Skeletal Muscle Dysfunction In Chronic Obstructive Pulmonary Disease Research Articles

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.

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.

Dysregulated myokines and signaling pathways in skeletal muscle dysfunction in a cigarette smoke-induced model of chronic obstructive pulmonary disease.

Skeletal muscle dysfunction is an important extrapulmonary comorbidity of chronic obstructive pulmonary disease (COPD). Muscle-derived cytokines (myokines) play important roles in skeletal muscle growth and function, but their contributions to skeletal muscle dysfunction in COPD have not been fully understood. In the current study, by using a well-established mouse model of COPD with skeletal muscle dysfunction, we found that the expressions of Fndc5 (fibronectin type III domain-containing protein 5, the precursor of irisin) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) were decreased, while myostatin (Mstn), phosphorylated extracellular regulated kinase (p-Erk1/2), and p-Smad3 expressions were upregulated in skeletal muscles from cigarette smoke-exposed mice and in cigarette smoke extract (CSE)-stimulated C2C12 myotubes. Treatment with Smad3 or Erk1/2 inhibitors partially restored the expression of Fndc5 in CSE-stimulated C2C12 myotubes. Taken together, CSE exposure, by upregulation of p-Erk1/2, promoted the expression of Mstn, which further inhibited Fndc5 expression by the p-Smad3/PGC-1α pathway, revealing a novel regulating mechanism of myokines in the pathogenesis of skeletal muscle comorbidities of COPD.

Myostatin is involved in skeletal muscle dysfunction in chronic obstructive pulmonary disease via Drp-1 mediated abnormal mitochondrial division.

BackgroundSkeletal muscle dysfunction (SMD) is one of the most prominent extrapulmonary effects of chronic obstructive pulmonary disease (COPD). Myostatin negatively regulates the growth of skeletal muscle. We confirmed that myostatin expression is significantly increased in the quadriceps femoris muscle tissue of rats with COPD and is involved in the development of SMD in COPD, but the mechanism by which this occurs has yet to be uncovered. Dynamin-related protein 1 (Drp-1) has been shown to promote apoptosis and affect cellular energy metabolism by mediating enhanced mitochondrial division. Preliminary findings from our group illustrated that mitochondrial division and Drp-1 expression were increased in COPD quadriceps femoris cells. However, it is not yet clear whether mitochondrial dynamics are affected by myostatin in COPD quadriceps myocytes.MethodsThe study sought to explore the effects and potential mechanisms of myostatin on skeletal muscle atrophy, mitochondrial dynamics, apoptosis, and the links between related processes in COPD.ResultsOur findings showed that cigarette smoke exposure stimulated an increase in myostatin, increased superoxide production, decreased mitochondrial membrane potential, significantly promoted Drp-1-mediated mitochondrial fission, and promoted apoptosis.ConclusionsIn summary, our study demonstrated that cigarette smoke led to increased Drp-1 expression and enhanced mitochondrial division by upregulating myostatin, which in turn promoted apoptosis and affected cellular energy metabolism, leading to the development of SMD in COPD. This study extends understandings of skeletal muscle function in COPD and provides a basis for the use of myostatin and Drp-1 as novel therapeutic targets for SMD in COPD.

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.

Ultrasonographic assessment of skeletal muscle mass and diaphragm function in patients with chronic obstructive pulmonary disease: A case-control study.

Background:Although muscle dysfunction is a major contributor to morbidity in chronic obstructive pulmonary disease (COPD), assessment of skeletal muscle, and diaphragm function is not routinely performed in COPD patients.Objectives:(1) The aim is to assess muscle dysfunction in COPD by measuring the zone of apposition of diaphragm, diaphragm excursion, thickness of diaphragm, and rectus femoris cross-sectional area (RFCSA) with ultrasonography. (2) To correlate the above assessments with spirometric parameters; notably forced expiratory volume in 1 s (FEV1).Methods:Twenty-four consecutive stable COPD patients and 18 controls were included after obtaining written informed consent. Demographic and clinical data, spirometric values, 6-min walk distance, and sonographic parameters mentioned above were compiled for the analysis.Results:All included participants were male with a mean age of 62.5 ± 8.4 years. The mean FEV1 in cases was 1.12 ± 0.4 L versus 2.41 ± 0.5 L in controls. The diaphragm thickness (1.8 ± 0.5 mm vs. 2.2 ± 0.6 mm; P = 0.005) and RFCSA was significantly lower in COPD patients (4.8 ± 1.3 cm2 vs. 6.12 ± 1.2 cm2; P = 0.02). However, diaphragm excursion (5.35 ± 2.8 cm vs. 7 ± 2.6 cm) although lower in COPD patients, was not significantly different between the groups. Correlation between FEV1 and ultrasound diaphragm measurements and RFCSA by Spearman's Rho correlation was poor (ρ = 0.2).Conclusion:Ultrasonographic assessment of the diaphragm and rectus femoris can be used as markers to assess skeletal muscle dysfunction in COPD as diaphragmatic function and RFCSA were lower in COPD patients.

Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease. What We Know and Can Do for Our Patients.

Skeletal muscle dysfunction occurs in patients with chronic obstructive pulmonary disease (COPD) and affects both ventilatory and nonventilatory muscle groups. It represents a very important comorbidity that is associated with poor quality of life and reduced survival. It results from a complex combination of functional, metabolic, and anatomical alterations leading to suboptimal muscle work. Muscle atrophy, altered fiber type and metabolism, and chest wall remodeling, in the case of the respiratory muscles, are relevant etiological contributors to this process. Muscle dysfunction worsens during COPD exacerbations, rendering patients progressively less able to perform activities of daily living, and it is also associated with poor outcomes. Muscle recovery measures consisting of a combination of pulmonary rehabilitation, optimized nutrition, and other strategies are associated with better prognosis when administered in stable patients as well as after exacerbations. A deeper understanding of this process' pathophysiology and clinical relevance will facilitate the use of measures to alleviate its effects and potentially improve patients' outcomes. In this review, a general overview of skeletal muscle dysfunction in COPD is offered to highlight its relevance and magnitude to expert practitioners and scientists as well as to the average clinician dealing with patients with chronic respiratory diseases.

Genetic variants predicting aerobic capacity response to training are also associated with skeletal muscle oxidative capacity in moderate-to-severe COPD.

Muscle oxidative capacity is a major determinant of maximum oxygen uptake (V̇O2max). V̇O2max predicts survival in humans. Muscle oxidative capacity is low in chronic obstructive pulmonary disease (COPD) and can be assessed from the muscle oxygen consumption recovery rate constant (k) by near-infrared spectroscopy. We hypothesized that 11 SNPs, previously associated with the increase in V̇O2max following exercise training, would correlate with k in 152 non-Hispanic White and African American smokers with and without COPD. Associations were adjusted for age, weight, FEV1% predicted, steps/day, and principal components of genetic ancestry. No SNPs were significantly associated with k. rs2792022 within BTAF1 (β = 0.130, P = 0.053) and rs24575771 within SLC22A3 (β = 0.106, P = 0.058) approached nominal significance. Case-control stratification identified three SNPs nominally associated with k in moderate-to-severe COPD (rs6481619 within SVIL β = 0.152, P = 0.013; BTAF1 β = 0.196, P = 0.046; rs7386139 within DEPTOR β = 0.159, P = 0.047). These data support further study of the genomic contributions to skeletal muscle dysfunction in COPD.

Resistance training and exercise tolerance during high-intensity exercise: moving beyond just running economy and muscle strength.

Resistance training and exercise tolerance during high-intensity exercise: moving beyond just running economy and muscle strength.

Molecular mechanisms underlying COPD-muscle dysfunction unveiled through a systems medicine approach.

Skeletal muscle dysfunction is a systemic effect in one-third of patients with chronic obstructive pulmonary disease (COPD), characterized by high reactive-oxygen-species (ROS) production and abnormal endurance training-induced adaptive changes. However, the role of ROS in COPD remains unclear, not least because of the lack of appropriate tools to study multifactorial diseases. We describe a discrete model-driven method combining mechanistic and probabilistic approaches to decipher the role of ROS on the activity state of skeletal muscle regulatory network, assessed before and after an 8-week endurance training program in COPD patients and healthy subjects. In COPD, our computational analysis indicates abnormal training-induced regulatory responses leading to defective tissue remodeling and abnormal energy metabolism. Moreover, we identified tnf, insr, inha and myc as key regulators of abnormal training-induced adaptations in COPD. The tnf-insr pair was identified as a promising target for therapeutic interventions. Our work sheds new light on skeletal muscle dysfunction in COPD, opening new avenues for cost-effective therapies. It overcomes limitations of previous computational approaches showing high potential for the study of other multi-factorial diseases such as diabetes or cancer. jroca@clinic.ub.es or martacascante@ub.eduSupplementary information: Supplementary data are available at Bioinformatics online.

No TWEAK for COPD

To the Editor: The therapy with the greatest functional benefit in chronic obstructive pulmonary disease (COPD) is pulmonary rehabilitation [1]; while the mode of action is probably multifactorial the functional benefit of pulmonary rehabilitation is associated with strength gain in the quadriceps [2]. This suggests that muscle hypertrophy, or countering atrophy, could be at least one of the mechanisms through which pulmonary rehabilitation is beneficial. However, despite the success of pulmonary rehabilitation, there are several occasions in which an effective adjunctive drug therapy might have a place in clinical practice; for example in patients who are too unwell to exercise, in patients unwilling or unable to complete pulmonary rehabilitation, or indeed to magnify or extend benefit in those who do. In order to conduct stratified medicine studies of future novel anabolic agents for skeletal muscle dysfunction in COPD, biomarkers to identify potential responders will be required. In particular, it is likely that such therapies may be aimed at subsets of patients with COPD rather than, as is the …

Skeletal muscle mitochondrial dysfunction during chronic obstructive pulmonary disease: central actor and therapeutic target

Muscle dysfunction is a common complication and an important prognostic factor in chronic obstructive pulmonary disease (COPD). As therapeutic strategies are still needed to treat this complication, gaining more insight into the process that leads to skeletal muscle decline in COPD appears to be an important issue. This review focuses on mitochondrial involvement in limb skeletal muscle alterations (decreased muscle mass, strength, endurance and power and increased fatigue) in COPD. Mitochondria are the main source of energy for the cells; they are involved in production of reactive oxygen species and activate an important pathway that leads to apoptosis. In COPD patients, skeletal muscles are characterized by decreased mitochondrial density and biogenesis, impaired activity and coupling of mitochondrial respiratory chain complexes, increased mitochondrial production of reactive oxygen species and, possibly, increased apoptosis. Of particular interest, a sedentary lifestyle, hypoxia, hypercapnia, tobacco smoking, corticosteroid therapy and, possibly, inflammation participate in this mitochondrial dysfunction, which is accessible to conventional therapies, such as exercise and tobacco cessation, as well as, potentially, to more innovative approaches, such as antioxidant treatment and supplementation with polyunsaturated fatty acids.

Nutritional targets to enhance exercise performance in chronic obstructive pulmonary disease

This review presents current knowledge regarding the rationale and efficacy of nutrition as an ergogenic aid to enhance the effects of exercise and training in chronic obstructive pulmonary disease (COPD). Altered body composition and skeletal muscle dysfunction in COPD suggest that exercise capacity can be targeted via several metabolic routes. Muscle metabolic alterations in COPD include a reduced oxidative metabolism and enhanced susceptibility for oxidative stress. Muscle wasting may be associated with deficiencies of vitamin D and low branched-chain amino acid levels. Exercise training is of established benefit in COPD but clear-cut clinical trial evidence to support the performance enhancing effect of nutritional intervention is lacking. One randomized controlled trial suggested that augmentation of training with polyunsaturated fatty acids may improve exercise capacity. Conflicting results are reported on dietary creatine supplementation in patients with COPD receiving pulmonary rehabilitation and results from acute intervention studies do not directly imply long-term effects of glutamate or glutamine supplementation as an ergogenic aid in COPD. Recent data indicate that not only muscle but also visceral fat may be an important additional target for combined nutrition and exercise intervention in COPD to improve physical performance and decrease cardiometabolic risk. There is a clear need for adequately powered and controlled intervention and maintenance trials to establish the role of nutritional supplementation in the enhancement of exercise performance and training and the wider management of the systemic features of the disease.

Impaired muscle mitochondrial density and/or function: a COPD-specific mitochondropathy or simply deconditioning?

Chronic obstructive pulmonary disease (COPD) is a pulmonary disease with some systemic consequences. Skeletal muscle dysfunction is one of the earliest systemic manifestations of COPD in some patients, and contributes to limited exercise capacity and poor health outcomes. The aetiology of skeletal muscle abnormalities in COPD is not fully understood, but probably represents a combination of deconditioning, muscle atrophy and nutritional deficiencies. Studies have shown that skeletal muscle from patients with COPD displays other abnormalities including increased oxidative stress, muscle fibre apoptosis and mitochondrial dysfunction. Indeed, reduced mitochondrial density and function are recognised as important components of skeletal muscle dysfunction in COPD, and reduced oxidative capacity at a skeletal muscle level is likely to contribute to exercise limitation in this population. Mitochondrial density and function are potential therapeutic targets in COPD, but it remains uncertain whether impaired mitochondrial density and/or function are attributable to ageing, inactivity and deconditioning, a COPD-specific “mitochondropathy”, or a combination of these factors. However, endurance exercise training is known to increase mitochondrial density and function in healthy volunteers, whether determined by, for example, measurements of maximal activities of mitochondrial enzymes or oxygen consumption and adenosine triphosphate production rates in …

Skeletal Muscle Dysfunction and Pulmonary Rehabilitation in COPD

Chronic obstructive pulmonary disease (COPD) is now well recognized as a systemic disorder. Apart from the lungs, the musculoskeletal system is one of the most frequently affected organs. Skeletal muscle dysfunction contributes independently to symptoms, impaired health status, increased health care resource usage, and reduced survival. Pulmonary impairment is largely irreversible and therefore the skeletal muscles represent a potential site to improve functioning and symptoms in patients with COPD. The etiology of skeletal muscle dysfunction in COPD is probably multifactorial with varying contributions from physical inactivity, systemic inflammation, hormone imbalance, tissue hypoxia, nutritional abnormalities, oxidative stress, genetic susceptibility, and chronic corticosteroid use. Exercise training is effective at reversing skeletal muscle dysfunction, and pulmonary rehabilitation, a largely exercise-based intervention, has become a cornerstone in the management of COPD. This article summarizes the structural and functional characteristics of skeletal muscle dysfunction in COPD, reviews the possible contributing factors, and describes the effect of pulmonary rehabilitation on skeletal muscle structure and function.

Exercise and muscle dysfunction in COPD: implications for pulmonary rehabilitation

Skeletal muscle dysfunction in COPD (chronic obstructive pulmonary disease) patients, particularly of the quadriceps, is of clinical interest because it not only influences the symptoms that limit exercise, but may also contribute directly to poor exercise performance and health status, increased healthcare utilization, and mortality. Furthermore, unlike the largely irreversible impairment of the COPD lung, skeletal muscles represent a potential site to improve patients' level of function and quality of life. However, despite expanding knowledge of potential contributing factors and greater understanding of molecular mechanisms of muscle wasting, only one intervention has been shown to be effective in reversing COPD muscle dysfunction, namely exercise training. Pulmonary rehabilitation, an intervention based on individually tailored exercise training, has emerged as arguably the most effective non-pharmacological intervention in improving exercise capacity and health status in COPD patients. The present review describes the effects of chronic exercise training on skeletal muscles and, in particular, focuses on the known effects of pulmonary rehabilitation on the quadriceps muscle in COPD. We also describe the current methods to augment the effects of pulmonary rehabilitation and speculate how greater knowledge of the molecular pathways of skeletal muscle wasting may aid the development of novel pharmaceutical agents.

Skeletal muscle dysfunction in COPD: clinical and laboratory observations

COPD (chronic obstructive pulmonary disease), although primarily a disease of the lungs, exhibits secondary systemic manifestations. The skeletal muscles are of particular interest because their function (or dysfunction) not only influences the symptoms that limit exercise, but may contribute directly to poor exercise performance. Furthermore, skeletal muscle weakness is of great clinical importance in COPD as it is recognized to contribute independently to poor health status, increased healthcare utilization and even mortality. The present review describes the current knowledge of the structural and functional abnormalities of skeletal muscles in COPD and the possible aetiological factors. Increasing knowledge of the molecular pathways of muscle wasting will lead to the development of new therapeutic agents and strategies to combat COPD muscle dysfunction.

Peroxisome proliferator-activated receptor expression is reduced in skeletal muscle in COPD

Chronic obstructive pulmonary disease (COPD) is a multiorgan systemic disease. The systemic features are skeletal muscle weakness and cachexia, the latter being associated with systemic inflammation. The exact mechanisms underlying skeletal muscle dysfunction in COPD remain obscure. Recent evidence suggests involvement of the peroxisome proliferator-activated receptors (PPARs) and PPAR-gamma coactivator (PGC)-1alpha in regulation of skeletal muscle morphology and metabolism, and mitochondrial transcription factor A (TFAM) has been implicated in the process of mitochondrial biogenesis. The aim of the present exploratory study was, therefore, to compare these factors in the skeletal muscle of nine healthy control subjects and 14 COPD patients stratified by cachexia. PPAR-gamma, PPAR-delta and TFAM were measured at the mRNA and protein level by real-time quantitative PCR and Western blotting, respectively. PPAR-alpha and PGC-1alpha were meansured at the mRNA level. PPAR-delta and TFAM protein content, as well as PGC-1alpha mRNA levels, were decreased in the skeletal muscle of COPD patients compared with healthy controls. The cachectic COPD subgroup was further characterised by decreased PPAR-alpha mRNA expression and decreased TFAM protein and mRNA levels compared with noncachectic COPD patients. In addition, PPAR-alpha mRNA levels in skeletal muscle correlated negatively with inflammatory markers in plasma. Therefore, a disturbed expression of these regulatory factors may well underlie the disturbed skeletal muscle functioning in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease: the contribution of skeletal muscle dysfunction to exercise intolerance

Chronic obstructive pulmonary disease (COPD) is characterised by pathological changes in lung tissue and disordered respiratory mechanics. The exercise intolerance exhibited by individuals with COPD is related to a variety of factors including airflow obstruction, pulmonary hyperinflation, gas exchange abnormalities, and peripheral muscle dysfunction. This review examines the extent of skeletal muscle dysfunction in moderate-to-severe COPD, and its relationship to exercise intolerance. There are two distinct characteristics of skeletal muscle dysfunction in COPD – loss of muscle mass and dysfunction of the remaining muscle tissue. Abnormalities have been identified in the structural and functional determinants of skeletal muscle function (strength and endurance), and are also observed in the enzymatic profile and metabolic response to exercise in subjects with the disease. Understanding the nature of skeletal muscle dysfunction in COPD is critical to the interpretation of exercise performance in affected subjects. Furthermore, skeletal muscle dysfunction represents a partially reversible consequence of COPD, that may be ameliorated by specific exercise training strategies.

Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

During the last decade evidence has been accumulated on the role of skeletal muscle dysfunction in reducing exercise capacity and affecting the quality of life of patients with chronic obstructive pulmonary disease (COPD). An appreciable body of research has helped to identify morphological and biochemical alterations, physiological consequences, and possible therapeutic interventions. There are, however, still many areas of uncertainty. For example it is not clear how much of the alterations are within the muscle itself or the consequence of the altered environment in which the muscle works. Similarly it is not clear how much of the impairment is simply due to aging and chronic inactivity. Another key issue is the possible additive effect of drugs often used in COPD patients, such as steroids, beta 2-agonist and cyclosporin. A specific additional layer of complexity comes from nutritional considerations and in particular loss of muscle mass which not infrequently accompanies severe disease and even greater exercise intolerance. Studies on the effects of training or other therapeutic interventions have shown that muscle dysfunction is partially reversible. There is, however, a clear need for studies based on cellular and molecular methods aimed to clarify the role of factors such as oxidative stress, inflammation and nutritional deficiencies on skeletal muscle structure and function. The focus of this review is to highlight the current knowledge on skeletal muscle dysfunction in COPD and briefly summarize the possible therapeutic implications.