Content area
Full text
Background
Chronic obstructive pulmonary disease (COPD) is an increasing health problem and it is predicted to be the third most common cause of death worldwide by 2020 [1]. In COPD patients, skeletal muscle weakness is an extra-pulmonary manifestation that markedly reduces their quality of life and survival. Quadriceps weakness [2-4] and a decrease in quadriceps endurance [5, 6] have been reported in patients with COPD. Skeletal muscle strength in COPD, measured by maximum voluntary contraction (MVC), is lower in approximately a third of all COPD patients than in age-matched controls [7]. Quadriceps strength is a better predictor of mortality in COPD than FEV1 in patients with moderate to very severe lung function impairment [8].
Skeletal muscle in COPD shows cellular structural changes, including a reduction in type I fibres, fibre cross-sectional area and capillary contacts to muscle fibres [9], several metabolic changes and activation of the proinflammatory transcription factor nuclear factor-kappa B (NF-?B) [10], mitochondrial dysfunction [11] and enhanced autophagy [12]. Recently, it was reported that the histone deacetylases (HDAC) 3 and HDAC4 might be associated with muscle dysfunction in COPD [13, 14]. These reports were descriptive and failed to demonstrate the precise molecular relationship between HDAC reduction and muscle dysfunction. Furthermore, data suggesting the potential molecular mechanisms of depression of HDACs in COPD muscle were not shown. The precise molecular mechanisms of muscle weakness underlying COPD need to be elucidated.
HDAC are a family of enzymes that remove acetyl groups from amino acids, usually lysine residues, and modify inflammatory gene expression by regulating histone acetylation and chromatin structure as well as through non-histone protein acetylation. There are 11 isoforms of Type I and II HDACs [15]. We have previously shown that total HDAC activity is reduced in peripheral lung and alveolar macrophages from COPD patients, and that the reduction correlates with the degree of airflow limitation [16]. In particular, the protein levels and mRNA levels of HDAC2 and HDAC5 mRNA levels were reduced in peripheral lung obtained from COPD patients [16].
HDACs also target non-histone proteins, including transcription factors such as NF-?B, and a reduction of HDAC induces hyperacetylation of NF-?B. NF-?B is activated in lung epithelial cells and macrophages of COPD patients and regulates the increased expression of proinflammatory cytokines, such as tumour...