ste20-like kinases 1/2 (MST1/2) of FAPs prevented apoptosis and reduced interleukin-6 secretion in vivo and in vitro, which impaired myoblast proliferation and differentiation, as well as impaired muscle regeneration. Deletion of Mst1/2 increased co-localization of Yes-associated protein (YAP) with Smad2/3 in nuclei and promoted differentiation of FAPs toward myofibroblasts, resulting in excessive collagen deposition and skeletal muscle fibrosis. Meanwhile, inhibition of MST1/2 increased YAP/Transcriptional co-activator with PDZ-binding motif activation, which promoted activation of the WNT/β-catenin pathway and impaired the differentiation of FAPs toward adipocytes. These results reveal a new mechanism for MST1/2 action in disrupted skeletal muscle regeneration and fibrosis via regulation of FAP apoptosis and differentiation. MST1/2 is a potential therapeutic target for the treatment of some myopathies.
Insights
Blocking mammalian Ste20-like kinases 1/2 (MST1/2) in fibroblast/adipose progenitors (FAPs) disrupts skeletal muscle regeneration and promotes fibrosis by altering FAP differentiation and collagen deposition.
Area of Science:
- Muscle regeneration and fibrosis research.
- Cell fate determination in progenitor cells.
Background:
- Skeletal muscle regeneration defects are linked to fibrosis.
- Fibroblast/adipose progenitor (FAP) roles in these processes are not fully understood.
Purpose of the Study:
- Investigate the role of mammalian Ste20-like kinases 1/2 (MST1/2) in regulating FAP fate.
- Elucidate the mechanism by which MST1/2 influences skeletal muscle regeneration and fibrosis.
Main Methods:
- Utilized inducible conditional knockout mice to delete Mst1/2 in FAPs.
- Assessed apoptosis, interleukin-6 secretion, myoblast behavior, and FAP differentiation in vivo and in vitro.
- Analyzed YAP/Smad2/3 co-localization and WNT/β-catenin pathway activation.
Main Results:
- Blocking MST1/2 in FAPs prevented apoptosis and reduced IL-6 secretion, impairing muscle regeneration.
- Mst1/2 deletion promoted FAP differentiation into myofibroblasts, increasing collagen deposition and fibrosis.
- MST1/2 inhibition enhanced YAP activation, promoting WNT/β-catenin signaling and hindering adipocyte differentiation.
Conclusions:
- MST1/2 regulates FAP apoptosis and differentiation, impacting skeletal muscle regeneration and fibrosis.
- MST1/2 represents a potential therapeutic target for myopathies characterized by fibrosis.
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