Cargando…

Retinoic acid signalling in fibro/adipogenic progenitors robustly enhances muscle regeneration

BACKGROUND: During muscle regeneration, excessive formation of adipogenic and fibrogenic tissues, from their respective fibro/adipogenic progenitors (FAPs), impairs functional recovery. Intrinsic mechanisms controlling the proliferation and differentiation of FAPs remain largely unexplored. METHODS:...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhao, Liang, Son, Jun Seok, Wang, Bo, Tian, Qiyu, Chen, Yanting, Liu, Xiangdong, de Avila, Jeanene M., Zhu, Mei-Jun, Du, Min
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519288/
https://www.ncbi.nlm.nih.gov/pubmed/32980698
http://dx.doi.org/10.1016/j.ebiom.2020.103020
_version_ 1783587547085012992
author Zhao, Liang
Son, Jun Seok
Wang, Bo
Tian, Qiyu
Chen, Yanting
Liu, Xiangdong
de Avila, Jeanene M.
Zhu, Mei-Jun
Du, Min
author_facet Zhao, Liang
Son, Jun Seok
Wang, Bo
Tian, Qiyu
Chen, Yanting
Liu, Xiangdong
de Avila, Jeanene M.
Zhu, Mei-Jun
Du, Min
author_sort Zhao, Liang
collection PubMed
description BACKGROUND: During muscle regeneration, excessive formation of adipogenic and fibrogenic tissues, from their respective fibro/adipogenic progenitors (FAPs), impairs functional recovery. Intrinsic mechanisms controlling the proliferation and differentiation of FAPs remain largely unexplored. METHODS: Here, we investigated the role of retinoic acid (RA) signalling in regulating FAPs and the subsequent effects on muscle restoration from a cardiotoxin-induced injury. Blockage of retinoic acid receptor (RAR) signalling was achieved through dominant negative retinoic acid receptor α (RARα403) expression specific in PDGFRα+ FAPs in vivo and by BMS493 treatment in vitro. Effects of RAR-signalling on FAP cellularity and muscle regeneration were also investigated in a high-fat diet-induced obese mice model. FINDINGS: Supplementation of RA increased the proliferation of FAPs during the early stages of regeneration while suppressing FAP differentiation and promoting apoptosis during the remodelling stage. Loss of RAR-signalling caused ectopic adipogenic differentiation of FAPs and impaired muscle regeneration. Furthermore, obesity disrupted the cellular transition of FAPs and attenuated muscle regeneration. Supplementation of RA to obese mice not only rescued impaired muscle fibre regeneration, but also inhibited infiltration of fat and fibrotic tissues during muscle repair. These beneficial effects were abolished after blocking RAR-signalling in FAPs of obese mice. INTERPRETATION: These data suggest that RAR-signalling in FAPs is a critical therapeutic target for suppressing differentiation of FAPs and facilitating the regeneration of muscle and other tissues. FUNDING: This study was supported by grants from the National Institutes of Health (R01-HD067449 and R21-AG049976) to M.D.
format Online
Article
Text
id pubmed-7519288
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-75192882020-09-30 Retinoic acid signalling in fibro/adipogenic progenitors robustly enhances muscle regeneration Zhao, Liang Son, Jun Seok Wang, Bo Tian, Qiyu Chen, Yanting Liu, Xiangdong de Avila, Jeanene M. Zhu, Mei-Jun Du, Min EBioMedicine Research Paper BACKGROUND: During muscle regeneration, excessive formation of adipogenic and fibrogenic tissues, from their respective fibro/adipogenic progenitors (FAPs), impairs functional recovery. Intrinsic mechanisms controlling the proliferation and differentiation of FAPs remain largely unexplored. METHODS: Here, we investigated the role of retinoic acid (RA) signalling in regulating FAPs and the subsequent effects on muscle restoration from a cardiotoxin-induced injury. Blockage of retinoic acid receptor (RAR) signalling was achieved through dominant negative retinoic acid receptor α (RARα403) expression specific in PDGFRα+ FAPs in vivo and by BMS493 treatment in vitro. Effects of RAR-signalling on FAP cellularity and muscle regeneration were also investigated in a high-fat diet-induced obese mice model. FINDINGS: Supplementation of RA increased the proliferation of FAPs during the early stages of regeneration while suppressing FAP differentiation and promoting apoptosis during the remodelling stage. Loss of RAR-signalling caused ectopic adipogenic differentiation of FAPs and impaired muscle regeneration. Furthermore, obesity disrupted the cellular transition of FAPs and attenuated muscle regeneration. Supplementation of RA to obese mice not only rescued impaired muscle fibre regeneration, but also inhibited infiltration of fat and fibrotic tissues during muscle repair. These beneficial effects were abolished after blocking RAR-signalling in FAPs of obese mice. INTERPRETATION: These data suggest that RAR-signalling in FAPs is a critical therapeutic target for suppressing differentiation of FAPs and facilitating the regeneration of muscle and other tissues. FUNDING: This study was supported by grants from the National Institutes of Health (R01-HD067449 and R21-AG049976) to M.D. Elsevier 2020-09-24 /pmc/articles/PMC7519288/ /pubmed/32980698 http://dx.doi.org/10.1016/j.ebiom.2020.103020 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Paper
Zhao, Liang
Son, Jun Seok
Wang, Bo
Tian, Qiyu
Chen, Yanting
Liu, Xiangdong
de Avila, Jeanene M.
Zhu, Mei-Jun
Du, Min
Retinoic acid signalling in fibro/adipogenic progenitors robustly enhances muscle regeneration
title Retinoic acid signalling in fibro/adipogenic progenitors robustly enhances muscle regeneration
title_full Retinoic acid signalling in fibro/adipogenic progenitors robustly enhances muscle regeneration
title_fullStr Retinoic acid signalling in fibro/adipogenic progenitors robustly enhances muscle regeneration
title_full_unstemmed Retinoic acid signalling in fibro/adipogenic progenitors robustly enhances muscle regeneration
title_short Retinoic acid signalling in fibro/adipogenic progenitors robustly enhances muscle regeneration
title_sort retinoic acid signalling in fibro/adipogenic progenitors robustly enhances muscle regeneration
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519288/
https://www.ncbi.nlm.nih.gov/pubmed/32980698
http://dx.doi.org/10.1016/j.ebiom.2020.103020
work_keys_str_mv AT zhaoliang retinoicacidsignallinginfibroadipogenicprogenitorsrobustlyenhancesmuscleregeneration
AT sonjunseok retinoicacidsignallinginfibroadipogenicprogenitorsrobustlyenhancesmuscleregeneration
AT wangbo retinoicacidsignallinginfibroadipogenicprogenitorsrobustlyenhancesmuscleregeneration
AT tianqiyu retinoicacidsignallinginfibroadipogenicprogenitorsrobustlyenhancesmuscleregeneration
AT chenyanting retinoicacidsignallinginfibroadipogenicprogenitorsrobustlyenhancesmuscleregeneration
AT liuxiangdong retinoicacidsignallinginfibroadipogenicprogenitorsrobustlyenhancesmuscleregeneration
AT deavilajeanenem retinoicacidsignallinginfibroadipogenicprogenitorsrobustlyenhancesmuscleregeneration
AT zhumeijun retinoicacidsignallinginfibroadipogenicprogenitorsrobustlyenhancesmuscleregeneration
AT dumin retinoicacidsignallinginfibroadipogenicprogenitorsrobustlyenhancesmuscleregeneration