Cargando…

TAK1 inhibition improves myoblast differentiation and alleviates fibrosis in a mouse model of Duchenne muscular dystrophy

BACKGROUND: Transforming growth factor‐β‐activated kinase 1 (TAK1) plays a key role in regulating fibroblast and myoblast proliferation and differentiation. However, the TAK1 changes associated with Duchenne muscular dystrophy (DMD) are poorly understood, and it remains unclear how TAK1 regulation c...

Descripción completa

Detalles Bibliográficos
Autores principales: Xu, Dengqiu, Li, Sijia, Wang, Lu, Jiang, Jingwei, Zhao, Lei, Huang, Xiaofei, Sun, Zeren, Li, Chunjie, Sun, Lixin, Li, Xihua, Jiang, Zhenzhou, Zhang, Luyong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890152/
https://www.ncbi.nlm.nih.gov/pubmed/33236534
http://dx.doi.org/10.1002/jcsm.12650
_version_ 1783652455906541568
author Xu, Dengqiu
Li, Sijia
Wang, Lu
Jiang, Jingwei
Zhao, Lei
Huang, Xiaofei
Sun, Zeren
Li, Chunjie
Sun, Lixin
Li, Xihua
Jiang, Zhenzhou
Zhang, Luyong
author_facet Xu, Dengqiu
Li, Sijia
Wang, Lu
Jiang, Jingwei
Zhao, Lei
Huang, Xiaofei
Sun, Zeren
Li, Chunjie
Sun, Lixin
Li, Xihua
Jiang, Zhenzhou
Zhang, Luyong
author_sort Xu, Dengqiu
collection PubMed
description BACKGROUND: Transforming growth factor‐β‐activated kinase 1 (TAK1) plays a key role in regulating fibroblast and myoblast proliferation and differentiation. However, the TAK1 changes associated with Duchenne muscular dystrophy (DMD) are poorly understood, and it remains unclear how TAK1 regulation could be exploited to aid the treatment of this disease. METHODS: Muscle biopsies were obtained from control donors or DMD patients for diagnosis (n = 6 per group, male, 2–3 years, respectively). Protein expression of phosphorylated TAK1 was measured by western blot and immunofluorescence analysis. In vivo overexpression of TAK1 was performed in skeletal muscle to assess whether TAK1 is sufficient to induce or aggravate atrophy and fibrosis. To explore whether TAK1 inhibition protects against muscle damage, mdx (loss of dystrophin) mice were treated with adeno‐associated virus (AAV)‐short hairpin TAK1 (shTAK1) or NG25 (a TAK1 inhibitor). Serum analysis, skeletal muscle performance and histology, muscle contractile function, and gene and protein expression were performed. RESULTS: We found that TAK1 was activated in the dystrophic muscles of DMD patients (n = 6, +72.2%, P < 0.001), resulting in fibrosis ( +65.9% for fibronectin expression, P < 0.001) and loss of muscle fibres (−32.5%, P < 0.01). Moreover, TAK1 was activated by interleukin‐1β, tumour necrosis factor‐α, and transforming growth factor‐β1 (P < 0.01). Overexpression of TAK1 by AAV vectors further aggravated fibrosis (n = 8, +39.6% for hydroxyproline content, P < 0.01) and exacerbated muscle wasting (−31.6%, P < 0.01) in mdx mice; however, these effects were reversed in mdx mice by treatment with AAV‐short hairpin TAK1 (shTAK1) or NG25 (a TAK1 inhibitor). The molecular mechanism underlying these effects may be related to the prevention of TAK1‐mediated transdifferentiation of myoblasts into fibroblasts, thereby reducing fibrosis and increasing myoblast differentiation. CONCLUSIONS: Our findings show that TAK1 activation exacerbated fibrosis and muscle degeneration and that TAK1 inhibition can improve whole‐body muscle quality and the function of dystrophic skeletal muscle. Thus, TAK1 inhibition may constitute a novel therapy for DMD.
format Online
Article
Text
id pubmed-7890152
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-78901522021-02-26 TAK1 inhibition improves myoblast differentiation and alleviates fibrosis in a mouse model of Duchenne muscular dystrophy Xu, Dengqiu Li, Sijia Wang, Lu Jiang, Jingwei Zhao, Lei Huang, Xiaofei Sun, Zeren Li, Chunjie Sun, Lixin Li, Xihua Jiang, Zhenzhou Zhang, Luyong J Cachexia Sarcopenia Muscle Original Articles BACKGROUND: Transforming growth factor‐β‐activated kinase 1 (TAK1) plays a key role in regulating fibroblast and myoblast proliferation and differentiation. However, the TAK1 changes associated with Duchenne muscular dystrophy (DMD) are poorly understood, and it remains unclear how TAK1 regulation could be exploited to aid the treatment of this disease. METHODS: Muscle biopsies were obtained from control donors or DMD patients for diagnosis (n = 6 per group, male, 2–3 years, respectively). Protein expression of phosphorylated TAK1 was measured by western blot and immunofluorescence analysis. In vivo overexpression of TAK1 was performed in skeletal muscle to assess whether TAK1 is sufficient to induce or aggravate atrophy and fibrosis. To explore whether TAK1 inhibition protects against muscle damage, mdx (loss of dystrophin) mice were treated with adeno‐associated virus (AAV)‐short hairpin TAK1 (shTAK1) or NG25 (a TAK1 inhibitor). Serum analysis, skeletal muscle performance and histology, muscle contractile function, and gene and protein expression were performed. RESULTS: We found that TAK1 was activated in the dystrophic muscles of DMD patients (n = 6, +72.2%, P < 0.001), resulting in fibrosis ( +65.9% for fibronectin expression, P < 0.001) and loss of muscle fibres (−32.5%, P < 0.01). Moreover, TAK1 was activated by interleukin‐1β, tumour necrosis factor‐α, and transforming growth factor‐β1 (P < 0.01). Overexpression of TAK1 by AAV vectors further aggravated fibrosis (n = 8, +39.6% for hydroxyproline content, P < 0.01) and exacerbated muscle wasting (−31.6%, P < 0.01) in mdx mice; however, these effects were reversed in mdx mice by treatment with AAV‐short hairpin TAK1 (shTAK1) or NG25 (a TAK1 inhibitor). The molecular mechanism underlying these effects may be related to the prevention of TAK1‐mediated transdifferentiation of myoblasts into fibroblasts, thereby reducing fibrosis and increasing myoblast differentiation. CONCLUSIONS: Our findings show that TAK1 activation exacerbated fibrosis and muscle degeneration and that TAK1 inhibition can improve whole‐body muscle quality and the function of dystrophic skeletal muscle. Thus, TAK1 inhibition may constitute a novel therapy for DMD. John Wiley and Sons Inc. 2020-11-25 2021-02 /pmc/articles/PMC7890152/ /pubmed/33236534 http://dx.doi.org/10.1002/jcsm.12650 Text en © 2020 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Xu, Dengqiu
Li, Sijia
Wang, Lu
Jiang, Jingwei
Zhao, Lei
Huang, Xiaofei
Sun, Zeren
Li, Chunjie
Sun, Lixin
Li, Xihua
Jiang, Zhenzhou
Zhang, Luyong
TAK1 inhibition improves myoblast differentiation and alleviates fibrosis in a mouse model of Duchenne muscular dystrophy
title TAK1 inhibition improves myoblast differentiation and alleviates fibrosis in a mouse model of Duchenne muscular dystrophy
title_full TAK1 inhibition improves myoblast differentiation and alleviates fibrosis in a mouse model of Duchenne muscular dystrophy
title_fullStr TAK1 inhibition improves myoblast differentiation and alleviates fibrosis in a mouse model of Duchenne muscular dystrophy
title_full_unstemmed TAK1 inhibition improves myoblast differentiation and alleviates fibrosis in a mouse model of Duchenne muscular dystrophy
title_short TAK1 inhibition improves myoblast differentiation and alleviates fibrosis in a mouse model of Duchenne muscular dystrophy
title_sort tak1 inhibition improves myoblast differentiation and alleviates fibrosis in a mouse model of duchenne muscular dystrophy
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890152/
https://www.ncbi.nlm.nih.gov/pubmed/33236534
http://dx.doi.org/10.1002/jcsm.12650
work_keys_str_mv AT xudengqiu tak1inhibitionimprovesmyoblastdifferentiationandalleviatesfibrosisinamousemodelofduchennemusculardystrophy
AT lisijia tak1inhibitionimprovesmyoblastdifferentiationandalleviatesfibrosisinamousemodelofduchennemusculardystrophy
AT wanglu tak1inhibitionimprovesmyoblastdifferentiationandalleviatesfibrosisinamousemodelofduchennemusculardystrophy
AT jiangjingwei tak1inhibitionimprovesmyoblastdifferentiationandalleviatesfibrosisinamousemodelofduchennemusculardystrophy
AT zhaolei tak1inhibitionimprovesmyoblastdifferentiationandalleviatesfibrosisinamousemodelofduchennemusculardystrophy
AT huangxiaofei tak1inhibitionimprovesmyoblastdifferentiationandalleviatesfibrosisinamousemodelofduchennemusculardystrophy
AT sunzeren tak1inhibitionimprovesmyoblastdifferentiationandalleviatesfibrosisinamousemodelofduchennemusculardystrophy
AT lichunjie tak1inhibitionimprovesmyoblastdifferentiationandalleviatesfibrosisinamousemodelofduchennemusculardystrophy
AT sunlixin tak1inhibitionimprovesmyoblastdifferentiationandalleviatesfibrosisinamousemodelofduchennemusculardystrophy
AT lixihua tak1inhibitionimprovesmyoblastdifferentiationandalleviatesfibrosisinamousemodelofduchennemusculardystrophy
AT jiangzhenzhou tak1inhibitionimprovesmyoblastdifferentiationandalleviatesfibrosisinamousemodelofduchennemusculardystrophy
AT zhangluyong tak1inhibitionimprovesmyoblastdifferentiationandalleviatesfibrosisinamousemodelofduchennemusculardystrophy