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Targeted regulation of TAK1 counteracts dystrophinopathy in a DMD mouse model

Muscular dystrophies make up a group of genetic neuromuscular disorders that involve severe muscle wasting. TGF-β–activated kinase 1 (TAK1) is an important signaling protein that regulates cell survival, growth, and inflammation. TAK1 has been recently found to promote myofiber growth in the skeleta...

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Autores principales: Roy, Anirban, Koike, Tatiana E., Joshi, Aniket S., Tomaz da Silva, Meiricris, Mathukumalli, Kavya, Wu, Mingfu, Kumar, Ashok
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10322678/
https://www.ncbi.nlm.nih.gov/pubmed/37071470
http://dx.doi.org/10.1172/jci.insight.164768
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author Roy, Anirban
Koike, Tatiana E.
Joshi, Aniket S.
Tomaz da Silva, Meiricris
Mathukumalli, Kavya
Wu, Mingfu
Kumar, Ashok
author_facet Roy, Anirban
Koike, Tatiana E.
Joshi, Aniket S.
Tomaz da Silva, Meiricris
Mathukumalli, Kavya
Wu, Mingfu
Kumar, Ashok
author_sort Roy, Anirban
collection PubMed
description Muscular dystrophies make up a group of genetic neuromuscular disorders that involve severe muscle wasting. TGF-β–activated kinase 1 (TAK1) is an important signaling protein that regulates cell survival, growth, and inflammation. TAK1 has been recently found to promote myofiber growth in the skeletal muscle of adult mice. However, the role of TAK1 in muscle diseases remains poorly understood. In the present study, we have investigated how TAK1 affects the progression of dystrophic phenotype in the mdx mouse model of Duchenne muscular dystrophy (DMD). TAK1 is highly activated in the dystrophic muscle of mdx mice during the peak necrotic phase. While targeted inducible inactivation of TAK1 inhibits myofiber injury in young mdx mice, it results in reduced muscle mass and contractile function. TAK1 inactivation also causes loss of muscle mass in adult mdx mice. By contrast, forced activation of TAK1 through overexpression of TAK1 and TAB1 induces myofiber growth without having any deleterious effect on muscle histopathology. Collectively, our results suggest that TAK1 is a positive regulator of skeletal muscle mass and that targeted regulation of TAK1 can suppress myonecrosis and ameliorate disease progression in DMD.
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spelling pubmed-103226782023-07-07 Targeted regulation of TAK1 counteracts dystrophinopathy in a DMD mouse model Roy, Anirban Koike, Tatiana E. Joshi, Aniket S. Tomaz da Silva, Meiricris Mathukumalli, Kavya Wu, Mingfu Kumar, Ashok JCI Insight Research Article Muscular dystrophies make up a group of genetic neuromuscular disorders that involve severe muscle wasting. TGF-β–activated kinase 1 (TAK1) is an important signaling protein that regulates cell survival, growth, and inflammation. TAK1 has been recently found to promote myofiber growth in the skeletal muscle of adult mice. However, the role of TAK1 in muscle diseases remains poorly understood. In the present study, we have investigated how TAK1 affects the progression of dystrophic phenotype in the mdx mouse model of Duchenne muscular dystrophy (DMD). TAK1 is highly activated in the dystrophic muscle of mdx mice during the peak necrotic phase. While targeted inducible inactivation of TAK1 inhibits myofiber injury in young mdx mice, it results in reduced muscle mass and contractile function. TAK1 inactivation also causes loss of muscle mass in adult mdx mice. By contrast, forced activation of TAK1 through overexpression of TAK1 and TAB1 induces myofiber growth without having any deleterious effect on muscle histopathology. Collectively, our results suggest that TAK1 is a positive regulator of skeletal muscle mass and that targeted regulation of TAK1 can suppress myonecrosis and ameliorate disease progression in DMD. American Society for Clinical Investigation 2023-05-22 /pmc/articles/PMC10322678/ /pubmed/37071470 http://dx.doi.org/10.1172/jci.insight.164768 Text en © 2023 Roy et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Roy, Anirban
Koike, Tatiana E.
Joshi, Aniket S.
Tomaz da Silva, Meiricris
Mathukumalli, Kavya
Wu, Mingfu
Kumar, Ashok
Targeted regulation of TAK1 counteracts dystrophinopathy in a DMD mouse model
title Targeted regulation of TAK1 counteracts dystrophinopathy in a DMD mouse model
title_full Targeted regulation of TAK1 counteracts dystrophinopathy in a DMD mouse model
title_fullStr Targeted regulation of TAK1 counteracts dystrophinopathy in a DMD mouse model
title_full_unstemmed Targeted regulation of TAK1 counteracts dystrophinopathy in a DMD mouse model
title_short Targeted regulation of TAK1 counteracts dystrophinopathy in a DMD mouse model
title_sort targeted regulation of tak1 counteracts dystrophinopathy in a dmd mouse model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10322678/
https://www.ncbi.nlm.nih.gov/pubmed/37071470
http://dx.doi.org/10.1172/jci.insight.164768
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