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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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Epigenetic profile in the diaphragm of mild-to-moderate COPD patients.The main results encountered in the study are briefly depicted in the figure. Arrows express significant differences in COPD patients compared to controls. Main findings were that HDAC4 and MEF2C protein levels were increased, whereas miR-1, miR-133, and miR-206 expression levels were downregulated in diaphragms of COPD patients compared to controls. Abbreviations: COPD, chronic obstructive pulmonary disease; HDACs, histone deacetylases; silent mating type information regulation 2 homolog (SIRT)-1, silent information regulator 1; miR, microRNA; TFs, transcription factors; MEF, myocyte-enhancer factor; YY1, yin yang 1; SRF, serum response factor; and BAF, BRG1-associated factors.
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pone-0111514-g009: Epigenetic profile in the diaphragm of mild-to-moderate COPD patients.The main results encountered in the study are briefly depicted in the figure. Arrows express significant differences in COPD patients compared to controls. Main findings were that HDAC4 and MEF2C protein levels were increased, whereas miR-1, miR-133, and miR-206 expression levels were downregulated in diaphragms of COPD patients compared to controls. Abbreviations: COPD, chronic obstructive pulmonary disease; HDACs, histone deacetylases; silent mating type information regulation 2 homolog (SIRT)-1, silent information regulator 1; miR, microRNA; TFs, transcription factors; MEF, myocyte-enhancer factor; YY1, yin yang 1; SRF, serum response factor; and BAF, BRG1-associated factors.

Mentions: The main findings in the current study were that in the diaphragm of patients with COPD of a wide range of airway obstruction and normal body composition compared to healthy controls, the expression of muscle-specific microRNAs such as miR-1, miR-133, and miR-206 was downregulated, while levels of miR-486, miR-27a, miR-29b, and miR-181a did not differ between the study subjects. Moreover, protein levels of HDAC4 and MEF2C were greater in the respiratory muscles of the patients than in the controls. No significant differences were observed in total protein acetylation and HAT levels, in the content of several muscle-specific transcription factors, or SUMOylation expression in the diaphragm between patients and control subjects (Figure 9). As a group, patients exhibited moderate airflow limitation, reduced diffusion and exercise capacities, as well as a moderately decrease in diaphragm force as measured by transdiaphragmatic pressure. As far as we are concerned, the present study is the first to have characterized the epigenetic profile of the main respiratory muscle of patients with COPD.


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)

Epigenetic profile in the diaphragm of mild-to-moderate COPD patients.The main results encountered in the study are briefly depicted in the figure. Arrows express significant differences in COPD patients compared to controls. Main findings were that HDAC4 and MEF2C protein levels were increased, whereas miR-1, miR-133, and miR-206 expression levels were downregulated in diaphragms of COPD patients compared to controls. Abbreviations: COPD, chronic obstructive pulmonary disease; HDACs, histone deacetylases; silent mating type information regulation 2 homolog (SIRT)-1, silent information regulator 1; miR, microRNA; TFs, transcription factors; MEF, myocyte-enhancer factor; YY1, yin yang 1; SRF, serum response factor; and BAF, BRG1-associated factors.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111514-g009: Epigenetic profile in the diaphragm of mild-to-moderate COPD patients.The main results encountered in the study are briefly depicted in the figure. Arrows express significant differences in COPD patients compared to controls. Main findings were that HDAC4 and MEF2C protein levels were increased, whereas miR-1, miR-133, and miR-206 expression levels were downregulated in diaphragms of COPD patients compared to controls. Abbreviations: COPD, chronic obstructive pulmonary disease; HDACs, histone deacetylases; silent mating type information regulation 2 homolog (SIRT)-1, silent information regulator 1; miR, microRNA; TFs, transcription factors; MEF, myocyte-enhancer factor; YY1, yin yang 1; SRF, serum response factor; and BAF, BRG1-associated factors.
Mentions: The main findings in the current study were that in the diaphragm of patients with COPD of a wide range of airway obstruction and normal body composition compared to healthy controls, the expression of muscle-specific microRNAs such as miR-1, miR-133, and miR-206 was downregulated, while levels of miR-486, miR-27a, miR-29b, and miR-181a did not differ between the study subjects. Moreover, protein levels of HDAC4 and MEF2C were greater in the respiratory muscles of the patients than in the controls. No significant differences were observed in total protein acetylation and HAT levels, in the content of several muscle-specific transcription factors, or SUMOylation expression in the diaphragm between patients and control subjects (Figure 9). As a group, patients exhibited moderate airflow limitation, reduced diffusion and exercise capacities, as well as a moderately decrease in diaphragm force as measured by transdiaphragmatic pressure. As far as we are concerned, the present study is the first to have characterized the epigenetic profile of the main respiratory muscle of patients with COPD.

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