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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.

Muscle dysfunction is a major comorbidity in Chronic Obstructive Pulmonary Disease (COPD). Several biological mechanisms including epigenetic events regulate muscle mass and function in models of muscle atrophy. Investigations conducted so far have focused on the elucidation of biological mechanisms involved in muscle dysfunction in advanced COPD. We assessed whether the epigenetic profile may be altered in the vastus lateralis of patients with mild COPD, normal body composition, and mildly impaired muscle function and exercise capacity. In vastus lateralis (VL) of mild COPD patients with well-preserved body composition and in healthy age-matched controls, expression of DNA methylation, muscle-enriched microRNAs, histone acetyltransferases (HTAs) and deacetylases (HDACs), protein acetylation, small ubiquitin-related modifier (SUMO) ligases, and muscle structure were explored. All subjects were clinically evaluated. Compared to healthy controls, in the VL of mild COPD patients, muscle function and exercise capacity were moderately reduced, DNA methylation levels did not differ, miR-1 expression levels were increased and positively correlated with both forced expiratory volume in one second (FEV1) and quadriceps force, HDAC4 protein levels were increased, and muscle fiber types and sizes were not different. Moderate skeletal muscle dysfunction is a relevant feature in patients with mild COPD and preserved body composition. Several epigenetic events are differentially expressed in the limb muscles of these patients, probably as an attempt to counterbalance the underlying mechanisms that alter muscle function and mass. The study of patients at early stages of their disease is of interest as they are a target for timely therapeutic interventions that may slow down the course of the disease and prevent the deleterious effects of major comorbidities. This study has been supported by Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES); Fondo de Investigaciones Sanitarias (FIS) 11/02029; FIS 12/02534; SAF-2011-26908; 2009-SGR-393; Sociedad Española de Neumología y Cirugía Torácica (SEPAR) 2009; Fundació Catalana de Pneumologia (FUCAP) 2011; FUCAP 2012; and Marató TV3 (MTV3-07-1010) (Spain). Dr. Esther Barreiro was a recipient of the European Respiratory Society (ERS) COPD Research Award 2008