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

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.

SUBMITTER: Puig-Vilanova E

PROVIDER: S-EPMC4219759 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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

Puig-Vilanova Ester E Aguiló Rafael R Rodríguez-Fuster Alberto A Martínez-Llorens Juana J Gea Joaquim J Barreiro Esther E

PloS one 20141104 11

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 ra ...[more]

PMID: 25369292

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Project description:BackgroundLimb muscle dysfunction is prevalent in chronic obstructive pulmonary disease (COPD) and it has important clinical implications, such as reduced exercise tolerance, quality of life, and even survival. Since the previous American Thoracic Society/European Respiratory Society (ATS/ERS) statement on limb muscle dysfunction, important progress has been made on the characterization of this problem and on our understanding of its pathophysiology and clinical implications.PurposeThe purpose of this document is to update the 1999 ATS/ERS statement on limb muscle dysfunction in COPD.MethodsAn interdisciplinary committee of experts from the ATS and ERS Pulmonary Rehabilitation and Clinical Problems assemblies determined that the scope of this document should be limited to limb muscles. Committee members conducted focused reviews of the literature on several topics. A librarian also performed a literature search. An ATS methodologist provided advice to the committee, ensuring that the methodological approach was consistent with ATS standards.ResultsWe identified important advances in our understanding of the extent and nature of the structural alterations in limb muscles in patients with COPD. Since the last update, landmark studies were published on the mechanisms of development of limb muscle dysfunction in COPD and on the treatment of this condition. We now have a better understanding of the clinical implications of limb muscle dysfunction. Although exercise training is the most potent intervention to address this condition, other therapies, such as neuromuscular electrical stimulation, are emerging. Assessment of limb muscle function can identify patients who are at increased risk of poor clinical outcomes, such as exercise intolerance and premature mortality.ConclusionsLimb muscle dysfunction is a key systemic consequence of COPD. However, there are still important gaps in our knowledge about the mechanisms of development of this problem. Strategies for early detection and specific treatments for this condition are also needed.

Project description:The maximal oxygen uptake (VO2max) is the gold standard measure of aerobic exercise capacity and is an important outcome measure in patients with chronic obstructive pulmonary disease (COPD). And respiratory muscle performance is also an important functional parameter for COPD patients. In addition to the traditional respiratory muscle strength test, the Test of Incremental Respiratory Endurance has recently been introduced and validated in patients with COPD. However, the relationship between VO2 and respiratory muscle performance in COPD is not well understood. Therefore, this study investigated the correlations among VO2 and respiratory muscle performance and other functional markers in COPD. A total of 32 patients with COPD were enrolled. All study participants underwent the following assessments: cardiopulmonary exercise test, pulmonary function test, respiratory muscle strength test, peripheral muscle strength test, and bioelectrical impedance analysis. When comparing VO2peak and respiratory muscle parameters, the sustained maximal inspiratory pressure (SMIP) was the only factor with a significant relationship with VO2peak. Among other functional parameters, the forced expiratory volume in one second (FEV1) showed the strongest correlation with VO2peak. It was followed by phase angle values of lower limbs, leg extension peak torque, age, and total skeletal muscle mass. When comparing respiratory muscle performance with other functional parameters, the SMIP showed the strongest correlation with hand grip strength, followed by peak cough flow, forced vital capacity, maximal inspiratory pressure, and FEV1. The results showed that the SMIP was more significantly correlated with VO2peak than the static measurement of respiratory muscle strength. This suggests that TIRE may be a useful assessment tool for patients with COPD. Additionally, FEV1 and other functional markers were significantly correlated with VO2peak, suggesting that various parameters may be used to evaluate aerobic power indirectly.

Project description:ObjectiveSkeletal muscle dysfunction is an important comorbidity in patients with chronic obstructive pulmonary disease (COPD), and is associated with poor quality of life and reduced survival, but the mechanisms involved remain elusive. Ferroptosis is a newly discovered type of cell death resulting from iron-dependent lipid peroxide accumulation. The purpose of this study was to examine whether ferroptosis is involved in COPD-associated skeletal muscle dysfunction.MethodsA mouse model of COPD was established after 24 weeks of cigarette smoke (CS) exposure, and mRNA sequencing, hematoxylin-eosin (H&E) staining, immunostaining (IF), RT-PCR, and Western blot were utilized to identify the changes in gastrocnemius muscles. In vitro, C2C12 myotubes were treated with CS extract (CSE) and evaluated for ferroptosis-related molecules. The pathways regulating ferroptosis were then explored in CSE-stimulated myotubes.ResultsCompared with controls, COPD mice showed an enriched ferroptosis pathway. Gpx4 was decreased, while hypoxia-inducible factor (Hif) 2α was increased, at gene and protein levels. A reduced level of GSH, but increased cell death, Fe2+, lipid ROS, LPO, and 4-HNE were observed in COPD mice or in CSE-stimulated C2C12 myotubes, which could be ameliorated by ferroptosis inhibitors. The expression of myostatin (MSTN) was enhanced in COPD mice and CSE-stimulated myotubes. MSTN up-regulated HIF2α expression and led to ferroptosis in myotubes, whereas inhibition of MSTN binding to its receptor or inhibition/knockdown of HIF2α resulted in decreased cell death, and partially restored GPX4 and GSH.ConclusionCS exposure induced ferroptosis in vivo and in vitro. Mechanistically, CS-exposure upregulated MSTN which further induced ferroptosis through HIF2α in skeletal muscles, which may contribute to muscle dysfunction through impairing metabolic capacity and decreasing muscle fiber numbers, revealing a potential novel therapeutic target for COPD-related skeletal muscle dysfunction.

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

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

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