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Reduced HDAC2 in skeletal muscle of COPD patients

BACKGROUND: Skeletal muscle weakness in chronic obstructive pulmonary disease (COPD) is an important predictor of poor prognosis, but the molecular mechanisms of muscle weakness in COPD have not been fully elucidated. The aim of this study was to investigate the role of histone deacetylases(HDAC) in...

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Autores principales: To, Masako, Swallow, Elisabeth B., Akashi, Kenich, Haruki, Kosuke, Natanek, S Amanda, Polkey, Michael I., Ito, Kazuhiro, Barnes, Peter J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438490/
https://www.ncbi.nlm.nih.gov/pubmed/28526090
http://dx.doi.org/10.1186/s12931-017-0588-8
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author To, Masako
Swallow, Elisabeth B.
Akashi, Kenich
Haruki, Kosuke
Natanek, S Amanda
Polkey, Michael I.
Ito, Kazuhiro
Barnes, Peter J.
author_facet To, Masako
Swallow, Elisabeth B.
Akashi, Kenich
Haruki, Kosuke
Natanek, S Amanda
Polkey, Michael I.
Ito, Kazuhiro
Barnes, Peter J.
author_sort To, Masako
collection PubMed
description BACKGROUND: Skeletal muscle weakness in chronic obstructive pulmonary disease (COPD) is an important predictor of poor prognosis, but the molecular mechanisms of muscle weakness in COPD have not been fully elucidated. The aim of this study was to investigate the role of histone deacetylases(HDAC) in skeletal muscle weakness in COPD. METHODS AND RESULTS: Twelve COPD patients, 8 smokers without COPD (SM) and 4 healthy non-smokers (NS) were recruited to the study. HDAC2 protein expression in quadriceps muscle biopsies of COPD patients (HDAC2/β-actin: 0.59 ± 0.34) was significantly lower than that in SM (1.9 ± 1.1, p = 0.0007) and NS (1.2 ± 0.7, p = 0.029). HDAC2 protein in skeletal muscle was significantly correlated with forced expiratory volume in 1 s % predicted (FEV(1) % pred) (r(s) = 0.53, p = 0.008) and quadriceps maximum voluntary contraction force (MVC) (r(s) = 0.42, p = 0.029). HDAC5 protein in muscle biopsies of COPD patients (HDAC5/β-actin: 0.44 ± 0.26) was also significantly lower than that in SM (1.29 ± 0.39, p = 0.0001) and NS (0.98 ± 0.43, p = 0.020). HDAC5 protein in muscle was significantly correlated with FEV(1) % pred (r(s) = 0.64, p = 0.0007) but not with MVC (r(s) = 0.30, p = 0.180). Nuclear factor-kappa B (NF-κB) DNA binding activity in muscle biopsies of COPD patients (10.1 ± 7.4) was significantly higher than that in SM (3.9 ± 7.3, p = 0.020) and NS (1.0 ± 1.2, p = 0.004and significantly correlated with HDAC2 decrease (r(s) = −0.59, p = 0.003) and HDAC5 (r(s) = 0.050, p = 0.012). HDAC2 knockdown by RNA interference in primary skeletal muscle cells caused an increase in NF-κB activity, NF-κB acetylation and basal tumour necrosis factor (TNF)-α production, as well as progressive cell death through apoptosis. CONCLUSION: Skeletal muscle weakness in COPD may result from HDAC2 down-regulation in skeletal muscle via acetylation and activation of NF-κB. The restoration of HDAC2 levels might be a therapeutic target for improving skeletal muscle weakness in COPD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12931-017-0588-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-54384902017-05-22 Reduced HDAC2 in skeletal muscle of COPD patients To, Masako Swallow, Elisabeth B. Akashi, Kenich Haruki, Kosuke Natanek, S Amanda Polkey, Michael I. Ito, Kazuhiro Barnes, Peter J. Respir Res Research BACKGROUND: Skeletal muscle weakness in chronic obstructive pulmonary disease (COPD) is an important predictor of poor prognosis, but the molecular mechanisms of muscle weakness in COPD have not been fully elucidated. The aim of this study was to investigate the role of histone deacetylases(HDAC) in skeletal muscle weakness in COPD. METHODS AND RESULTS: Twelve COPD patients, 8 smokers without COPD (SM) and 4 healthy non-smokers (NS) were recruited to the study. HDAC2 protein expression in quadriceps muscle biopsies of COPD patients (HDAC2/β-actin: 0.59 ± 0.34) was significantly lower than that in SM (1.9 ± 1.1, p = 0.0007) and NS (1.2 ± 0.7, p = 0.029). HDAC2 protein in skeletal muscle was significantly correlated with forced expiratory volume in 1 s % predicted (FEV(1) % pred) (r(s) = 0.53, p = 0.008) and quadriceps maximum voluntary contraction force (MVC) (r(s) = 0.42, p = 0.029). HDAC5 protein in muscle biopsies of COPD patients (HDAC5/β-actin: 0.44 ± 0.26) was also significantly lower than that in SM (1.29 ± 0.39, p = 0.0001) and NS (0.98 ± 0.43, p = 0.020). HDAC5 protein in muscle was significantly correlated with FEV(1) % pred (r(s) = 0.64, p = 0.0007) but not with MVC (r(s) = 0.30, p = 0.180). Nuclear factor-kappa B (NF-κB) DNA binding activity in muscle biopsies of COPD patients (10.1 ± 7.4) was significantly higher than that in SM (3.9 ± 7.3, p = 0.020) and NS (1.0 ± 1.2, p = 0.004and significantly correlated with HDAC2 decrease (r(s) = −0.59, p = 0.003) and HDAC5 (r(s) = 0.050, p = 0.012). HDAC2 knockdown by RNA interference in primary skeletal muscle cells caused an increase in NF-κB activity, NF-κB acetylation and basal tumour necrosis factor (TNF)-α production, as well as progressive cell death through apoptosis. CONCLUSION: Skeletal muscle weakness in COPD may result from HDAC2 down-regulation in skeletal muscle via acetylation and activation of NF-κB. The restoration of HDAC2 levels might be a therapeutic target for improving skeletal muscle weakness in COPD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12931-017-0588-8) contains supplementary material, which is available to authorized users. BioMed Central 2017-05-19 2017 /pmc/articles/PMC5438490/ /pubmed/28526090 http://dx.doi.org/10.1186/s12931-017-0588-8 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
To, Masako
Swallow, Elisabeth B.
Akashi, Kenich
Haruki, Kosuke
Natanek, S Amanda
Polkey, Michael I.
Ito, Kazuhiro
Barnes, Peter J.
Reduced HDAC2 in skeletal muscle of COPD patients
title Reduced HDAC2 in skeletal muscle of COPD patients
title_full Reduced HDAC2 in skeletal muscle of COPD patients
title_fullStr Reduced HDAC2 in skeletal muscle of COPD patients
title_full_unstemmed Reduced HDAC2 in skeletal muscle of COPD patients
title_short Reduced HDAC2 in skeletal muscle of COPD patients
title_sort reduced hdac2 in skeletal muscle of copd patients
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438490/
https://www.ncbi.nlm.nih.gov/pubmed/28526090
http://dx.doi.org/10.1186/s12931-017-0588-8
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