Diaphragm specimens were also obtained in healthy controls for the purpose of the investigation, and both patients and control individuals were clinically and functionally evaluated. 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. 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. In the present investigation, as also shown in former studies, patients undergoing thoracotomy exhibited mild-tomoderate and severe COPD together with a moderate decrease in their exercise performance and in both respiratory and limb muscle strengths. Additionally, as also previously reported, signs of chronic disease were evidenced by the significant rise in levels of general inflammatory parameters observed in the COPD patients. Importantly, despite that total respiratory muscle force was not reduced in the patients, the specific assessment of diaphragm strength showed a significant reduction of this parameter in that group compared to values detected in the control subjects. The degree of diaphragm muscle dysfunction seen in the patients may not be sufficiently relevant to induce a significant clinical impact at rest, but it could certainly have implications during exercise and exacerbations. In line with these findings, proportions and sizes of the diaphragm muscle Dasatinib Src-bcr-Abl inhibitor fibers did not differ between patients and control subjects in the study. It is likely that changes taking place in muscle structure towards a more fatigue-resistant phenotype require a more drastic loss in muscle strength of the diaphragm, which is, in turn, directly related to the degree of the airway obstruction. In the present study, most of the patients exhibited mild and moderate airflow limitation, while only three patients had severe COPD. In previous studies from our group and others, respiratory muscle strength and diaphragm force parameters were more significantly reduced than in the current investigation as COPD patients were more severe. Moreover, in those investigations a fibertype switch towards a more resistant phenotype was also observed in the diaphragm of the severe COPD patients. In fact, in the study, the negative correlation encountered between the degrees of the airway obstruction as measured by FEV1 and the proportions of the slow-twitch fibers in the diaphragm further support these conclusions. Importantly, expression of the muscle-specific microRNAs miR1, -133, and -206 was downregulated in the diaphragm of patients with mild-to-moderate and severe COPD, whereas the expression of miR-486 did not differ between patients and controls.