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Sarcopenia is a major comorbidity in chronic obstructive pulmonary (COPD). Whether deficient muscle repair mechanisms and regeneration exist in the vastus lateralis (VL) of sarcopenic COPD remains debatable. In the VL of control subjects and severe COPD patients with/without sarcopenia, satellite cells (SCs) were identified (immunofluorescence, specific antibodies, anti-Pax-7, and anti-Myf-5): activated (Pax-7+/Myf-5+), quiescent/regenerative potential (Pax-7+/Myf-5-), and total SCs, nuclear activation (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling [TUNEL]), and muscle fiber type (morphometry and slow- and fast-twitch, and hybrid fibers), muscle damage (hematoxylin-eosin staining), muscle regeneration markers (Pax-7, Myf-5, myogenin, and MyoD), and myostatin levels were identified. Compared to controls, in VL of sarcopenic COPD patients, myostatin content, activated SCs, hybrid fiber proportions, TUNEL-positive cells, internal nuclei, and muscle damage significantly increased, while quadriceps muscle strength, numbers of Pax-7+/Myf-5- and slow- and fast-twitch, and hybrid myofiber areas decreased. In the VL of sarcopenic and nonsarcopenic patients, TUNEL-positive cells were greater, whereas muscle regeneration marker expression was lower than in controls. In VL of severe COPD patients regardless of the sarcopenia level, the muscle regeneration process is triggered as identified by SC activation and increased internal nuclei. Nonetheless, a lower regenerative potential along with significant alterations in muscle phenotype and damage, and increased myostatin were prominently seen in sarcopenic COPD.

Whether a deficiency in muscle repair and regeneration may exist in the lower limb muscles of COPD patients remains debatable. We hypothesized that the negative regulator myotastin may inhibit muscle regeneration potential in sarcopenic COPD patients. In vastus lateralis (VL) of control subjects and severe COPD patients with and without sarcopenia, satellite cells (SC) were identified (immunofluorescence, anti-Pax7 and anti-myf5): activated (Pax7+ and myf5+), quiescent/regenerative potential (Pax7+ and myf-5-), and total SC, nuclear activation (TUNEL assay), and muscle fiber type (morphometry, hybrid fibers), muscle damage, muscle regeneration markers (Pax7, myf-5, myogenin, and myoD), and myostatin levels were identified. Compared to control subjects and normal body composition COPD, in the VL of sarcopenic COPD patients, myostatin protein levels, activated SC, hybrid fibers, TUNEL-positive cells, internal nuclei, and total abnormal fraction were significantly increased, while quadriceps muscle strength, numbers of Pax7+ and myf-5- and slow- and fast-twitch muscle fiber areas decreased. In VL of sarcopenic and non-sarcopenic COPD patients, TUNEL-positive cell counts were greater, whereas expression of muscle regeneration markers was lower than in controls. Myostatin may have interfered with the process of muscle cell proliferation early on during the regeneration process, thus leading to poor muscle growth and development following injury in COPD patients with sarcopenia. This may be another relevant mechanism of muscle mass loss in COPD. Method: CIBERES, FIS 18/00075 (FEDER), SEPAR 2018, and unrestricted grant from Menarini SA 2018.

With the 60th anniversary of the CIBA symposium, it is worth evaluating research questions that should be prioritized in the future. Coming research initiatives can be summarized in 10 main areas. (1) From epidemiology the impact of new forms of electronic cigarettes on prevalence and mortality of COPD will be sought. (2) The study of the disease endotypes and its relationship phenotypes will have to be unraveled in the next decade. (3) Diagnosis of COPD faces several challenges opening the possibility of a change in the definition of the disease itself. (4) Patients' classification and risk stratification will need to be clarified and reassessed. (5) The asthma-COPD overlap dilemma will have to be clarified and define whether both conditions represent one only chronic airway disease again. (6) Integrating comorbidities in COPD care will be key in a progressively ageing population to improve clinical care in a chronic care model. (7) Nonpharmacological management have areas for research including pulmonary rehabilitation and vaccines. (8) Improving physical activity should focus research because of the clear prognostic impact. (9). Pharmacological therapies present several challenges including efficacy and safety issues with current medications and the development of biological therapy. (10) The definition, identification, categorization and specific therapy of exacerbations will also be an area of research development. During the next decade, we have a window of opportunity to address these research questions that will put us on the path for precision medicine.

Resumen: Introducción: La enfermedad pulmonar obstructiva crónica (EPOC) es la patología respiratoria que causa mayor morbimortalidad a nivel mundial. Los parámetros de función pulmonar y las manifestaciones sistémicas se han definido como factores pronósticos, sin embargo, presentan limitaciones. El objetivo ha sido analizar si la fuerza muscular inspiratoria sería un reflejo de la insuflación pulmonar y, por tanto, un factor pronóstico de los pacientes con EPOC. Método: Se seleccionaron pacientes con EPOC que se realizaron previamente una valoración de la fuerza muscular respiratoria no invasiva y una prueba de función pulmonar desde enero de 2015 hasta octubre de 2017. Posteriormente, se revisó la mortalidad hasta el 1 de marzo de 2020. Resultados: Se incluyeron 140 pacientes con EPOC (estadio GOLD I 5%, II 73,4% y III 21,6%) de los cuales un 10% fallecieron durante el seguimiento. La obstrucción bronquial, definida por volumen espiratorio forzado en el primer segundo (FEV1) fue un buen predictor de mortalidad (p = 0,004). La hiperinsuflación pulmonar, definida como relación capacidad inspiratoria/capacidad pulmonar total (CI/CPT) inferior a 25 y CI inferior al 65% de los valores de referencia, incrementaba la mortalidad en los pacientes con EPOC (p = 0,001 y p = 0,06, respectivamente). En la presente cohorte la fuerza de los músculos inspiratorios, valorada mediante la presión nasal durante una inhalación máxima (SNIP) no fue un factor pronóstico (p = 0,629). Conclusión: En los pacientes con EPOC, la hiperinsuflación pulmonar es un factor pronóstico, no así la función muscular inspiratoria. La función muscular inspiratoria de los pacientes de los EPOC no solo depende de la mecánica pulmonar, sino que también de factores intrínsecos de los propios músculos. Abstract: Introduction: Chronic obstructive pulmonary disease (COPD) is the respiratory disease that causes the greatest morbidity and mortality worldwide. Lung function parameters and systemic manifestations have been defined as prognostic factors; however, they have limitations. The aim of this study was to analyze whether inspiratory muscle strength could reflect lung hyperinflation, and therefore serve as a prognostic factor in COPD patients. Method: We selected COPD patients who had performed a non-invasive respiratory muscle strength assessment and lung function testing between January 2015 and October 2017. Mortality was subsequently followed up until March 1, 2020. Results: We included 140 COPD patients (GOLD stage I 5%, II 73.4%, and III 21.6%), of whom 10% died during follow-up. Bronchial obstruction, defined by FEV1, was a good predictor of mortality (p = 0.004). Lung hyperinflation, defined as inspiratory capacity (IC)/total lung capacity less than 25 and IC less than 65% of predicted increased mortality in COPD patients (p = 0.001 and p = 0.06, respectively). In this cohort, inspiratory muscle strength, measured by SNIP, was not a prognostic factor (p = 0.629). Conclusion: In COPD patients, lung hyperinflation is a prognostic factor, but inspiratory muscle function is not. Inspiratory muscle function in COPD patients depends not only on lung mechanics but also on intrinsic muscle factors.

In patients with chronic obstructive pulmonary disease (COPD), skeletal muscle dysfunction is a major comorbidity that negatively impacts their exercise capacity and quality of life. In the current guidelines, the most recent literature on the various aspects of COPD muscle dysfunction has been included. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) scale has been used to make evidence-based recommendations on the different features. Compared to a control population, one third of COPD patients exhibited a 25% decline in quadriceps muscle strength, even at early stages of their disease. Although both respiratory and limb muscles are altered, the latter are usually more severely affected. Numerous factors and biological mechanisms are involved in the etiology of COPD muscle dysfunction. Several tests are proposed in order to diagnose and evaluate the degree of muscle dysfunction of both respiratory and limb muscles (peripheral), as well as to identify the patients' exercise capacity (six-minute walking test and cycloergometry). Currently available therapeutic strategies including the different training modalities and pharmacological and nutritional support are also described.

Chronic obstructive pulmonary disease (COPD) is a complex disorder with extrapulmonary manifestations. Even though there is some knowledge regarding sex differences in the lung disease, little is known about extrapulmonary manifestations. Our aim was to analyze the specific profile of muscle dysfunction, structure, and biology in COPD women. Twenty-one women and 19 men with stable COPD as well as 15 controls were included. Nutritional status, physical activity, lung and muscle function, exercise capacity, and quality of life were assessed. In addition, blood, breath condensate, and quadriceps muscle samples were tested for inflammatory markers. Moreover, fiber phenotype, signs of damage–regeneration, and the expression of key genes linked to myogenesis and inflammation were assessed in the muscle. Inflammatory markers were increased in all body compartments but no correlation was found among them. Muscle dysfunction was present in both COPD groups but was more marked in women. The opposite occurred with the increase in the percentage of type II fibers that was lower in women despite a similar level of airway obstruction as in men. Female COPD also showed higher signs of muscle damage than COPD men who, in contrast, exhibited slightly higher signs of regeneration. We conclude that sex influences muscle phenotype and function in COPD.

Introduction: Patients with Chronic Obstructive Pulmonary Diseases (COPD) have skeletal muscle dysfunction. In these patients, skeletal muscle dysfunction has impact on the quality of life and mortality. However, its relevance is unknown in other chronic respiratory diseases such as bronchiectasis, which shares some deleterious factors with COPD. Accordingly, our aim was to describe the structure and function of skeletal muscle ( vastus lateralis ) in patients with non-cystic fibrosis bronchiectasis (non-CF BCH), valuing its relationship with exercise capacity and physical activity. Methods: 29 patients with non-CF BCH and 8 healthy subjects of similar age were recruited. Anthropometry, body composition (bioimpedance), health-related quality of life (QoL, Quittner9s questionnaire), physical activity (accelerometer), exercise capacity (6 minute walking test), lung function, and respiratory and limb muscle function were assessed in all subjects. In addition, open biopsies of the vastus lateralis were obtained for the analysis of structural signs of muscle damage/regeneration (McGowan technique) and fiber typing. Results: Patients with non-CF BCH showed a moderate obstructive pattern, nutritional disorders (decreased a 13% in fat-free mass index), decreased exercise capacity and physical activity compared to controls. In addition, skeletal muscle strength was also lower in the group of patients, however, no structural alterations were observed in the vastus lateralis . Conclusion: Patients with non-CF BCH have shown skeletal muscle dysfunction that could limit their daily activities and exercise capacity. However, they do not depict changes in the structure of the skeletal muscle.

Introduction: Inspiratory muscle strength is usually assessed thorough the determination of static mouth pressure (PImax). However, since this manoeuvre presents certain problems, alternative techniques have been developed over the last few years. One of the most promising is determination of sniff nasal inspiratory pressure (SNIP). Aim: To evaluate SNIP assessment as an alternative for the evaluation of the inspiratory muscle strength. Methods: Subjects were consecutively included and assigned to one of three different groups: control (8), COPD patients (23) and patients with neuromuscular disorders (21). Different maximal inspiratory pressures were determined: (a) dynamic in the esophagus (maximal sniff Pes, reference variable), (b) PImax, and (c) SNIP. Results: Both SNIP and MIP showed an excellent correlation with Pes (r=0.835 and 0.752, respectively, P

To the Editor: Quadriceps weakness and atrophy is present in approximately 30% of patients with chronic obstructive pulmonary disease (COPD) in secondary care (1, 2). The quadriceps also displays a shift in fiber type so that there are fewer type I (oxidative) fibers and more type II (glycolytic) fibers (3). Pulmonary rehabilitation only partially addresses this fiber shift (4). Muscle mass (5) and strength (6) are both associated with increased mortality, but the prognostic significance of fiber shift is unknown. In a retrospective multicenter analysis of 392 patients from four sites (see Tables E1–E4 in the online supplement), mortality data were collated, as part of audit procedures, on outpatients with stable COPD who had undergone a vastus lateralis biopsy between 1995 and 2013. Data from these subjects have been previously published (e.g., References 2, 4, 5). Fiber proportion, reported as the percentage of type II fibers (type II fiber %), was established by immunohistochemistry. Fiber shift, evaluated as a dichotomous variable, was considered to have occurred when the proportion of type II fibers was greater than 68% (men) or greater than 65% (women) based on normal ranges established from an age-matched healthy population published by Natanek and colleagues (3). Body mass index (BMI), fat-free mass index (FFMI), dominant leg isometric quadriceps maximum voluntary contraction (QMVC and QMVC/BMI), mid-thigh cross-sectional area determined by computed tomography scan (MTCSA), residual volume normalized to total lung capacity (RV/TLC), and percent predicted value for the carbon monoxide transfer factor corrected for hemoglobin (TLCOc), when available, were included in subanalyses. Data were analyzed for the whole dataset and also after splitting the group into those with an FEV1 less than 50% predicted and those with an FEV1 greater than or equal to 50% predicted. Further details on the methodology and statistical analyses are presented in the online supplement. Some of the results of this study have been previously reported in abstract form (7). Patients were followed up for a median of 1,699 days (127–6,601 d); 102 of 392 (26.7%) patients died during follow-up (Table E6). Cohort characteristics are presented in Tables 1 and ​and22 and Tables E1–E5. One hundred fifty-one patients had Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I/II disease and 241 had GOLD stage III/IV disease. Those who died were older and had a lower FEV1 % predicted, and there was a greater male preponderance (Table E6A). One hundred seventy-seven (45.1%) of the patients had fiber shift. The patients who died had a higher percentage of type II fibers (69.5% [62.2, 76.3%] vs. 66.0% [54.0, 74.2%]; P = 0.002) and a higher proportion of them exhibited fiber shift (58% vs. 41%, P = 0.004). BMI, FFMI, QMVC, MTCSA, and TLCOc were all lower, and RV/TLC higher, in those who died (Table E6B). Table 1. Core Characteristics of the Cohort (n = 392) in Addition to Univariate and Multivariate Analyses Including Type II Fiber Proportion Dichotomized into the Occurrence of Fiber Shift Table 2. Core Characteristics of the Cohort (n = 392) in Addition to Univariate and Multivariate Analyses Including Type II Fiber Proportion as a Continuous Measure In the cohort considered as a whole, both type II fiber % and the presence of fiber shift were univariate predictors of mortality, as were age and FEV1 % predicted (Tables 1 and ​and2).2). In a multivariate analysis including fiber shift as a dichotomous variable, fiber shift was retained, as were age and FEV1 % predicted, Table 1. When age, FEV1 % predicted, and type II fiber % were entered into a multivariate analysis, age and FEV1 % predicted were retained as independent predictors, but the association between fiber type and mortality just missed statistical significance (Table 2). The relationship between FEV1 and fiber proportion is shown in Figure 1A, and survival as a function of fiber shift, adjusted for age and FEV1, is shown in Figure 1B. Additional data regarding other lung function and muscle parameters are presented in Tables E7–E10. FEV1 expressed in liters and TLCOc were also univariate predictors of mortality; however, RV/TLC was not. When including TLCOc in the analysis (n = 209), fiber shift, age, FEV1 % predicted, and TLCOc were all independent predictors of mortality. In other subanalyses, BMI, FFMI, QMVC, QMVC/BMI, and MTCSA were not univariate predictors of mortality. Figure 1. (A) The relationship between type II fiber percentage and FEV1 % predicted (dashed lines demonstrate the 95% confidence interval), and (B) survival curves for those with fiber shift (n = 177) and those without fiber shift (n = 215) after adjusting for ... When limiting the analysis to those with an FEV1 greater than or equal to 50% predicted, age was the only predictor of mortality (hazard ratio [HR], 1.16; 95% CI, 1.07, 1.25; P < 0.0001; Table E11). In a multivariate analysis confined to those with an FEV1 less than 50%, fiber shift was retained as an independent predictor (HR, 1.71; 95% CI, 1.08, 2.71; P = 0.02), as were age (HR, 1.06; 95% CI, 1.03, 1.09; P < 0.0001), and FEV1 % predicted (HR, 0.96; 95% CI, 0.94, 0.99; P = 0.002; Table E12A). In a separate analysis confined to those with an FEV1 less than 50%, type II fiber % was not retained as an independent predictor (HR, 1.014; 95% CI, 0.996, 1.032; P = 0.13), whereas age and FEV1 % predicted were (Table E12B). Fiber shift in the vastus lateralis of patients with COPD was associated with increased mortality, although this association was weaker when lung function and age were included in the analysis. This finding was pronounced in patients with GOLD stage III/IV disease but undetectable in those with GOLD stage I/II disease. The relationship between skeletal muscle atrophy (5) and weakness (6) with mortality has been previously noted in COPD. However, we believe the present analysis is timely because we (3) and others (8) have recently shown that the nature of skeletal muscle involvement in COPD is heterogeneous rather than uniform. No prior study has related quadriceps biopsy appearances to long-term outcome in COPD. Given the known relationship between exercise capacity and survival (9), these data are consistent with our prior studies, which demonstrated a relationship between fiber shift (although not fiber atrophy) and impaired exercise capacity (3) and functional performance (10). Nevertheless, it remains unclear whether fiber shift causes poor exercise tolerance or is a manifestation of exercise intolerance and reduced physical activity, which are both associated with increased mortality in COPD (9, 11). Both concepts can be supported by in vivo models that demonstrate that muscle disuse results in type I to type II fiber shift (12) and that fiber shift toward a type I fiber predominance increases exercise performance (13). Due to the retrospective nature of the current analysis, exercise performance and physical activity data were not available for inclusion in this report, so a causative role for fiber shift in mortality cannot be demonstrated from this study. A prospective study would have been preferable and could also have considered other factors of relevance, including pulmonary rehabilitation over the intervening period. Despite the limitations of the current study, it is doubtful that a prospective study of comparable size and duration will ever be done. Interest in pharmacological management of skeletal muscle dysfunction is growing (14), and addressing fiber shift may eventually become a therapeutic possibility. Further studies to address whether the reversal of fiber shift is of benefit are of value.

The respiratory muscles of patients with chronic obstructive pulmonary disease (COPD) display evidence of structural damage in parallel with signs of adaptation. We hypothesized that this can only be explained by the simultaneous activation of satellite cells. The aim of this study was to analyze the number and activation of those cells along with the expression of markers of microstructural damage that are frequently associated with regeneration.The study included 8 patients with severe COPD (mean [SD] forced expiratory volume in 1 second, 33% [9%] of predicted) and 7 control subjects in whom biopsies were performed of the external intercostal muscle. The samples were analyzed by light microscopy to assess muscle fiber phenotype, electron microscopy to identify satellite cells, and real-time polymerase chain reaction to analyze the expression of the following markers: insulin-like growth factor 1, mechano growth factor, and embryonic and perinatal myosin heavy chains (MHC) as markers of microstructural damage; Pax-7 and m-cadherin as markers of the presence and activation of satellite cells, respectively; and MHC-I, IIa, and IIx as determinants of muscle fiber phenotype.The patients had larger fibers than healthy subjects (54 [6] vs 42 [4] microm(2); P.01) with a similar or slightly increased proportion of satellite cells, as measured by ultrastructural analysis (4.3% [1%] vs 3.7% [3.5%]; P.05) or expression of Pax-7 (5.5 [4.1] vs 1.6 [0.8] arbitrary units [AU]; P.05). In addition, there was greater activation of satellite cells in the patients, as indicated by increased expression of m-cadherin (3.8 [2.1] vs 1.0 [1.2] AU; P=.05). This was associated with increased expression of markers of microstructural damage: insulin-like growth factor 1, 0.35 (0.34) vs 0.09 (0.08) AU (P.05); mechano growth factor, 0.45 (0.55) vs 0.13 (0.17) AU (P=.05).The intercostal muscles of patients with severe COPD show indirect signs of microstructural damage accompanied by satellite cell activation. This suggests the presence of ongoing cycles of lesion and repair that could partially explain the maintenance of the structural properties of the muscle.

Respiratory muscle dysfunction is a common problem in patients with chronic obstructive pulmonary disease (COPD) and has mostly been related to pulmonary hyperinflation [1, 2]. Associated diaphragm shortening and deleterious changes in the muscle force-length relationship cause a reduction in the muscles’ capacity to generate pressure, placing them at a mechanical disadvantage [1, 3]. Specifically, both inspiratory muscle strength and mechanical efficiency may be reduced in COPD patients [1, 4–6], although, at iso-volume, the contractile strength of the diaphragm in COPD is preserved or may even be improved in some cases [7]. The ratio between transdiaphragmatic pressure and electrical diaphragm activity has been used as a measure of respiratory muscle efficiency [8, 9]. However, in clinical practice, it is complex to measure this parameter directly, as invasive measures are required and these are uncomfortable for patients [4]. During contraction, respiratory muscle fibres vibrate laterally [10]. These vibrations are related to the mechanical activation of these muscles and can be non-invasively recorded through accelerometers positioned on the surface of the skin, proximal to the muscles: this is called respiratory muscle mechanomyogram (MMG) [11–13]. The analysis of the mechanical activation of inspiratory muscles through the MMG might be a useful alternative approach for assessing respiratory muscles function in patients with COPD [13, 14]. MMG reflects the mechanical counterpart of the neural activity measured by electromyography. Respiratory muscle MMG provide some advantages over surface diaphragmatic electromyography with regards to simplicity of use. First of all, MMG recording is easy and simple to implement: MMG is acquired using a small accelerometer attached to the skin surface, whereas electromyography typically uses three electrodes. Secondly, as it is a mechanical signal, MMG is not susceptible to bioelectrical interference. Furthermore, the signal to noise ratio of MMG is typically higher than that of the electromyography, requiring less amplification and electrical shielding. In addition, the MMG recording does not require skin preparation and it is not influenced by changes in the skin impedance. The aim of the present study was to noninvasively evaluate the mechanical activation of inspiratory muscles and its efficiency (EMMG) during tidal volume breathing in patients with severe-to-very severe COPD. With this in mind, we investigated the peak inspiratory mouth pressure (IPpeak) and respiratory muscle MMG acquired under both quiet breathing (QB) and maximal voluntary ventilation (MVV) conditions during an incremental respiratory flow protocol.

The aim of the present study was to measure bilateral asynchrony in patients suffering from Chronic Obstructive Pulmonary Disease (COPD) performing an incremental inspiratory load protocol. Bilateral asynchrony was estimated by the comparison of respiratory movements derived from diaphragm mechanomyographic (MMGdi) signals, acquired by means of capacitive accelerometers placed on left and right sides of the rib cage. Three methods were considered for asynchrony evaluation: Lissajous figure, Hilbert transform and Motto's algorithm. Bilateral asynchrony showed an increase at 20, 40 and 60% (values of normalized inspiratory pressure by their maximum value reached in the last inspiratory load) while the very severe group showed and increase at 20, 40, 80, and 100 % during the protocol. These increments in the phase's shift can be due to an increase of the inspiratory load along the protocol, and also as a consequence of distress and fatigue. In summary, this work evidenced the capability to estimate bilateral asynchrony in COPD patients. These preliminary results also showed that the use of capacitive accelerometers can be a suitable sensor for recording of respiratory movement and evaluation of asynchrony in COPD patients.

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.

Introduction Muscle dysfunction is one of the most extensively studied manifestations of COPD. Metabolic changes in muscle are difficult to study in vivo, due to the lack of non-invasive techniques. Our aim was to evaluate metabolic activity simultaneously in various muscle groups in COPD patients. Methods Thirty-nine COPD patients and 21 controls with normal lung function, due to undergo computed axial and positron emission tomography for staging of localized lung lesions were included. After administration of 18-fluordeoxyglucose, images of 2 respiratory muscles (costal and crural diaphragm, and rectus abdominus) and 2 peripheral muscles (brachial biceps and quadriceps) were obtained, using the standard uptake value as the glucose metabolism index. Results Standard uptake value was higher in both portions of the diaphragm than in the other muscles of all subjects. Moreover, the crural diaphragm and rectus abdominus showed greater activity in COPD patients than in the controls (1.8±0.7 vs 1.4±0.8; and 0.78±0.2 vs 0.58±0.1; respectively, P

Muscle injury has clinical relevance in diseased individuals because it is associated with muscle dysfunction in terms of decreased strength and/or endurance. This study was aimed at answering three questions: whether the presence of chronic obstructive pulmonary disease (COPD) is associated with peripheral muscle injury; whether muscle injury is associated with some of the relevant functional impairment in the muscles; and whether muscle injury can be solely justified by deconditioning. Twenty-one male COPD patients were eligible for the study. Seven healthy volunteers recruited from the general population were included as controls. Function of the quadriceps muscle was assessed through specific single-leg exercise (strength and endurance). Cellular (light microscopy) and subcellular (electron microscopy) techniques were used to evaluate muscle injury on biopsies from the vastus lateralis muscle. Signs of injury were found in muscles from both control and COPD patients, not only in cases showing severe airflow obstruction but also in the mild or moderate stages of the disease. Current smoking and presence of COPD were significantly associated with increased injury of the muscle as assessed by light and electron microscopy techniques. The authors conclude that peripheral muscle injury is evident in mild, moderate, and severe stages of COPD even in the absence of respiratory failure, hypercapnia, chronic steroid treatment, low body weight, or some coexisting disease. These findings support the theory that systemic factors with deleterious effect are acting on peripheral muscles of smokers with COPD, increasing the susceptibility of the muscle fibers to membrane and sarcomere injury.

The aim of this study was to evaluate the respiratory muscles efficiency during a progressive incremental flow (IF) respiratory test in healthy and Chronic Obstructive Pulmonary Disease (COPD) subjects. To achieve this, the relationship between mouth Inspiratory Pressure (IP) increment, which is a measure of the force produced by respiratory muscles, and respiratory muscular activity increment, evaluated by means of Mechanomyografic (MMG) signals of the diaphragm muscle, was analyzed. Moreover, the correlation between the respiratory efficiency measure and the obstruction severity of the subjects was also examined. Data from two groups of subjects were analyzed. One group consisted of four female subjects (two healthy subjects and two moderate COPD patients) and the other consisted of ten male subjects (six severe and four very severe COPD patients). All subjects performed an easy IF respiratory test, in which small IP values were reached. We have found that there is an increase of amplitude and a displacement towards low frequencies in the MMG signals when the IP increases. Furthermore, it has also been found that respiratory muscles efficiency is lower when greater the obstructive severity of the patients is, and it is lower in women than in men. These results suggest that the information provided by MMG signals could be used to evaluate the muscular efficiency in healthy and COPD subjects

Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with several modifiable (sedentary life-style, smoking, malnutrition, hypoxemia) and non-modifiable (age, co-morbidities, severity of pulmonary function, respiratory infections) risk factors. We hypothesise that most of these risk factors may have a converging and deleterious effects on both respiratory and peripheral muscle function in COPD patients. METHODS: A multicentre study was carried out in 121 COPD patients (92% males, 63 ± 11 yr, FEV(1), 49 ± 17%pred). Assessments included anthropometrics, lung function, body composition using bioelectrical impedance analysis (BIA), and global muscle function (peripheral muscle (dominant and non-dominant hand grip strength, HGS), inspiratory (PI(max)), and expiratory (PE(max)) muscle strength). GOLD stage, clinical status (stable vs. non-stable) and both current and past hospital admissions due to COPD exacerbations were included as covariates in the analyses. RESULTS: Respiratory and peripheral muscle weakness were observed in all subsets of patients. Muscle weakness, was significantly associated with both current and past hospitalisations. Patients with history of multiple admissions showed increased global muscle weakness after adjusting by FEV(1) (PE(max), OR = 6.8, p < 0.01; PI(max), OR = 2.9, p < 0.05; HGSd, OR = 2.4, and HGSnd, OR = 2.6, p = 0.05). Moreover, a significant increase in both respiratory and peripheral muscle weakness, after adjusting by FEV(1), was associated with current acute exacerbations. CONCLUSIONS: Muscle dysfunction, adjusted by GOLD stage, is associated with an increased risk of hospital admissions due to acute episodes of exacerbation of the disease. Current exacerbations further deteriorate muscle dysfunction. Sources of support: Supported in part by grants from “SEPAR-Area de Enfermeri´a y Fisioterapia” and BAE06/90061. CIBERES (Instituto de Salud Carlos III, Ministerio de Sanidad, Spain).

The study of mechanomyographic (MMG) signals of respiratory muscles is a promising noninvasive technique in order to evaluate the respiratory muscular effort and efficiency. In this work, the MMG signal of the diaphragm muscle it is evaluated in order to assess the respiratory muscular function in Chronic Obstructive Pulmonary Disease (COPD) patients. The MMG signals from left and right hemidiaphragm were acquired using two capacitive accelerometers placed on both left and right sides of the costal wall surface. The MMG signals and the inspiratory pressure signal were acquired while the COPD patients carried out an inspiratory load respiratory test. The population of study is composed of a group of 6 patients with severe COPD (FEV1>50% ref and DLCO

OBJECTIVE: The current pressure on conventional inpatient care units represents a very serious problem for respiratory medicine departments. The aim of this study was to analyze the impact of a new instrument—a short-stay respiratory unit—on the quality of care delivered by the respiratory medicine department of a tertiary care hospital. MATERIAL AND METHODS: The short-stay respiratory unit consisted of 4 conventional hospital beds managed by a pulmonologist. The beds were only used to treat patients diagnosed with exacerbation of chronic obstructive pulmonary disease or bronchial asthma, community-acquired pneumonia, or suspected lung cancer, and stays were intended to only last for less than 4 days. Analyzing a range of healthcare quality variables, we compared the quality of care delivered during the first 6 months the unit was in operation (October 2005 to March 2006) to that delivered in the same period 12 months earlier. RESULTS: The study included 147 patients admitted to the short-stay unit. The mean (SD) age of the patients was 64 (17) years and 79% were men. The mean length of stay was 3.3 (1.6) days—only 1.4% of patients stayed for longer than 4 days—and the readmission rate was 2.7%. There were no deaths. The existence of the short-stay respiratory unit led to a 30% decrease in the overall mean length of stay in the respiratory medicine department (11.8 [4.6] vs 8.3 [2.6] days; P

Muscle dysfunction is a characteristic feature of chronic obstructive pulmonary disease (COPD). Recent studies suggest that cytokines may operate as local regulators of both muscle function and regeneration. The aim of the present study was to characterise the expression of different cytokines in the external intercostal muscle of COPD. Muscle biopsies were obtained from 25 stable COPD patients and eight healthy controls. Local tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, -6 and -10 expressions (real-time PCR and ELISA), sarcolemmal damage (immunohistochemistry), and the transcript levels of CD18 were assessed. Muscle TNF-alpha and IL-6 transcripts were significantly higher in COPD patients compared with controls, and IL-1beta and sarcolemmal damage showed a strong tendency in the same direction. Similar results were observed at protein level. The CD18 panleukocyte marker was similar in COPD and controls. Respiratory muscle function was impaired in COPD patients and it correlated to both the severity of lung function impairment and TNF-alpha muscle expression. Chronic obstructive pulmonary disease is associated with the upregulation of pro-inflammatory cytokines in the intercostal muscles. This phenomenon might be involved in respiratory muscle dysfunction.

Objective Magnetic stimulation of the diaphragm allows its strength to be assessed. The clinical applications of this technique are becoming more widespread given that the patient's cooperation is not required. The aim of the present study was to compare this inhalation technique with traditional voluntary forced inspiration (sniff test) in a group of patients with chronic obstructive pulmonary disease (COPD). Patients and methods Sixteen men with moderate-to-severe COPD were studied (mean [SD] forced expiratory volume in 1 second, 35% [15%] of the reference value). For all patients, the maximal transdiaphragmatic pressure (a measure of the contractility of the muscle) was determined at peak inspiration and during cervical magnetic stimulation. Results A moderate correlation between measurements with the 2 techniques was observed. The value obtained with stimulation was approximately 20% of that obtained with voluntary inhalation (22 [7] cm H2O vs 97 [27] cm H2O, respectively). The stimulation technique yielded an intraindividual coefficient of variation of 12% (7%) and an interindividual one of 33% (6%). Very similar values for these coefficients were obtained with forced inhalation. Qualitative analysis of the stimulation technique showed it to have a high sensitivity (89%) for diagnosing muscle weakness, with few fake negatives. In contrast, specificity was very low (43%), and false positives for muscle weakness were relatively common. The overall effectiveness of the prediction was acceptable (69%). Conclusions Cervical magnetic stimulation appears to be a good clinical option for ruling out diaphragm weakness. It is particularly indicated in patients with limited capacity for understanding instructions or those unable to cooperate.

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

The study of mechanomyographic (MMG) signals of respiratory muscles is a promising technique in order to evaluate the respiratory muscular effort. In this work MMG signals from left and right hemidiaphragm (MMGl and MMGr, respectively) acquired during a respiratory protocol have been analyzed. The acquisition of both MMG signals was carried out by means of two capacitive accelerometers placed on both left and right sides of the costal wall. The signals were recorded in a group of six patients with Chronic Obstructive Pulmonary Disease (COPD). It has been observed that with the increase of inspiratory pressure it takes place an increase of the amplitude and a displacement toward low frequencies in both left and right MMG signals. Furthermore, it has been seen that the increase of amplitude and the decrease of frequency in MMG signals are more pronounced in severe COPD patients. This behaviour is similar for both MMGl and MMGr signals. Results suggest that the use of MMG signals could be potentially useful for the evaluation of the respiratory muscular function in COPD patients.

There is a lack of instruments for assessing respiratory muscle activation during the breathing cycle in clinical conditions. The aim of the present study was to evaluate the usefulness of the respiratory muscle mechanomyogram (MMG) for non-invasively assessing the mechanical activation of the inspiratory muscles of the lower chest wall in both patients with chronic obstructive pulmonary disease (COPD) and healthy subjects, and to investigate the relationship between inspiratory muscle activation and pulmonary function parameters. Both inspiratory mouth pressure and respiratory muscle MMG were simultaneously recorded under two different respiratory conditions, quiet breathing and incremental ventilatory effort, in 13 COPD patients and 7 healthy subjects. The mechanical activation of the inspiratory muscles was characterised by the non-linear multistate Lempel-Ziv index (MLZ) calculated over the inspiratory time of the MMG signal. Subsequently, the efficiency of the inspiratory muscle mechanical activation was expressed as the ratio between the peak inspiratory mouth pressure to the amplitude of the mechanical activation. This activation estimated using the MLZ index correlated strongly with peak inspiratory mouth pressure throughout the respiratory protocol in both COPD patients (r = 0.80, p