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Reduced HDAC2 in skeletal muscle of COPD patients

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Title: Reduced HDAC2 in skeletal muscle of COPD patients
Authors: To, M
Swallow, EB
Akashi, K
Haruki, K
Natanek, SA
Polkey, MI
Ito, K
Barnes, PJ
Item Type: Journal Article
Abstract: 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 (FEV1 % pred) (rs = 0.53, p = 0.008) and quadriceps maximum voluntary contraction force (MVC) (rs = 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 FEV1 % pred (rs = 0.64, p = 0.0007) but not with MVC (rs = 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 (rs = -0.59, p = 0.003) and HDAC5 (rs = 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.
Issue Date: 19-May-2017
Date of Acceptance: 16-May-2017
URI: http://hdl.handle.net/10044/1/48595
DOI: https://dx.doi.org/10.1186/s12931-017-0588-8
ISSN: 1465-993X
Publisher: BioMed Central
Journal / Book Title: Respiratory Research
Volume: 18
Copyright Statement: © The Author(s). 2017. Open Access This 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.
Keywords: Science & Technology
Life Sciences & Biomedicine
Respiratory System
COPD
Skeletal muscle dysfunction
HDAC2
Nuclear factor-kappa B
Apoptosis
OBSTRUCTIVE PULMONARY-DISEASE
NF-KAPPA-B
HISTONE DEACETYLASE ACTIVITY
QUADRICEPS STRENGTH
GENE-EXPRESSION
ACTIVATION
ENDURANCE
WEAKNESS
PROFILE
TRANSCRIPTION
1102 Cardiovascular Medicine And Haematology
1103 Clinical Sciences
Publication Status: Published
Conference Place: England
Article Number: 99
Appears in Collections:National Heart and Lung Institute
Airway Disease
Faculty of Medicine



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