Chronic Obstructive Pulmonary Disease Cachexia Research Articles

Update on the Etiology, Assessment, and Management of COPD Cachexia: Considerations for the Clinician.

Cachexia is a commonly observed but frequently neglected extra-pulmonary manifestation in patients with chronic obstructive pulmonary disease (COPD). Cachexia is a multifactorial syndrome characterized by severe loss of body weight, muscle, and fat, as well as increased protein catabolism. COPD cachexia places a high burden on patients (eg, increased mortality risk and disease burden, reduced exercise capacity and quality of life) and the healthcare system (eg, increased number, length, and cost of hospitalizations). The etiology of COPD cachexia involves a complex interplay of non-modifiable and modifiable factors (eg, smoking, hypoxemia, hypercapnia, physical inactivity, energy imbalance, and exacerbations). Addressing these modifiable factors is needed to prevent and treat COPD cachexia. Oral nutritional supplementation combined with exercise training should be the primary multimodal treatment approach. Adding a pharmacological agent might be considered in some, but not all, patients with COPD cachexia. Clinicians and researchers should use longitudinal measures (eg, weight loss, muscle mass loss) instead of cross-sectional measures (eg, low body mass index or fat-free mass index) where possible to evaluate patients with COPD cachexia. Lastly, in future research, more detailed phenotyping of cachectic patients to enable a better comparison of included patients between studies, prospective longitudinal studies, and more focus on the impact of exacerbations and the role of biomarkers in COPD cachexia, are highly recommended.

Heme metabolism genes Downregulated in COPD Cachexia

IntroductionCachexia contributes to increased mortality and reduced quality of life in Chronic Obstructive Pulmonary Disease (COPD) and may be associated with underlying gene expression changes. Our goal was to identify differential gene expression signatures associated with COPD cachexia in current and former smokers.MethodsWe analyzed whole-blood gene expression data from participants with COPD in a discovery cohort (COPDGene, N = 400) and assessed replication (ECLIPSE, N = 114). To approximate the consensus definition using available criteria, cachexia was defined as weight-loss > 5% in the past 12 months or low body mass index (BMI) (< 20 kg/m2) and 1/3 criteria: decreased muscle strength (six-minute walk distance < 350 m), anemia (hemoglobin < 12 g/dl), and low fat-free mass index (FFMI) (< 15 kg/m2 among women and < 17 kg/m2 among men) in COPDGene. In ECLIPSE, cachexia was defined as weight-loss > 5% in the past 12 months or low BMI and 3/5 criteria: decreased muscle strength, anorexia, abnormal biochemistry (anemia or high c-reactive protein (> 5 mg/l)), fatigue, and low FFMI. Differential gene expression was assessed between cachectic and non-cachectic subjects, adjusting for age, sex, white blood cell counts, and technical covariates. Gene set enrichment analysis was performed using MSigDB.ResultsThe prevalence of COPD cachexia was 13.7% in COPDGene and 7.9% in ECLIPSE. Fourteen genes were differentially downregulated in cachectic versus non-cachectic COPD patients in COPDGene (FDR < 0.05) and ECLIPSE (FDR < 0.05).DiscussionSeveral replicated genes regulating heme metabolism were downregulated among participants with COPD cachexia. Impaired heme biosynthesis may contribute to cachexia development through free-iron buildup and oxidative tissue damage.

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.

The phosphodiesterase-4 inhibitor roflumilast reverts proteolysis in skeletal muscle cells of patients with COPD cachexia.

Peripheral muscle weakness and mass loss are characteristic features in severe chronic obstructive pulmonary disease (COPD). We hypothesized that the phosphodiesterase (PDE)-4 inhibitor roflumilast-induced cAMP may ameliorate proteolysis and metabolism in skeletal muscles of COPD patients with severe muscle wasting. In myogenic precursor cells (isolated from muscle biopsies and cultured up to obtain differentiated myotubes) from 10 severe COPD patients and 10 healthy controls, which were treated with 1 μM roflumilast N-oxide (RNO) for three time cohorts (1, 6, and 24 h), genes of antioxidant defense and oxidative stress marker, myogenesis and muscle metabolism, proteolysis (tyrosine release assay) and ubiquitin-proteasome system markers, autophagy, and myosin isoforms were analyzed using RT-PCR and immunoblotting. In COPD patients at 6 h RNO treatment, myotube tyrosine release, total protein ubiquitination, and tripartite motif-containing protein 32 levels were significantly lower than healthy controls, whereas at 24 h RNO treatment, myotube myosin heavy chain ( MyHC) -I and MyHC-IIx expression levels were upregulated in both patients and controls. In the 6-h RNO cohort, in patients and controls, myotube expression of nuclear factor (erythroid-derived 2)-like 2 ( NRF2) and its downstream antioxidants sirtuin-1, FGF-inducible 14, and insulin-like growth factor-1 was upregulated, whereas that of myocyte-specific enhancer factor 2C, myogenic differentiation, myogenin, myostatin, atrogin-1, and muscle RING-finger protein-1 was downregulated. In myotubes of severe COPD patients with cachexia, roflumilast-induced cAMP signaling exerts beneficial effects by targeting muscle protein breakdown (tyrosine release), along with reduced expression of proteolytic markers of the ubiquitin-proteasome system and that of myostatin. In both patients and controls, roflumilast also favored antioxidant defense through upregulation of the NRF2 pathway and that of the histone deacetylase sirtuin-1, whereas it improved the expression of slow- and fast-twitch myosin isoforms. These findings show that muscle dysfunction and wasting may be targeted by roflumilast-induced cAMP signaling in COPD. These results have potential therapeutic implications, as this PDE-4 inhibitor is currently available for the treatment of systemic inflammation and exacerbations in patients with severe COPD. NEW & NOTEWORTHY In myotubes of cachectic chronic obstructive pulmonary disease (COPD) patients, cAMP signaling exerted beneficial effects by targeting muscle proteolysis and reducing gene expression of proteolytic markers of the ubiquitin-proteasome system and that of myostatin. In myotubes of patients and controls, roflumilast also favored antioxidant defense through upregulation of the nuclear factor (erythroid-derived 2)-like 2 pathway, of sirtuin-1, and of gene expression of slow- and fast-twitch isoforms. These findings have potential clinical implications for the treatment of muscle wasting in patients with COPD and cachexia.

Molecular modeling of Gly80 and Ser80 variants of human group IID phospholipase A2 and their receptor complexes: potential basis for weight loss in chronic obstructive pulmonary disease.

Weight loss is a well known systemic manifestation of chronic obstructive pulmonary disease (COPD). A Gly80Ser mutation on human group IID secretory phospholipase A2 (sPLA2) enhances expression of the cytokines that are responsible for weight loss. In this study, we seek to establish a structural correlation of wild type sPLA2 and the Gly80Ser mutation with function. sPLA2 with glycine and serine at the 80th positions and the M-type receptor were modelled. The enzymes were docked to the receptor and molecular dynamics was carried out to 70ns. Structural analysis revealed the enzymes to comprise three helices (H1-H3), two short helices (SH1 and SH2), and five loops including a calcium binding loop (L1-L5), and to be stabilized by seven disulfide bonds. The overall backbone folds of the two models are very similar, with main chain RMSD of less than 1Å. The active site within the substrate binding channel shows a catalytic triad of water-His67-Asp112, showing a hydrogen bonded network. Major structural differences between wild type and mutant enzymes were observed locally at the site of the mutation and in their global conformations. These differences include: (1) loop-L3 between H2 and H3, which bears residue Gly80 in the wild type, is in a closed conformation with respect to the channel opening, while in the mutant enzyme it adopts a relatively open conformation; (2) the mutant enzyme is less compact and has higher solvent accessible surface area; and (3) interfacial binding contact surface area is greater, and the quality of interactions with the receptor is better in the mutant enzyme as compared to the wild type. Therefore, the structural differences delineated in this study are potential biophysical factors that could determine the increased potency of the mutant enzyme with macrophage receptor for cytokine secreting function, resulting in exacerbation of cachexia in COPD.

Effect of Megestrol Acetate and Testosterone on Body Composition and Hormonal Responses in COPD Cachexia.

Background: Underweight chronic obstructive pulmonary disease (COPD) patients with involuntary weight loss have a poor prognosis; no effective therapy is currently available. We conducted the first clinical trial seeking to determine whether combination therapy with an appetite stimulant and an anabolic steroid would have beneficial effects on body composition for patients with COPD cachexia. Methods: We conducted a 12-week pilot study in which 4 men and 5 women (age 64±10 y, forced expiratory volume in 1 second [FEV1] 31±9 %pred., body mass index [BMI] 18±3 kg/m2) with low-normal testosterone levels (average 532±45ng/dl in men and 12.4±5.3ng/dl in women) and weight loss ≥10 lbs over the previous year were treated with oral megestrol acetate 800mg/day plus weekly testosterone enanthate injections, initially 125 mg in men and 40 mg in women, with doses subsequently adjusted targeting circulating nadir testosterone levels of 850 and 300 ng/dl, respectively. Results: On treatment, nadir testosterone level increases averaged 160±250 ng/dl (NS) in men and 322±49 (p<0.001) ng/dl in women. Body weight increased in all individuals, with average end-intervention weight gain of 3.1±2.2 kg (p<0.005). Two women and 2 men had COPD exacerbations and did not complete the 12-week study. In the 5 individuals who completed, dual energy x ray absorptiometry (DEXA) scans revealed an average 2.0±1.5 kg lean mass and 2.3±1.7 kg fat mass increase (each p<0.05). No adverse effects of treatment were detected. Conclusions: Combination therapy reversed the trajectory of involuntary weight loss and increased lean mass in cachectic COPD patients. Though the interventions were apparently well tolerated, participant drop-out rate was high. Larger randomized placebo-controlled long-term studies with functional outcomes are needed.

Cachexia as a major underestimated and unmet medical need: facts and numbers

Cachexia is a serious, however underestimated and underrecognised medical consequence of malignant cancer, chronic heart failure (CHF), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), cystic fibrosis, rheumatoid arthritis, Alzheimer's disease, infectious diseases, and many other chronic illnesses. The prevalence of cachexia is high, ranging from 5% to 15% in CHF or COPD to 60% to 80% in advanced cancer. By population prevalence, the most frequent cachexia subtypes are in order: COPD cachexia, cardiac cachexia (in CHF), cancer cachexia, and CKD cachexia. In industrialized countries (North America, Europe, Japan), the overall prevalence of cachexia (due to any disease) is growing and currently about 1%, i.e., about nine million patients. The relative prevalence of cachexia is somewhat less in Asia, but is a growing problem there as well. In absolute terms, cachexia is, in Asia (due to the larger population), as least as big a problem as in the Western world. Cachexia is also a big medical problem in South America and Africa, but data are scarce. A consensus statement recently proposed to diagnose cachexia in chronic diseases when there is weight loss exceeding 5% within the previous 3–12 months combined with symptoms characteristic for cachexia (e.g., fatigue), loss of skeletal muscle and biochemical abnormalities (e.g., anemia or inflammation). Treatment approaches using anabolics, anti-catabolic therapies, appetite stimulants, and nutritional interventions are under development. A more thorough understanding of the pathophysiology of cachexia development and progression is needed that likely will lead to combination therapies being developed. These efforts are greatly needed as presence of cachexia is always associated with high-mortality and poor-symptom status and dismal quality of life. It is thought that in cancer, more than 30% of patients die due to cachexia and more than 50% of patients with cancer die with cachexia being present. In other chronic illnesses, one can estimate that up to 30% of patients die with some degree of cachexia being present. Mortality rates of patients with cachexia range from 10% to 15% per year (COPD), to 20% to 30% per year (CHF, CKD) to 80% in cancer.

The pathophysiology of cachexia in chronic obstructive pulmonary disease

The focus of this review is on translation of putative mechanisms of altered energy metabolism and muscle maintenance in cachexia to clinical comparative and intervention studies on chronic obstructive pulmonary disease (COPD). Pulmonary cachexia is a well recognized feature of COPD, but its cause is poorly understood. Recent studies have shed new light on the molecular mechanisms that underlie cachexia in this disorder. In addition to muscle wasting, COPD patients also suffer from so-called loss of peripheral 'muscle oxidative phenotype', rendering these muscles less energy efficient and more prone to oxidative stress, which may in turn augment loss of muscle mass. Recent translational approaches have clearly advanced our understanding of the pathophysiology of cachexia in COPD. Although this complex clinical syndrome may clearly benefit from multidimensional interventions, for a tailored therapeutic approach based on distinct wasting and pulmonary phenotypes, more mechanistic knowledge on abnormal regulation of energy balance and muscle maintenance in COPD cachexia is needed.

Possible mechanisms underlying the development of cachexia in COPD

About 25% of patients with chronic obstructive pulmonary disease (COPD) will develop cachexia (fat-free body mass index <17 kg.m(-2) (males) or <14 kg.m(-2) (females)). This is associated with approximately 50% reduction in median survival. The pathogenetic mechanism has been variously suggested to result from the following: 1) energy imbalance; 2) disuse atrophy; 3) tissue hypoxia from arterial hypoxaemia; 4) systemic inflammation; and 5) anabolic hormonal insufficiency. Genetic polymorphisms implicate inflammatory cytokines, especially interleukin (IL)-1beta, but IL-6 and tumour necrosis factor (TNF)-alpha do not show polymorphisms in these patients. Early reports of elevated TNF-alpha levels suggested a role for inflammation, but recent studies have not shown elevated levels of either IL-6 or TNF-alpha. Therapeutic trials of nutritional support, hormonal supplementation, anti-TNF-alpha immunotherapy, ghrelin and antioxidants have been conducted, but only a few have shown any benefits in muscle structure and function. Considerably more mechanistic knowledge is needed before therapeutic recommendations can be made. At this time, it is not possible to attribute cachexia in COPD unequivocally to inflammation or any other cause, and much more research is needed. To date, studies have been predominantly cross-sectional, with measurements made only after cachexia has developed. Future research should target prospective observation, studying patients as cachexia progresses, since once cachexia is established, inflammatory cytokine levels may not be abnormal.

Nutritional and metabolic modulation in chronic obstructive pulmonary disease management.

In this paper the perspective for nutritional modulation of systemic impairment in patients with chronic obstructive pulmonary disease (COPD) is discussed. Progressive weight loss is characterised by disease-specific elevated energy requirements unbalanced by dietary intake. Weight gain per se can be achieved by caloric supplementation while future studies may prove efficacy of amino acid modulation to stimulate protein synthesis and enhance muscle anabolism. Disproportionate muscle wasting resembles the cachexia syndrome as described in other chronic wasting diseases (cancer, chronic heart failure, acquired immunodeficiency syndrome (AIDS)). There is yet no adequate nutritional strategy available to treat cachexia in COPD. Muscle substrate metabolism has hardly been investigated, but the few data available point towards a decreased fat oxidative capacity that may show similarities with the "metabolic syndrome" as described in type II diabetes and obesity and could theoretically benefit from polyunsaturated fatty acid modulation. To adequately target the different therapeutic options, clearly more clinical (intervention) studies are needed in chronic obstructive pulmonary disease patients that are adequately characterised by local and systemic impairment and in which molecular and metabolic markers are linked to functional outcome.