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mir-22-3p/KLF6/MMP14 axis in fibro-adipogenic progenitors regulates fatty infiltration in muscle degeneration
Yu Lin1, Zheng Wen-Jie1, Li Chang-Qing1
1Department of Orthopaedics, the Second Affiliated Xinqiao Hospital of Army Medical University, Chongqing, China.
Abstract:
Fibro/adipogenic progenitors (FAPs) are the main cellular source of fatty degeneration in muscle injury; however, the underlying mechanism of FAP adipogenesis in muscle degeneration needs to be further examined. Matrix metalloproteinase 14 (MMP-14) has been reported to induce the adipogenesis of 3T3-L1 preadipocytes, but whether MMP-14 also regulates the differentiation of FAPs remains unclear. To investigate whether and how MMP-14 regulates FAP adipogenesis and fatty infiltration in muscle degeneration, we examined MMP-14 expression in degenerative muscles and tested the effect of MMP-14 on FAP adipogenesis in vitro and in vivo. As expected, MMP-14 enhanced FAP adipogenesis and fatty infiltration in degenerative muscles; moreover, blocking endogenous MMP-14 in injured muscles facilitated muscle repair. Further investigations revealed that Kruppel-like factor 6 (KLF6) was a transcription factor associated with MMP-14 and acted as an "on-off" switch in the differentiation of FAPs into adipocytes or myofibroblasts. Moreover, KLF6 was the target gene of miR-22-3p, which was downregulated during FAP adipogenesis both in vitro and in vivo, and overexpression of miR-22-3p markedly prevented FAP adipogenesis and attenuated fatty degeneration in muscles. Our study revealed that miR-22-3p/KLF6/MMP-14 is a novel pathway in FAP adipogenesis and that inhibiting KLF6 is a potential strategy for the treatment of muscular degenerative diseases.
Insights
Fibro/adipogenic progenitors (FAPs) drive fatty degeneration in muscle injury. A novel miR-22-3p/KLF6/MMP-14 pathway promotes FAP adipogenesis, suggesting KLF6 inhibition as a therapeutic strategy for muscle diseases.
Area of Science:
- Muscle regeneration and cellular biology
- Molecular mechanisms of adipogenesis
- Biochemistry of extracellular matrix remodeling
Background:
- Fibro/adipogenic progenitors (FAPs) are key contributors to fatty degeneration following muscle injury.
- The precise mechanisms regulating FAP adipogenesis in muscle degeneration remain incompletely understood.
- Matrix metalloproteinase 14 (MMP-14) is known to induce adipogenesis in certain cell types, but its role in FAPs is unclear.
Purpose of the Study:
- To investigate the role and mechanism of MMP-14 in FAP adipogenesis and fatty infiltration during muscle degeneration.
- To identify key molecular players and pathways involved in FAP differentiation in the context of muscle injury.
- To explore potential therapeutic targets for mitigating fatty degeneration in muscular degenerative diseases.
Main Methods:
- Analysis of MMP-14 expression in degenerative muscle tissues.
- In vitro and in vivo experiments to assess the effect of MMP-14 on FAP adipogenesis.
- Investigation of the regulatory relationship between MMP-14, Kruppel-like factor 6 (KLF6), and miR-22-3p.
- Assessment of the impact of blocking endogenous MMP-14 and manipulating miR-22-3p levels on muscle repair and fatty degeneration.
Main Results:
- MMP-14 significantly enhanced FAP adipogenesis and fatty infiltration in degenerative muscles.
- Blocking endogenous MMP-14 in injured muscles promoted muscle repair.
- KLF6 was identified as a transcription factor acting as a switch for FAP differentiation into adipocytes or myofibroblasts.
- KLF6 is a target gene of miR-22-3p, which is downregulated during FAP adipogenesis.
- Overexpression of miR-22-3p inhibited FAP adipogenesis and reduced fatty degeneration in muscles.
Conclusions:
- The study reveals a novel miR-22-3p/KLF6/MMP-14 pathway regulating FAP adipogenesis.
- KLF6 functions as a critical regulator in FAP differentiation.
- Inhibition of KLF6 presents a potential therapeutic strategy for treating muscular degenerative diseases characterized by fatty infiltration.
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