IL-36R deletion mitigates cigarette smoke-induced airway inflammation and skeletal muscle dysfunction.

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.

Skeletal muscle dysfunction is one of the important comorbidities of chronic obstructive pulmonary disease (COPD); however, the underlying mechanisms remain largely unknown. RANKL (receptor activator of nuclear factor κB ligand), a key mediator in osteoclast differentiation, was also found to play a role in skeletal muscle pathogenesis. Whether RANKL is involved in COPD-related skeletal muscle dysfunction is as-of-yet unknown. We examined the expression of RANKL/RANK in skeletal muscles from mice exposed to cigarette smoke (CS) for 24 weeks. Grip strength and exercise capacity as well as muscular morphology were evaluated in CS-exposed mice with or without anti-RANKL treatment. The expressions of protein synthesis- or muscle growth-related molecules (IGF-1, myogenin, and myostatin), muscle-specific ubiquitin E3 ligases (MuRF1 and atrogin-1), and the NF-κb inflammatory pathway were also evaluated in skeletal muscles. The effect of CS extract on RANKL/RANK expression and that of exogenous RANKL on the ubiquitin-proteasome pathway in C2C12 myotubes were investigated in vitro. Long-term CS exposure induced skeletal muscle dysfunction and atrophy together with upregulation of RANKL/RANK expression in a well-established mouse model of COPD. RANKL neutralization prevented skeletal muscle dysfunction and atrophy. RANKL inhibition decreased expressions of myostatin and MuRF1/Atrogin1 and suppressed the NF-κb pathway in skeletal muscles from CS-exposed mice. In in vitro experiments with C2C12 myotubes, CS extract induced expression of RANKL/RANK, and exogenous RANKL induced activation of the ubiquitin-proteasome pathway and NF-κb pathway via RANK. Our results revealed an important role of the RANKL/RANK pathway in muscle atrophy induced by CS exposure, suggesting that RANKL may be a potential therapeutic target in COPD-related 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.

To the Editor : From the outset of this communication it is important to acknowledge the different definitions of the terms “dysfunction” (abnormal or impaired function) and “disuse” (a lack of use) ([9][1]). The latter most certainly exists in patients with chronic obstructive pulmonary

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.

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 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.

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.

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.

HDAC9 inhibition reduces skeletal muscle atrophy and enhances regeneration in mice with cigarette smoke-induced COPD

Airway bacteria, airway inflammation, lung structure and skeletal muscle dysfunctionare all recognised as important components of chronic obstructive pulmonary disease(COPD), yet the interplay between these components is not well understood.Within this thesis I present an observational study exploring relationships betweenairway inflammation and molecular measures of potentially pathogenic bacteria. I haveshown that airway bacterial detection is associated with increased airway inflammationin stable COPD, and that this association appears to be driven by Haemophilusinfluenzae.I then present a cross-sectional and longitudinal study using dual energy x-rayabsorptiometry measurements of body composition and have shown that airwaybacterial load and inflammation are independent of body composition changes, and thatloss of skeletal muscle is not associated with accelerated airway inflammation or lungfunction decline.Within a multi-centre exacerbation cohort study I have shown that sputum bacterial loadis only weakly associated with quadriceps muscle strength in stable COPD. In additionI have shown only a small, short-lived reduction in quadriceps strength at exacerbation,suggesting that community managed exacerbations may have limited impact on longterm decline in muscle and physical function in COPD patients.Finally, I present the results of a single centre study that has shown that air trappingmeasured using quantitative computed tomography (QCT) makes the strongest uniquecontribution to airflow obstruction in COPD. Moreover, H. influenzae bacterial load isrelated to QCT measured small airways disease, and this association is independent ofthe amount of neutrophilic airways inflammation.In summary, within this thesis I provide data demonstrating significant relationshipsbetween H. influenzae, airway inflammation and lung structural changes in COPD. Bycontrast, my findings suggest that inflammation, and in particular overspill ofpulmonary inflammation is not a key pathophysiological mechanism leading to skeletalmuscle depletion or dysfunction in COPD.

Skeletal muscle atrophy and dysfunction are common comorbidities in chronic obstructive pulmonary disease (COPD), with cigarette smoke (CS) exposure being a significant contributing factor. However, the underlying mechanisms remain unclear. Inflammation driven by damage-associated molecular patterns (DAMPs), such as High-mobility group box 1 (HMGB1), may play a crucial role. This study investigated the involvement of HMGB1-mediated pyroptosis associated with skeletal muscle atrophy in COPD. Serum HMGB1 levels were measured in healthy nonsmokers and patients with COPD. Additionally, midthigh circumference and body mass index (BMI) were assessed in patients with COPD, and their correlations with HMGB1 levels were analyzed. Treatment with glycyrrhizin (GL, a direct inhibitor of HMGB1) in CS-exposed mice was further used to demonstrate the effect of HMGB1 on skeletal muscle. A C2C12 cell model exposed to cigarette smoke extract (CSE) was employed to elucidate the role of the HMGB1/Toll-like receptor 4 (TLR4)-NLR family pyrin domain-containing 3 (NLRP3)-gasdermin D (GSDMD)-Caspase-1 pathway. In patients with COPD, serum HMGB1 levels were significantly higher than in healthy individuals and negatively correlated with midthigh circumference and BMI. Treatment with GL in CS-exposed mice led to the reversal of muscle atrophy and dysfunction, alongside a reduction in the expression of TLR4 and pyroptosis-associated factors within skeletal muscle. In vitro experiments demonstrated that CSE increased HMGB1, which promoted skeletal muscle atrophy by driving inflammation through the HMGB1/TLR4-NLRP3-GSDMD-Caspase-1 pathway. HMGB1 induced by CS may trigger skeletal muscle atrophy. It promotes inflammation through HMGB1/TLR4-NLRP3-GSDMD-Caspase-1-mediated pyroptosis, thereby exacerbating muscle wasting. Therefore, the pathway represents a potential novel therapeutic target for skeletal muscle atrophy.NEW & NOTEWORTHY This study reveals that the levels of High-mobility group box 1 (HMGB1) protein in patients with chronic obstructive pulmonary disease (COPD) are significantly higher than in healthy nonsmoking individuals and are negatively correlated with the degree of skeletal muscle atrophy. Through in vivo and in vitro experiments, we have confirmed that HMGB1 promotes inflammatory responses through the HMGB1/TLR4-NLRP3-GSDMD-Caspase-1-mediated pyroptosis pathway, thereby exacerbating muscle wasting. This pathway represents a potential novel therapeutic target for the treatment of skeletal muscle atrophy.

Skeletal muscle dysfunction is a common extrapulmonary comorbidity of chronic obstructive pulmonary disease (COPD) and is associated with decreased quality-of-life and survival in patients. The autophagy lysosome pathway is one of the proteolytic systems that significantly affect skeletal muscle structure and function. Intriguingly, both promoting and inhibiting autophagy have been observed to improve COPD skeletal muscle dysfunction, yet the mechanism is unclear. This paper first reviewed the effects of macroautophagy and mitophagy on the structure and function of skeletal muscle in COPD, and then explored the mechanism of autophagy mediating the dysfunction of skeletal muscle in COPD. The results showed that macroautophagy- and mitophagy-related proteins were significantly increased in COPD skeletal muscle. Promoting macroautophagy in COPD improves myogenesis and replication capacity of muscle satellite cells, while inhibiting macroautophagy in COPD myotubes increases their diameters. Mitophagy helps to maintain mitochondrial homeostasis by removing impaired mitochondria in COPD. Autophagy is a promising target for improving COPD skeletal muscle dysfunction, and further research should be conducted to elucidate the specific mechanisms by which autophagy mediates COPD skeletal muscle dysfunction, with the aim of enhancing our understanding in this field.

BackgroundCeramides are known for their harmful, cell-autonomous effects in cigarette smoke (CS)-triggered chronic obstructive pulmonary disease (COPD), yet their potential role as intercellular signals in COPD pathogenesis remains unclear. This study aims to investigate whether ceramides act as cell-nonautonomous mediators of COPD development by transmitting metabolic stress from pulmonary macrophages to endothelial cells (ECs), compromising endothelial function and thereby orchestrating the pulmonary inflammation.MethodsWe analyzed single-cell RNA sequencing data from human lung tissues and bulk RNA sequencing data from alveolar macrophages (AMs) in COPD patients to investigate the transcriptomic profiles of ceramide biosynthesis enzymes. The expression changes of several key enzymes were validated in human lung sections, AMs isolated from CS-exposed mice, and cigarette smoke extract (CSE)-treated macrophages. Ceramide levels in macrophages and their extracellular vesicles (EVs) were quantified using mass spectroscopy lipidomics. EVs were further characterized by transmission electron microscopy and nanoparticle tracking analysis. The uptake of macrophage-derived EVs by ECs and their effects on endothelial barriers were evaluated in vitro using a co-culture system and in vivo using a CS-exposed COPD mouse model.ResultsCS exposure upregulated enzymes involved in de novo ceramide biosynthesis in pulmonary macrophages, increasing levels of long- and very long-chain ceramides. These ceramides were packaged into EVs and delivered to ECs, where they disrupted gap junctions, increased endothelial permeability, and impaired EC migration. Silencing these enzymes involved in de novo ceramide biosynthesis in pulmonary macrophages could block this metabolic communication between macrophages and ECs mediated by EV-delivered ceramides, protecting EC function from CS exposure. When intratracheally administered to CS-exposed mice, these ceramide-rich macrophage-derived EVs exacerbated COPD by facilitating endothelial barrier disruption.ConclusionOur study uncovered a novel mechanism in COPD pathogenesis, where pulmonary macrophages propagate CS-induced metabolic stress to ECs via ceramide-laden EVs, leading to endothelial barrier dysfunction. This intercellular pathway represents a potential target for therapeutic intervention in COPD.Graphical

Patients with chronic obstructive pulmonary disease (COPD) usually develop skeletal muscle dysfunction, which represents a major comorbidity in these patients and is strongly associated with mortality and other poor outcomes. Although clinical data indicates that accelerated protein degradation and metabolic disruption are common associations of muscle dysfunction in COPD, there is very limited data on the mechanisms regulating the process, in part, due to the lack of research performed on a validated animal model of pulmonary emphysema. This model deficiency complicates the translational value of data generated with highly reductionist settings. Here, we use an established transgenic animal model of COPD based on inducible IL-13-driven pulmonary emphysema (IL-13TG) to interrogate the mechanisms of skeletal muscle dysfunction. Skeletal muscles from these emphysematous mice develop most features present in COPD patients, including atrophy, decreased oxygen consumption, and reduced force-generation capacity. Analysis of muscle proteome indicates downregulation of succinate dehydrogenase C (SDH-C), which correlates with reduced enzymatic activity, also consistent with previous clinical observations. Ontology terms identified with human data, such as ATP binding/bioenergetics are also downregulated in this animal's skeletal muscles. Moreover, chronic exercise can partially restore muscle mass, metabolic and force-generation capacity, and SDH activity in COPD mice. We conclude that this animal model of COPD/emphysema is an adequate platform to further investigate mechanisms of muscle dysfunction in this setting and demonstrates multiple approaches that can be used to address specific mechanisms regulating this process.NEW & NOTEWORTHY Skeletal muscle dysfunction is a relevant comorbidity in patients with chronic obstructive pulmonary disease (COPD). Mechanistic research in the area has so far been accomplished with models based on specific exposures to otherwise healthy animals, and no investigation using an established and validated animal model of COPD has been accomplished. We present an animal model of COPD that was previously shown to recapitulate pulmonary functional and histologic features present in patients with COPD, and demonstrates most of the features present in patients with pulmonary emphysema-associated muscle dysfunction, which we proposed as an adequate tool to develop mechanistic research in the area.