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Epigenetic mechanisms in respiratory muscle dysfunction of patients with chronic obstructive pulmonary disease.

Puig-Vilanova E, Aguiló R, Rodríguez-Fuster A, Martínez-Llorens J, Gea J, Barreiro E - PLoS ONE (2014)

Bottom Line: Moreover, in the diaphragm of the COPD patients, muscle-specific microRNA expression was downregulated, while HDAC4 and myocyte enhancer factor (MEF)2C protein levels were higher, and DNA methylation levels, muscle fiber types and sizes did not differ between patients and controls.In the main respiratory muscle of COPD patients with a wide range of disease severity and normal body composition, muscle-specific microRNAs were downregulated, while HDAC4 and MEF2C levels were upregulated.These findings may offer novel therapeutic strategies to specifically target respiratory muscle dysfunction in patients with COPD.

View Article: PubMed Central - PubMed

Affiliation: Pulmonology Department-Muscle and Respiratory System Research Unit (URMAR), IMIM-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona Biomedical Research Park (PRBB), Barcelona, Spain; Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.

ABSTRACT
Epigenetic events are differentially expressed in the lungs and airways of patients with chronic obstructive pulmonary disease (COPD). Moreover, epigenetic mechanisms are involved in the skeletal (peripheral) muscle dysfunction of COPD patients. Whether epigenetic events may also regulate respiratory muscle dysfunction in COPD remains unknown. We hypothesized that epigenetic mechanisms would be differentially expressed in the main inspiratory muscle (diaphragm) of patients with COPD of a wide range of disease severity compared to healthy controls. In diaphragm muscle specimens (thoracotomy due to lung localized neoplasms) of sedentary patients with mild-to-moderate and severe COPD, with preserved body composition, and sedentary healthy controls, expression of muscle-enriched microRNAs, histone acetyltransferases (HATs) and deacetylases (HDACs), total DNA methylation and protein acetylation, small ubiquitin-related modifier (SUMO) ligases, muscle-specific transcription factors, and muscle structure were explored. All subjects were also clinically evaluated: lung and muscle functions and exercise capacity. Compared to healthy controls, patients exhibited moderate airflow limitation and diffusion capacity, and reduced exercise tolerance and transdiaphragmatic strength. Moreover, in the diaphragm of the COPD patients, muscle-specific microRNA expression was downregulated, while HDAC4 and myocyte enhancer factor (MEF)2C protein levels were higher, and DNA methylation levels, muscle fiber types and sizes did not differ between patients and controls. In the main respiratory muscle of COPD patients with a wide range of disease severity and normal body composition, muscle-specific microRNAs were downregulated, while HDAC4 and MEF2C levels were upregulated. It is likely that these epigenetic events act as biological adaptive mechanisms to better overcome the continuous inspiratory loads of the respiratory system in COPD. These findings may offer novel therapeutic strategies to specifically target respiratory muscle dysfunction in patients with COPD.

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Levels of expression of muscle-enriched microRNAs in the diaphragms of COPD patients and healthy controls.Mean values and standard deviation (relative expression) of miR-1, miR-133, and miR-206 expression was downregulated (*: p<0.05) in the diaphragms of COPD patients compared to controls (panels A, B, and C), while no differences (n.s., non-significant) were detected in miR-486 expression between the study groups (panel D). Samples were always run in triplicates and their corresponding expression was calculated as the mean value of the 3 measurements.
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pone-0111514-g002: Levels of expression of muscle-enriched microRNAs in the diaphragms of COPD patients and healthy controls.Mean values and standard deviation (relative expression) of miR-1, miR-133, and miR-206 expression was downregulated (*: p<0.05) in the diaphragms of COPD patients compared to controls (panels A, B, and C), while no differences (n.s., non-significant) were detected in miR-486 expression between the study groups (panel D). Samples were always run in triplicates and their corresponding expression was calculated as the mean value of the 3 measurements.

Mentions: Compared to healthy controls, expression levels of miR-1, -133, and -206 were significantly downregulated in the diaphragm of the patients (Figures 2A–2C), while levels of miR-486, -27a, -29b, and -181a did not differ between the study groups (Figures 2D and 3A–3C).


Epigenetic mechanisms in respiratory muscle dysfunction of patients with chronic obstructive pulmonary disease.

Puig-Vilanova E, Aguiló R, Rodríguez-Fuster A, Martínez-Llorens J, Gea J, Barreiro E - PLoS ONE (2014)

Levels of expression of muscle-enriched microRNAs in the diaphragms of COPD patients and healthy controls.Mean values and standard deviation (relative expression) of miR-1, miR-133, and miR-206 expression was downregulated (*: p<0.05) in the diaphragms of COPD patients compared to controls (panels A, B, and C), while no differences (n.s., non-significant) were detected in miR-486 expression between the study groups (panel D). Samples were always run in triplicates and their corresponding expression was calculated as the mean value of the 3 measurements.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219759&req=5

pone-0111514-g002: Levels of expression of muscle-enriched microRNAs in the diaphragms of COPD patients and healthy controls.Mean values and standard deviation (relative expression) of miR-1, miR-133, and miR-206 expression was downregulated (*: p<0.05) in the diaphragms of COPD patients compared to controls (panels A, B, and C), while no differences (n.s., non-significant) were detected in miR-486 expression between the study groups (panel D). Samples were always run in triplicates and their corresponding expression was calculated as the mean value of the 3 measurements.
Mentions: Compared to healthy controls, expression levels of miR-1, -133, and -206 were significantly downregulated in the diaphragm of the patients (Figures 2A–2C), while levels of miR-486, -27a, -29b, and -181a did not differ between the study groups (Figures 2D and 3A–3C).

Bottom Line: Moreover, in the diaphragm of the COPD patients, muscle-specific microRNA expression was downregulated, while HDAC4 and myocyte enhancer factor (MEF)2C protein levels were higher, and DNA methylation levels, muscle fiber types and sizes did not differ between patients and controls.In the main respiratory muscle of COPD patients with a wide range of disease severity and normal body composition, muscle-specific microRNAs were downregulated, while HDAC4 and MEF2C levels were upregulated.These findings may offer novel therapeutic strategies to specifically target respiratory muscle dysfunction in patients with COPD.

View Article: PubMed Central - PubMed

Affiliation: Pulmonology Department-Muscle and Respiratory System Research Unit (URMAR), IMIM-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona Biomedical Research Park (PRBB), Barcelona, Spain; Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.

ABSTRACT
Epigenetic events are differentially expressed in the lungs and airways of patients with chronic obstructive pulmonary disease (COPD). Moreover, epigenetic mechanisms are involved in the skeletal (peripheral) muscle dysfunction of COPD patients. Whether epigenetic events may also regulate respiratory muscle dysfunction in COPD remains unknown. We hypothesized that epigenetic mechanisms would be differentially expressed in the main inspiratory muscle (diaphragm) of patients with COPD of a wide range of disease severity compared to healthy controls. In diaphragm muscle specimens (thoracotomy due to lung localized neoplasms) of sedentary patients with mild-to-moderate and severe COPD, with preserved body composition, and sedentary healthy controls, expression of muscle-enriched microRNAs, histone acetyltransferases (HATs) and deacetylases (HDACs), total DNA methylation and protein acetylation, small ubiquitin-related modifier (SUMO) ligases, muscle-specific transcription factors, and muscle structure were explored. All subjects were also clinically evaluated: lung and muscle functions and exercise capacity. Compared to healthy controls, patients exhibited moderate airflow limitation and diffusion capacity, and reduced exercise tolerance and transdiaphragmatic strength. Moreover, in the diaphragm of the COPD patients, muscle-specific microRNA expression was downregulated, while HDAC4 and myocyte enhancer factor (MEF)2C protein levels were higher, and DNA methylation levels, muscle fiber types and sizes did not differ between patients and controls. In the main respiratory muscle of COPD patients with a wide range of disease severity and normal body composition, muscle-specific microRNAs were downregulated, while HDAC4 and MEF2C levels were upregulated. It is likely that these epigenetic events act as biological adaptive mechanisms to better overcome the continuous inspiratory loads of the respiratory system in COPD. These findings may offer novel therapeutic strategies to specifically target respiratory muscle dysfunction in patients with COPD.

Show MeSH
Related in: MedlinePlus