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TNF Signaling Acts Downstream of MiR-322/-503 in Regulating DM1 Myogenesis

Myotonic dystrophy type 1 (DM1) is caused by the expanded CUG repeats and usually displays defective myogenesis. Although we previously reported that ectopic miR-322/-503 expression improved myogenesis in DM1 by targeting the toxic RNA, the underlying pathways regulating myogenesis that were aberran...

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Autores principales: Li, Meng, Xu, Feng, Liu, Zhongxian, Wang, Chunguang, Zhao, Yun, Zhu, Guoping, Shen, Xiaopeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021394/
https://www.ncbi.nlm.nih.gov/pubmed/35464065
http://dx.doi.org/10.3389/fendo.2022.843202
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author Li, Meng
Xu, Feng
Liu, Zhongxian
Wang, Chunguang
Zhao, Yun
Zhu, Guoping
Shen, Xiaopeng
author_facet Li, Meng
Xu, Feng
Liu, Zhongxian
Wang, Chunguang
Zhao, Yun
Zhu, Guoping
Shen, Xiaopeng
author_sort Li, Meng
collection PubMed
description Myotonic dystrophy type 1 (DM1) is caused by the expanded CUG repeats and usually displays defective myogenesis. Although we previously reported that ectopic miR-322/-503 expression improved myogenesis in DM1 by targeting the toxic RNA, the underlying pathways regulating myogenesis that were aberrantly altered in DM1 and rescued by miR-322/-503 were still unknown. Here, we constructed DM1 and miR-322/-503 overexpressing DM1 myoblast models, which were subjected to in vitro myoblast differentiation along with their corresponding controls. Agreeing with previous findings, DM1 myoblast showed remarkable myogenesis defects, while miR-322/-503 overexpression successfully rescued the defects. By RNA sequencing, we noticed that Tumor necrosis factor (TNF) signaling was the only pathway that was significantly and oppositely altered in these two experimental sets, with it upregulated in DM1 and inhibited by miR-322/-503 overexpression. Consistently, hyperactivity of TNF signaling was detected in two DM1 mouse models. Blocking TNF signaling significantly rescued the myogenesis defects in DM1. On the contrary, TNF-α treatment abolished the rescue effect of miR-322/-503 on DM1 myogenesis. Taking together, these results implied that TNF signaling mediated the myogenesis defects in DM1 and might act downstream of miR-322/-503 in regulating the myogenesis in DM1. Moreover, the inhibition of TNF signaling benefiting myogenesis in DM1 provided us with a novel therapeutic strategy for DM1.
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spelling pubmed-90213942022-04-22 TNF Signaling Acts Downstream of MiR-322/-503 in Regulating DM1 Myogenesis Li, Meng Xu, Feng Liu, Zhongxian Wang, Chunguang Zhao, Yun Zhu, Guoping Shen, Xiaopeng Front Endocrinol (Lausanne) Endocrinology Myotonic dystrophy type 1 (DM1) is caused by the expanded CUG repeats and usually displays defective myogenesis. Although we previously reported that ectopic miR-322/-503 expression improved myogenesis in DM1 by targeting the toxic RNA, the underlying pathways regulating myogenesis that were aberrantly altered in DM1 and rescued by miR-322/-503 were still unknown. Here, we constructed DM1 and miR-322/-503 overexpressing DM1 myoblast models, which were subjected to in vitro myoblast differentiation along with their corresponding controls. Agreeing with previous findings, DM1 myoblast showed remarkable myogenesis defects, while miR-322/-503 overexpression successfully rescued the defects. By RNA sequencing, we noticed that Tumor necrosis factor (TNF) signaling was the only pathway that was significantly and oppositely altered in these two experimental sets, with it upregulated in DM1 and inhibited by miR-322/-503 overexpression. Consistently, hyperactivity of TNF signaling was detected in two DM1 mouse models. Blocking TNF signaling significantly rescued the myogenesis defects in DM1. On the contrary, TNF-α treatment abolished the rescue effect of miR-322/-503 on DM1 myogenesis. Taking together, these results implied that TNF signaling mediated the myogenesis defects in DM1 and might act downstream of miR-322/-503 in regulating the myogenesis in DM1. Moreover, the inhibition of TNF signaling benefiting myogenesis in DM1 provided us with a novel therapeutic strategy for DM1. Frontiers Media S.A. 2022-04-07 /pmc/articles/PMC9021394/ /pubmed/35464065 http://dx.doi.org/10.3389/fendo.2022.843202 Text en Copyright © 2022 Li, Xu, Liu, Wang, Zhao, Zhu and Shen https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Li, Meng
Xu, Feng
Liu, Zhongxian
Wang, Chunguang
Zhao, Yun
Zhu, Guoping
Shen, Xiaopeng
TNF Signaling Acts Downstream of MiR-322/-503 in Regulating DM1 Myogenesis
title TNF Signaling Acts Downstream of MiR-322/-503 in Regulating DM1 Myogenesis
title_full TNF Signaling Acts Downstream of MiR-322/-503 in Regulating DM1 Myogenesis
title_fullStr TNF Signaling Acts Downstream of MiR-322/-503 in Regulating DM1 Myogenesis
title_full_unstemmed TNF Signaling Acts Downstream of MiR-322/-503 in Regulating DM1 Myogenesis
title_short TNF Signaling Acts Downstream of MiR-322/-503 in Regulating DM1 Myogenesis
title_sort tnf signaling acts downstream of mir-322/-503 in regulating dm1 myogenesis
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021394/
https://www.ncbi.nlm.nih.gov/pubmed/35464065
http://dx.doi.org/10.3389/fendo.2022.843202
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