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Reducing the Excess Activin Signaling Rescues Muscle Degeneration in Myotonic Dystrophy Type 2 Drosophila Model

Expanded non-coding RNA repeats of CCUG are the underlying genetic causes for myotonic dystrophy type 2 (DM2). There is an urgent need for effective medications and potential drug targets that may alleviate the progression of the disease. In this study, 3140 small-molecule drugs from FDA-approved li...

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Autores principales: Deng, Jing, Guan, Xin-Xin, Zhu, Ying-Bao, Deng, Hai-Tao, Li, Guang-Xu, Guo, Yi-Chen, Jin, Peng, Duan, Ran-Hui, Huang, Wen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8948895/
https://www.ncbi.nlm.nih.gov/pubmed/35330385
http://dx.doi.org/10.3390/jpm12030385
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author Deng, Jing
Guan, Xin-Xin
Zhu, Ying-Bao
Deng, Hai-Tao
Li, Guang-Xu
Guo, Yi-Chen
Jin, Peng
Duan, Ran-Hui
Huang, Wen
author_facet Deng, Jing
Guan, Xin-Xin
Zhu, Ying-Bao
Deng, Hai-Tao
Li, Guang-Xu
Guo, Yi-Chen
Jin, Peng
Duan, Ran-Hui
Huang, Wen
author_sort Deng, Jing
collection PubMed
description Expanded non-coding RNA repeats of CCUG are the underlying genetic causes for myotonic dystrophy type 2 (DM2). There is an urgent need for effective medications and potential drug targets that may alleviate the progression of the disease. In this study, 3140 small-molecule drugs from FDA-approved libraries were screened through lethality and locomotion phenotypes using a DM2 Drosophila model expressing 720 CCTG repeats in the muscle. We identified ten effective drugs that improved survival and locomotor activity of DM2 flies, including four that share the same predicted targets in the TGF-β pathway. The pathway comprises two major branches, the Activin and BMP pathways, which play critical and complex roles in skeletal development, maintenance of homeostasis, and regeneration. The Drosophila model recapitulates pathological features of muscle degeneration in DM2, displaying shortened lifespan, a decline in climbing ability, and progressive muscle degeneration. Increased levels of p-smad3 in response to activin signaling were observed in DM2 flies. Decreased levels of activin signaling using additional specific inhibitors or genetic method ameliorated climbing defects, crushed thoraxes, structure, and organization of muscle fibers. Our results demonstrate that a decrease in activin signaling is sufficient to rescue muscle degeneration and is, therefore, a potential therapeutic target for DM2.
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spelling pubmed-89488952022-03-26 Reducing the Excess Activin Signaling Rescues Muscle Degeneration in Myotonic Dystrophy Type 2 Drosophila Model Deng, Jing Guan, Xin-Xin Zhu, Ying-Bao Deng, Hai-Tao Li, Guang-Xu Guo, Yi-Chen Jin, Peng Duan, Ran-Hui Huang, Wen J Pers Med Article Expanded non-coding RNA repeats of CCUG are the underlying genetic causes for myotonic dystrophy type 2 (DM2). There is an urgent need for effective medications and potential drug targets that may alleviate the progression of the disease. In this study, 3140 small-molecule drugs from FDA-approved libraries were screened through lethality and locomotion phenotypes using a DM2 Drosophila model expressing 720 CCTG repeats in the muscle. We identified ten effective drugs that improved survival and locomotor activity of DM2 flies, including four that share the same predicted targets in the TGF-β pathway. The pathway comprises two major branches, the Activin and BMP pathways, which play critical and complex roles in skeletal development, maintenance of homeostasis, and regeneration. The Drosophila model recapitulates pathological features of muscle degeneration in DM2, displaying shortened lifespan, a decline in climbing ability, and progressive muscle degeneration. Increased levels of p-smad3 in response to activin signaling were observed in DM2 flies. Decreased levels of activin signaling using additional specific inhibitors or genetic method ameliorated climbing defects, crushed thoraxes, structure, and organization of muscle fibers. Our results demonstrate that a decrease in activin signaling is sufficient to rescue muscle degeneration and is, therefore, a potential therapeutic target for DM2. MDPI 2022-03-02 /pmc/articles/PMC8948895/ /pubmed/35330385 http://dx.doi.org/10.3390/jpm12030385 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Deng, Jing
Guan, Xin-Xin
Zhu, Ying-Bao
Deng, Hai-Tao
Li, Guang-Xu
Guo, Yi-Chen
Jin, Peng
Duan, Ran-Hui
Huang, Wen
Reducing the Excess Activin Signaling Rescues Muscle Degeneration in Myotonic Dystrophy Type 2 Drosophila Model
title Reducing the Excess Activin Signaling Rescues Muscle Degeneration in Myotonic Dystrophy Type 2 Drosophila Model
title_full Reducing the Excess Activin Signaling Rescues Muscle Degeneration in Myotonic Dystrophy Type 2 Drosophila Model
title_fullStr Reducing the Excess Activin Signaling Rescues Muscle Degeneration in Myotonic Dystrophy Type 2 Drosophila Model
title_full_unstemmed Reducing the Excess Activin Signaling Rescues Muscle Degeneration in Myotonic Dystrophy Type 2 Drosophila Model
title_short Reducing the Excess Activin Signaling Rescues Muscle Degeneration in Myotonic Dystrophy Type 2 Drosophila Model
title_sort reducing the excess activin signaling rescues muscle degeneration in myotonic dystrophy type 2 drosophila model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8948895/
https://www.ncbi.nlm.nih.gov/pubmed/35330385
http://dx.doi.org/10.3390/jpm12030385
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