Chronic Obstructive Pulmonary Disease Muscle Research Articles

Computed tomography reveals hypertrophic remodelling of the diaphragm in cystic fibrosis but not in COPD.

Computed tomography (CT) is increasingly used for assessing skeletal muscle characteristics. In cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), reduced limb muscle mass predicts poor clinical outcomes. However, the degree to which quantity or quality of respiratory and nonrespiratory muscles is affected by these diseases remains controversial. Thoracic CT images of 29 CF, 21 COPD and 20 normal spirometry control subjects were analysed to measure indices of muscle quantity (volume or cross-sectional area) and quality (radiodensity) in respiratory (diaphragm, abdominal) and nonrespiratory (pectoralis, lumbar paraspinal) muscles. Multivariable linear regression assessed relationships of CT measurements with body mass index (BMI), forced expiratory volume in 1 s (FEV1) % pred, inflammation and infection biomarkers, nutritional status and CF genotype. Diaphragm volume in CF was significantly higher than in COPD (by 154%) or controls (by 140%). Abdominal muscle area in CF was also greater than in COPD (by 130%). Nonrespiratory muscles in COPD had more low radiodensity muscle (marker of lipid content) compared to CF and controls. In CF but not COPD, higher BMI and FEV1 % pred were independently associated with higher diaphragm and/or abdominal muscle quantity indices. Serum creatinine also predicted respiratory and nonrespiratory muscle quantity in CF, whereas other biomarkers including genotype correlated poorly with muscle CT parameters. Our data suggest that the CF diaphragm undergoes hypertrophic remodelling, whereas in COPD the nonrespiratory muscles show altered muscle quality consistent with greater lipid content. Thoracic CT can thus identify distinctive respiratory and nonrespiratory muscle remodelling signatures associated with different chronic lung diseases.

Revisiting Skeletal Muscle Dysfunction and Exercise in Chronic Obstructive Pulmonary Disease: Emerging Significance of Myokines.

Skeletal muscle dysfunction (SMD) is the most significant extrapulmonary complication and an independent prognostic indicator in patients with chronic obstructive pulmonary disease (COPD). Myokines, such as interleukin (IL)-6, IL-15, myostatin, irisin, and insulin-like growth factor (IGF)-1, play important roles in skeletal muscle mitochondrial function, protein synthesis and breakdown balance, and regeneration of skeletal muscles in COPD. As the main component of pulmonary rehabilitation, exercise can improve muscle strength, muscle endurance, and exercise capacity in patients with COPD, as well as improve the prognosis of SMD and COPD by regulating the expression levels of myokines. The mechanisms by which exercise regulates myokine levels are related to microRNAs. IGF-1 expression is upregulated by decreasing the expression of miR-1 or miR-29b. Myostatin downregulation and irisin upregulation are associated with increased miR-27a expression and decreased miR-696 expression, respectively. These findings suggest that myokines are potential targets for the prevention and treatment of SMD in COPD. A comprehensive analysis of the role and regulatory mechanisms of myokines can facilitate the development of new exercise-based therapeutic approaches for patients with COPD.

Maximal Inspiratory and Expiratory Pressures in Men with Chronic Obstructive Pulmonary Disease: A Cross-Sectional Study

Introduction: Respiratory muscle dysfunction is a cardinal feature in chronic obstructive pulmonary disease (COPD) contributing to decreased exercise capacity and pulmonary function test (PFT) limitation with progression of the disease. Maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) are reliable parameters for assessing the respiratory muscle strength. Aims: This study aims to measure maximal inspiratory and expiratory pressures in male COPD patients, to determine their correlates, and to study the relationship between the severity of COPD and respiratory muscle strength. Patients and Methods: This was an observational, cross-sectional study. A total of 100 males, who were known COPD patients and who were clinically stable, were recruited. Both inpatients and outpatients were studied. Spirometric PFT test was done, and MIP and MEP were measured using respiratory pressure meter. Descriptive statistics and Pearson's correlation were used. Results: The mean (± standard deviation) MIP and MEP were 47.73 (±19.6) cm H2O and 60.76 (±11.6) cm H2O, respectively. MIP and MEP showed a highly significant correlation (P

The role of muscle-specific MicroRNAs in patients with chronic obstructive pulmonary disease and skeletal muscle dysfunction.

Skeletal muscle dysfunction is a systematic manifestation of chronic obstructive pulmonary disease (COPD), which is manifested through the changes in the respiratory and peripheral muscle fiber types, reducing muscle strength and endurance, and muscle atrophy. Muscle dysfunction limits the daily mobility, negatively affects the quality of life, and may increase the patient's risk of mortality. MicroRNAs (miRNAs) as the regulators of gene expression, plays an important role in modulating skeletal muscle dysfunction in COPD by regulating skeletal muscle development (proliferation, differentiation), protein synthesis and degradation, inflammatory response, and metabolism. In particular, muscle-specific miRNAs (myomiRs) may play an important role in this process, although the different expression levels of myomiRs in COPD and skeletal muscle dysfunction and the mechanisms underlying their role remain unclear. In this paper, we review the differential expression of the myomiRs in COPD to identify myomiRs that play a role in skeletal muscle dysfunction in COPD. We further explore their possible mechanisms and action in order to provide new ideas for the prevention and treatment of the skeletal muscle dysfunction in COPD.

Integrating Mechanisms of Exacerbated Atrophy and Other Adverse Skeletal Muscle Impact in COPD.

The normal decline in skeletal muscle mass that occurs with aging is exacerbated in patients with chronic obstructive pulmonary disease (COPD) and contributes to poor health outcomes, including a greater risk of death. There has been controversy about the causes of this exacerbated muscle atrophy, with considerable debate about the degree to which it reflects the very sedentary nature of COPD patients vs. being precipitated by various aspects of the COPD pathophysiology and its most frequent proximate cause, long-term smoking. Consistent with the latter view, recent evidence suggests that exacerbated aging muscle loss with COPD is likely initiated by decades of smoking-induced stress on the neuromuscular junction that predisposes patients to premature failure of muscle reinnervation capacity, accompanied by various alterations in mitochondrial function. Superimposed upon this are various aspects of COPD pathophysiology, such as hypercapnia, hypoxia, and inflammation, that can also contribute to muscle atrophy. This review will summarize the available knowledge concerning the mechanisms contributing to exacerbated aging muscle affect in COPD, consider the potential role of comorbidities using the specific example of chronic kidney disease, and identify emerging molecular mechanisms of muscle impairment, including mitochondrial permeability transition as a mechanism of muscle atrophy, and chronic activation of the aryl hydrocarbon receptor in driving COPD muscle pathophysiology.

Muscle-Bone Crosstalk in Chronic Obstructive Pulmonary Disease.

Sarcopenia and osteoporosis are common musculoskeletal comorbidities of chronic obstructive pulmonary disease (COPD) that seriously affect the quality of life and prognosis of the patient. In addition to spatially mechanical interactions, muscle and bone can also serve as endocrine organs by producing myokines and osteokines to regulate muscle and bone functions, respectively. As positive and negative regulators of skeletal muscles, the myokines irisin and myostatin not only promote/inhibit the differentiation and growth of skeletal muscles, but also regulate bone metabolism. Both irisin and myostatin have been shown to be dysregulated and associated with exercise and skeletal muscle dysfunction in COPD. During exercise, skeletal muscles produce a large amount of IL-6 which acts as a myokine, exerting at least two different conflicting functions depending on physiological or pathological conditions. Remarkably, IL-6 is highly expressed in COPD, and considered to be a biomarker of systemic inflammation, which is associated with both sarcopenia and bone loss. For osteokines, receptor activator of nuclear factor kappa-B ligand (RANKL), a classical regulator of bone metabolism, was recently found to play a critical role in skeletal muscle atrophy induced by chronic cigarette smoke (CS) exposure. In this focused review, we described evidence for myokines and osteokines in the pathogenesis of skeletal muscle dysfunction/sarcopenia and osteoporosis in COPD, and proposed muscle-bone crosstalk as an important mechanism underlying the coexistence of muscle and bone diseases in COPD.

PECULIARITIES OF THE COMBINED COURSE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND TYPE 2 DIABETES MELLITUS

The aim of the research was to study the features of chronic obstructive pulmonarydisease (COPD) with concomitant diabetes mellitus (DM) type 2 by analyzing clinicaldata, external respiratory function (FAD), bioimpedance analysis, exercise tolerance,quality of life of patients and integrated index BODE.Material and methods. 102 patients with COPD and concomitant type 2 diabetes,divided into 2 groups: 53 patients with COPD (first group) and 49 patients with COPDand concomitant type 2 diabetes were examined. In addition to that COPD assessmenttest (CAT test), a 6-minute walk test were performed. The BODE integrated index wasused to assess the COPD severity of and prognosis. According to spirometry, the studyincluded COPD patients with a FEV1 / FJEL ratio less than 0.7 and with II, III and IVdegrees of bronchial obstruction according to the spirometric classification GOLD. Toassess the body composition the method of bioimpedance analysis (portable device BC-601 (TANITA, Japan) was used.Results. In the study of COPD clinical features with concomitant type 2 diabetes, therelationship between exacerbation frequency and the level of diabetes compensation (p<0.05) was revealed. The duration of inpatient treatment of patients with COPD withconcomitant type 2 diabetes was higher than in patients with COPD (p <0.05). It hasbeen also found that the main spirometric parameters and exercise tolerance in patientswith COPD with concomitant type 2 diabetes were significantly lower than in the groupof COPD patients, and muscle and bone mass, percentage of fat mass, visceral fat andmetabolic age were significantly higher than in the group of COPD patients. Whenassessing the quality of life of patients with COPD by CAT test, there was no significantdifference between groups of patients.Conclusions. In patients with COPD in the presence of concomitant type 2 diabetesthere are more frequent and prolonged exacerbations with severe clinical symptoms, aswell as lower basic spirometric parameters, tolerance to exercise (according to the testwith 6-minute walk) with significantly higher bioimpedance analysis (BMI, % fat mass,visceral fat, bone, muscle mass and metabolic age).Key words: chronic obstructive pulmonary disease, diabetes mellitus, spirometry,bioimpedance analysis, exercise tolerance.

Diagnostic and clinical values of non-cardiac ultrasound in COPD: A systematic review.

BackgroundClinical and research utility of non-cardiac ultrasound (US) in chronic obstructive pulmonary disease (COPD) has been widely investigated. However, there is no systematic review assessing the clinical values of non-cardiac US techniques in COPD.MethodsWe systematically searched electronic databases from inception to 24 June 2020. Two independent reviewers in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines extracted data. A narrative synthesis of the results was conducted considering non-cardiac US techniques that looked for diaphragm, muscles and bones in patients with COPD.ResultsIn total, 2573 abstracts were screened, and 94 full-text papers were reviewed. A total of 54 studies met the inclusion criteria. Thirty-five studies assessed the diaphragm, while 19 studies evaluated different muscles, including limb muscles and pulmonary lesions in COPD using US. Of the 54 included studies, 30% (16/54) evaluated the changes in either limb muscles or diaphragmatic features before and after physical interventions; 67% (36/54) assessed the correlations between sonographic features and COPD severity. Indeed, 14/15 and 9/13 studies reported a significant reduction in diaphragm excursion and thickness in COPD compared with healthy subjects, respectively; this was correlated significantly with the severity and prognosis of COPD. Three studies reported links between diaphragm length and COPD, where lower diaphragm length correlated with poorer prognosis and outcomes. Quadriceps (rectus femoris), ankle dorsiflexor (tibialis anterior) and vastus lateralis were the most common muscles in COPD assessed by US. More than 70% (12/17) of the studies reported a significant reduction in the cross-sectional area (CSA) of the rectus femoris, rectus femoris and vastus lateralis thickness in COPD compared with healthy subjects. Quadriceps CSA and thickness correlated positively with COPD prognosis, in which patients with reduced quadriceps CSA and thickness have higher risk of exacerbation, readmission and death.ConclusionUS measurements of diaphragm excursion and thickness, as well as lower limb muscles strength, size and thickness, may provide a safe, portable and effective alternative to radiation-based techniques in diagnosis and prognosis as well as tracking improvement postintervention in patients with COPD.

Is bilateral corticospinal connectivity impaired in patients with chronic obstructive pulmonary disease?

During moderate and high levels of quadriceps force production, the ipsilateral motor cortex is concomitantly activated with the contralateral motor cortex throughout the corpus callosum to generate the motor command. Chronic obstructive pulmonary disease (COPD) patients display a structurally impaired corpus callosum that may explain the reduced motor command in this population, which in turn contributes to COPD-related muscle weakness of the knee extensors. The study aimed to determine whether bilateral connectivity was impaired and ipsilateral activation was lowered during unilateral strength production of the knee extensors. Our results indicate impaired bilateral connectivity but preserved ipsilateral activation in patients during unilateral isometric contractions of 50% of maximum voluntary strength. The preservation of ipsilateral activation during force production despite impaired bilateral connectivity is consistent with a reorganization of bilateral motor network function that drives unilateral strength production. The contralateral primary motor cortex (M1) is not the only brain area implicated in motor command generation. During moderate and high levels of quadriceps force production, the ipsilateral M1 is concomitantly activated. Such activation is mediated by the corpus callosum, the main component of bilateral connectivity. Structural damage to the corpus callosum has been observed in chronic obstructive pulmonary disease (COPD) patients, which might reduce ipsilateral activation and contribute to the lower motor command associated with COPD muscle weakness. We thus aimed to determine whether bilateral connectivity and ipsilateral activation were impaired in COPD. Twenty-two COPD patients and 21 healthy age-matched controls were evaluated by transcranial magnetic stimulation, at rest and during 50% of maximal voluntary isometric contraction (MVIC) of the dominant vastus lateralis muscle. Bilateral connectivity was determined by the ipsilateral silent period (iSP) during 50% MVIC. Ipsilateral activation was determined as the increase in ipsilateral excitability from rest to 50% MVIC. As expected, COPD patients had significantly lower MVIC (-25%, p=0.03). These patients also showed a significantly lower iSP (-53%, p<0.001) compared to controls. The ipsilateral excitability was increased in patients and controls (×2.5 and ×3.5, respectively, p<0.001) but not differently between groups (p=0.84). Despite impaired bilateral connectivity in COPD, ipsilateral activation was not increased. Reorganization in the patients' interhemispheric pathways could explain the preserved ipsilateral activation.

Muscle Oxidative Capacity Is Reduced in Both Upper and Lower Limbs in COPD.

ABSTRACTIntroductionSkeletal muscle atrophy, weakness, mitochondrial loss, and dysfunction are characteristics of chronic obstructive pulmonary disease (COPD). It remains unclear whether muscle dysfunction occurs in both upper and lower limbs, because findings are inconsistent in the few studies where upper and lower limb muscle performance properties were compared within an individual. This study determined whether muscle oxidative capacity is low in upper and lower limbs of COPD patients compared with controls.MethodsOxidative capacity of the forearm and medial gastrocnemius was measured using near-infrared spectroscopy to determine the muscle O2 consumption recovery rate constant (k, min−1) in 20 COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2/3/4, n = 7/7/6) and 20 smokers with normal spirometry (CON). Muscle k is linearly proportional to oxidative capacity. Steps per day and vector magnitude units per minute (VMU·min−1) were assessed using triaxial accelerometry. Differences between group and limb were assessed by two-way ANOVA.ResultsThere was a significant main effect of group (F = 11.2, ηp2 = 0.13, P = 0.001): k was lower in both upper and lower limb muscles in COPD (1.01 ± 0.17 and 1.05 ± 0.24 min−1) compared with CON (1.29 ± 0.49 and 1.54 ± 0.60 min−1). There was no effect on k of limb (F = 1.8, ηp2 = 0.02, P = 0.18) or group–limb interaction (P = 0.35). (VMU·min−1) was significantly lower in COPD (−38%; P = 0.042). Steps per day did not differ between COPD (4738 ± 3194) and CON (6372 ± 2107; P = 0.286), although the difference exceeded a clinically important threshold (>600–1100 steps per day).ConclusionsCompared with CON, muscle oxidative capacity was lower in COPD in both upper (−20%) and lower (−30%) limbs. These data suggest that mitochondrial loss in COPD is not isolated to locomotor muscles.

Locomotor Muscles in COPD: The Rationale for Rehabilitative Exercise Training.

Exercise training as part of pulmonary rehabilitation is arguably the most effective intervention to improve tolerance to physical exertion in patients with chronic obstructive pulmonary disease (COPD). Owing to the fact that exercise training has modest effects on exertional ventilation, operating lung volumes and respiratory muscle performance, improving locomotor muscle structure and function are key targets for pulmonary rehabilitation in COPD. In the current concise review, we initially discuss whether patients’ muscles are exposed to deleterious factors. After presenting corroboratory evidence on this regard (e.g., oxidative stress, inflammation, hypoxemia, inactivity, and medications), we outline their effects on muscle macro- and micro-structure and related functional properties. We then finalize by addressing the potential beneficial consequences of different training strategies on these muscle-centered outcomes. This review provides, therefore, an up-to-date outline of the rationale for rehabilitative exercise training approaches focusing on the locomotor muscles in this patient population.

Evaluation of isokinetic muscle strength of upper limb and the relationship with pulmonary function and respiratory muscle strength in stable COPD patients.

BackgroundUpper limb muscle strength plays an important role in respiratory and pulmonary function, and limited research focuses on the role of strength and endurance of the elbow extensor and flexor. This study was conducted to accurately assess upper limb muscle function and quantified associations with pulmonary function and respiratory muscle strength in patients with stable chronic obstructive pulmonary disease (COPD).MethodsIn this cross-sectional study, patients with stable COPD treated in Yue-Yang Integrative Medicine Hospital from March 2014 to March 2016 were recruited. All participants underwent a pulmonary function test (forced expiratory volume in first second/forced vital capacity, FEV1/FVC; percentage value of predicted FEV1, FEV1%pred), a respiratory muscle strength test (maximal inspiratory pressure, MIP; maximal expiratory pressure, MEP), and an isokinetic test of dominant upper limb after a 24-hr interval (peak torque, PT; PT/body weight, PT/BW; total work, TW; endurance ratio, ER).ResultsA total of 88 patients with stable COPD (age: 65.5±8.7 years) were recruited, of which 73% (64 patients) were male. In the multiple stepwise regression analysis, sex remained as significant impactors in the final model for FEV1%pred (adjusted R2=0.243, P<0.001). Elbow flexor PT/BW and ER, sex, and BMI remained as significant impactors in the final model for FEV1/FVC (adjusted R2=0.255, P<0.01). Elbow flexor TW remained as significant impactors for MIP (adjusted R2=0.112, P=0.001), while elbow extensor PT and PT/BW and sex remained as significant impactors for MEP (adjusted R =0.385, P<0.01).ConclusionIn stable COPD, pulmonary function and respiratory muscle strength are associated with upper limb muscle strength. In particular, elbow flexor endurance is likely an important impactor for pulmonary function and inspiratory muscle strength, while elbow extensor strength is of importance for expiratory muscle strength.

Study of the diaphragm in chronic obstructive pulmonary disease using ultrasonography.

Aims and Objectives:The study aims to compare the changes in the diaphragm in chronic obstructive pulmonary disease (COPD) patients in Indian population with the help of ultrasound-guided examination. (1) Changes in thickness of the diaphragm during respiration (to rule out diaphragm muscle atrophy). (2) The movement of the diaphragm(correlates with strength and endurance of diaphragm fibres). (3) Zone of apposition(gives mechanical advantage to diaphragm). (4) Correlation with COPD severity by global initiative for chronic obstructive lung disease (GOLD) staging.Subjects and Methods:Forty-eight COPD patients attending OPD of DY Patil Hospital were recruited in the study and twenty age-matched controls were taken. Detailed history, pulmonary function test examination, and diaphragm study under ultrasonography was done.Results:The movement of diaphragm was reduced in mild to moderate COPD (A and B) but increased in COPD with Grade C. Movement of diaphragm was significantly more in cases with COPD Grade B (2.329 cm) and C (2.269 cm) as compared to controls (1.891 cm). Mean diaphragmatic thickness during inspiration and expiration, change in thickness, and zone of apposition were significantly higher in patients with COPD score Grade C as compared to Grade A or B. Zone of apposition was significantly decreased in Grade A (3.257 cm) and B (3.429 cm) compared to control (4.268 cm), while it was significantly increased in cases with Grade C (5.138 cm).Conclusion:The diaphragm is the main muscle of respiration, and study of diaphragm is very important in COPD. The diaphragm thickness, movement, and zone of apposition were significantly reduced in mild to moderate COPD but increased in severe COPD. This cannot be explained by physiotherapy or collagen accumulation. Hence, diaphragm muscle biopsy and electromyogram study in COPD patients will be required to get a better understanding of this muscle in COPD.

Differences in micro-RNA expression profile between vastus lateralis samples and myotubes in COPD cachexia.

Quadriceps muscle weakness and wasting are common comorbidities in chronic obstructive pulmonary disease (COPD). Micro-RNA expression upregulation may favor muscle mass growth and differentiation. We hypothesized that the profile of muscle-enriched micro-RNAs in cultured myotubes differs between patients with COPD of a wide range of body composition and healthy controls and that expression levels of those micro-RNAs from patients with COPD and controls differ between in vivo and in vitro conditions. Twenty-nine patients with COPD [ n = 15 with muscle wasting and fat-free mass index (FFMI) 15 kg/m2 and n = 14 with normal body composition and FFMI 18 kg/m2] and 10 healthy controls (FFMI 19 kg/m2) were consecutively recruited. Biopsies from the vastus lateralis muscle were obtained in all study subjects. A fragment of each biopsy was used to obtain primary cultures, in which muscle cells were first proliferated to be then differentiated into actual myotubes. In both sets of experiments (in vivo biopsies and in vitro myotubes) the following muscle-enriched micro-RNAs from all the study subjects were analyzed using quantitative real-time PCR amplification: micro-RNA (miR)-1, miR-133a, miR-206, miR-486, miR-29b, miR-27a, and miR-181a. Whereas the expression of miR-1, miR-206, miR-486, and miR-29b was upregulated in the muscle biopsies of patients with COPD compared with those of healthy controls, levels of none of the studied micro-RNAs in the myotubes (primary cultured cells) significantly differed between patients with COPD and the controls. We conclude from these findings that environmental factors (blood flow, muscle metabolism, and inflammation) taking place in vivo (biopsies) in muscles may account for the differences observed in micro-RNA expression between patients with COPD and controls. In the myotubes, however, the expression of the same micro-RNAs did not differ between the study subjects as such environmental factors were not present. These findings suggest that therapeutic strategies should rather target environmental factors in COPD muscle wasting as the profile of micro-RNA expression in myotubes was similar in patients to that observed in the healthy controls. NEW & NOTEWORTHY Environmental factors taking place in vivo (biopsies) in the muscles may explain differences observed in micro-RNA expression between patients with chronic obstructive pulmonary disease (COPD) and controls. In the myotubes, however, the expression of the same micro-RNAs did not differ between the study subjects as such environmental factors were not present. These findings suggest that therapeutic strategies should rather target environmental factors in COPD muscle wasting and cachexia as micro-RNA expression profile in myotubes was similar between patients and controls.

Theophylline inhibits cigarette smoke-induced inflammation in skeletal muscle by upregulating HDAC2 expression and decreasing NF-κB activation.

Inflammation is associated with skeletal muscle dysfunction and atrophy in patients with chronic obstructive pulmonary disease (COPD). Theophylline has an anti-inflammatory role in COPD. However, the effects of theophylline on inflammation in skeletal muscle in COPD have rarely been reported. The aims of this study were to explore whether theophylline has an anti-inflammatory effect on skeletal muscle in a mouse model of emphysema and to investigate the molecular mechanism underlying this effect. In mice, cigarette smoke (CS) exposure for 28 wk resulted in atrophy of the gastrocnemius muscle. Histone deacetylase 2 (HDAC2) and nuclear factor-κBp65 (NF-κBp65) mRNA and protein levels were significantly decreased and increased, respectively, in gastrocnemius muscle. This effect was revered by aminophylline. The exposure of murine skeletal muscle C2C12 cells to CS extract (CSE) significantly increased IL-8 and TNF-α levels as well as NF-κBp65 mRNA and protein levels and NF-κBp65 activity. This effect was reversed by theophylline. HDAC2 knockdown enhanced the activity of NF-κBp65 and increased IL-8 and TNF-α levels in C2C12 cells. CSE significantly increased the interaction of HDAC2 with NF-κBp65 in C2C12 cells. These data suggest that theophylline has an anti-inflammatory effect on skeletal muscle in a mouse model of emphysema by upregulating HDAC2 expression and decreasing NF-κBp65 activation.

Oxidative stress regulates autophagy in cultured muscle cells of patients with chronic obstructive pulmonary disease.

The proteolytic autophagy pathway is enhanced in the lower limb muscles of patients with chronic obstructive pulmonary disease (COPD). Reactive oxygen species (ROS) have been shown to regulate autophagy in the skeletal muscles, but the role of oxidative stress in the muscle autophagy of patients with COPD is unknown. We used cultured myoblasts and myotubes from the quadriceps of eight healthy subjects and twelve patients with COPD (FEV1% predicted: 102.0% and 32.0%, respectively; p < 0.0001). We compared the autophagosome formation, the expression of autophagy markers, and the autophagic flux in healthy subjects and the patients with COPD,and we evaluated the effects of the 3-methyladenine (3-MA) autophagy inhibitor on the atrophy of COPD myotubes. Autophagy was also assessed in COPD myotubes treated with an antioxidant molecule, ascorbic acid. Autophagosome formation was increased in COPD myoblasts and myotubes (p = 0.011; p < 0.001), and the LC3 2/LC3 1 ratio (p = 0.002), SQSTM1 mRNA and protein expression (p = 0.023; p = 0.007), BNIP3 expression (p = 0.031), and autophagic flux (p = 0.002) were higher in COPD myoblasts. Inhibition of autophagy with 3-MA increased the COPD myotube diameter (p < 0.001) to a level similar to the diameter of healthy subject myotubes. Treatment of COPD myotubes with ascorbic acid decreased ROS concentration (p < 0.001), ROS-induced protein carbonylation (p = 0.019), the LC3 2/LC3 1 ratio (p = 0.037), the expression of SQSTM1 (p < 0.001) and BNIP3 (p < 0.001), and increased the COPD myotube diameter (p < 0.001). Thus, autophagy signaling is enhanced in cultured COPD muscle cells. Furthermore, the oxidative stress level contributes to the regulation of autophagy, which is involved in the atrophy of COPD myotubes in vitro.

Muscle atrophy in chronic obstructive pulmonary disease: molecular basis and potential therapeutic targets.

Patients with chronic obstructive pulmonary disease (COPD) experience several systemic manifestations such skeletal muscle dysfunction with and without muscle mass loss. Moreover, frequent comorbidities such as nutritional abnormalities, heart failure, and pulmonary hypertension, which are frequently associated with COPD may further contribute to skeletal muscle mass loss and dysfunction. Muscle dysfunction impairs the patients' exercise capacity and quality of life as daily life activities may be hampered by this problem. Importantly, impaired muscle function and mass loss have been shown to impact negatively on the patients' prognosis and survival in several studies. Thus, this is a major clinical problem that deserves special attention in clinical settings. During the course of exacerbations muscle mass loss takes place, hence aggravating muscle status and performance even after hospital discharge, especially in the frequently exacerbator patients. Several factors and biological mechanisms are involved in the etiology of COPD muscle dysfunction. The biological mechanisms identified so far offer a niche for therapeutic interventions in the patients. In the current review, a general overview of the most relevant etiologic factors and their target biological mechanisms through which muscle mass loss and dysfunction take place in both the respiratory and lower limb muscles in COPD patients is provided. We conclude that more clinical research is still needed targeted to test several therapeutic interventions. Given its prognostic value, the assessment of skeletal muscle dysfunction should be included in the routine evaluation of patients with chronic respiratory disorders and in critical care settings.

Eccentric Ergometer Training Promotes Locomotor Muscle Strength but Not Mitochondrial Adaptation in Patients with Severe Chronic Obstructive Pulmonary Disease.

Eccentric ergometer training (EET) is increasingly being proposed as a therapeutic strategy to improve skeletal muscle strength in various cardiorespiratory diseases, due to the principle that lengthening muscle actions lead to high force-generating capacity at low cardiopulmonary load. One clinical population that may particularly benefit from this strategy is chronic obstructive pulmonary disease (COPD), as ventilatory constraints and locomotor muscle dysfunction often limit efficacy of conventional exercise rehabilitation in patients with severe disease. While the feasibility of EET for COPD has been established, the nature and extent of adaptation within COPD muscle is unknown. The aim of this study was therefore to characterize the locomotor muscle adaptations to EET in patients with severe COPD, and compare them with adaptations gained through conventional concentric ergometer training (CET). Male patients were randomized to either EET (n = 8) or CET (n = 7) for 10 weeks and matched for heart rate intensity. EET patients trained on average at a workload that was three times that of CET, at a lower perception of leg fatigue and dyspnea. EET led to increases in isometric peak strength and relative thigh mass (p < 0.01) whereas CET had no such effect. However, EET did not result in fiber hypertrophy, as morphometric analysis of muscle biopsies showed no increase in mean fiber cross-sectional area (p = 0.82), with variability in the direction and magnitude of fiber-type responses (20% increase in Type 1, p = 0.18; 4% decrease in Type 2a, p = 0.37) compared to CET (26% increase in Type 1, p = 0.04; 15% increase in Type 2a, p = 0.09). EET had no impact on mitochondrial adaptation, as revealed by lack of change in markers of mitochondrial biogenesis, content and respiration, which contrasted to improvements (p < 0.05) within CET muscle. While future study is needed to more definitively determine the effects of EET on fiber hypertrophy and associated underlying molecular signaling pathways in COPD locomotor muscle, our findings promote the implementation of this strategy to improve muscle strength. Furthermore, contrasting mitochondrial adaptations suggest evaluation of a sequential paradigm of eccentric followed by concentric cycling as a means of augmenting the training response and attenuating skeletal muscle dysfunction in patients with advanced COPD.

Using laser capture microdissection to study fiber specific signaling in locomotor muscle in COPD: A pilot study.

Quadriceps dysfunction is important in chronic obstructive pulmonary disease (COPD), with an associated increased proportion of type II fibers. Investigation of protein synthesis and degradation has yielded conflicting results, possibly due to study of whole biopsy samples, whereas signaling may be fiber-specific. Our objective was to develop a method for fiber-specific gene expression analysis. 12 COPD and 6 healthy subjects underwent quadriceps biopsy. Cryosections were immunostained for type II fibers, which were separated using laser capture microdissection (LCM). Whole muscle and different fiber populations were subject to quantitative polymerase chain reaction. Levels of muscle-RING-finger-protein-1 and Atrogin-1 were lower in type II fibers of COPD versus healthy subjects (P = 0.02 and P = 0.03, respectively), but differences were not apparent in whole muscle or type I fibers. We describe a novel method for studying fiber-specific gene expression in optimum cutting temperature compound-embedded muscle specimens. LCM offers a more sensitive way to identify molecular changes in COPD muscle. Muscle Nerve 55: 902-912, 2017.

Molecular and biological pathways of skeletal muscle dysfunction in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) will be a major leading cause of death worldwide in the near future. Weakness and atrophy of the quadriceps are associated with a significantly poorer prognosis and increased mortality in COPD. Despite that skeletal muscle dysfunction may affect both respiratory and limb muscle groups in COPD, the latter are frequently more severely affected. Therefore, muscle dysfunction in COPD is a common systemic manifestation that should be evaluated on routine basis in clinical settings. In the present review, several aspects of COPD muscle dysfunction are being reviewed, with special emphasis on the underlying biological mechanisms. Figures on the prevalence of COPD muscle dysfunction and the most relevant etiologic contributors are also provided. Despite that ongoing research will shed light into the contribution of additional mechanisms to COPD muscle dysfunction, current knowledge points toward the involvement of a wide spectrum of cellular and molecular events that are differentially expressed in respiratory and limb muscles. Such mechanisms are thoroughly described in the article. The contribution of epigenetic events on COPD muscle dysfunction is also reviewed. We conclude that in view of the latest discoveries, from now, on new avenues of research should be designed to specifically target cellular mechanisms and pathways that impair muscle mass and function in COPD using pharmacological strategies and/or exercise training modalities.