CT Scan-Derived Muscle, But Not Fat, Area Independently Predicts Mortality in COVID-19.

BACKGROUND: COVID-19 has demonstrated a highly variable disease course, from asymptomatic to severe illness and eventually death. Clinical parameters, as included in the 4C Mortality Score, can predict mortality accurately in COVID-19. Additionally, CT scan-derived low muscle and high adipose tissue cross-sectional areas (CSAs) have been associated with adverse outcomes in COVID-19. RESEARCH QUESTION: Are CT scan-derived muscle and adipose tissue CSAs associated with 30-day in-hospital mortality in COVID-19, independent of 4C Mortality Score? STUDY DESIGN AND METHODS: This was a retrospective cohort analysis of patients with COVID-19 seeking treatment at the ED of two participating hospitals during the first wave of the pandemic. Skeletal muscle and adipose tissue CSAs were collected from routine chest CT-scans at admission. Pectoralis muscle CSA was demarcated manually at the fourth thoracic vertebra, and skeletal muscle and adipose tissue CSA was demarcated at the first lumbar vertebra level. Outcome measures and 4C Mortality Score items were retrieved from medical records. RESULTS: Data from 578 patients were analyzed (64.6% men; mean age, 67.7 ± 13.5 years; 18.2% 30-day in-hospital mortality). Patients who died within 30 days demonstrated lower pectoralis CSA (median, 32.6 [interquartile range (IQR), 24.3-38.8] vs 35.4 [IQR, 27.2-44.2]; P = .002) than survivors, whereas visceral adipose tissue CSA was higher (median, 151.1 [IQR, 93.6-219.7] vs 112.9 [IQR, 63.7-174.1]; P = .013). In multivariate analyses, low pectoralis muscle CSA remained associated with 30-day in-hospital mortality when adjusted for 4C Mortality Score (hazard ratio, 0.98; 95% CI, 0.96-1.00; P = .038). INTERPRETATION: CT scan-derived low pectoralis muscle CSA is associated significantly with higher 30-day in-hospital mortality in patients with COVID-19 independently of the 4C Mortality Score.

Effects of a nutritional intervention on impaired behavior and cognitive function in an emphysematous murine model of COPD with endotoxin-induced lung inflammation.

One cluster of the extrapulmonary manifestations in chronic obstructive pulmonary disease (COPD) is related to the brain, which includes anxiety, depression and cognitive impairment. Brain-related comorbidities are related to worsening of symptoms and increased mortality in COPD patients. In this study, a murine model of COPD was used to examine the effects of emphysema and repetitive pulmonary inflammatory events on systemic inflammatory outcomes and brain function. In addition, the effect of a dietary intervention on brain-related parameters was assessed. Adult male C57Bl/6J mice were exposed to elastase or vehicle intratracheally (i.t.) once a week on three consecutive weeks. Two weeks after the final administration, mice were i.t. exposed to lipopolysaccharide (LPS) or vehicle for three times with a 10 day interval. A dietary intervention enriched with omega-3 PUFAs, prebiotic fibers, tryptophan and vitamin D was administered from the first LPS exposure onward. Behavior and cognitive function, the degree of emphysema and both pulmonary and systemic inflammation as well as blood-brain barrier (BBB) integrity and neuroinflammation in the brain were assessed. A lower score in the cognitive test was observed in elastase-exposed mice. Mice exposed to elastase plus LPS showed less locomotion in the behavior test. The enriched diet seemed to reduce anxiety-like behavior over time and cognitive impairments associated with the presented COPD model, without affecting locomotion. In addition, the enriched diet restored the disbalance in splenic T-helper 1 (Th1) and Th2 cells. There was a trend toward recovering elastase plus LPS-induced decreased expression of occludin in brain microvessels, a measure of BBB integrity, as well as improving expression levels of kynurenine pathway markers in the brain by the enriched diet. The findings of this study demonstrate brain-associated comorbidities - including cognitive and behavioral impairments - in this murine model for COPD. Although no changes in lung parameters were observed, exposure to the specific enriched diet in this model appeared to improve systemic immune disbalance, BBB integrity and derailed kynurenine pathway which may lead to reduction of anxiety-like behavior and improved cognition.

Effects of Cigarette Smoke on Adipose and Skeletal Muscle Tissue: In Vivo and In Vitro Studies.

Chronic obstructive pulmonary disease (COPD), often caused by smoking, is a chronic lung disease with systemic manifestations including metabolic comorbidities. This study investigates adaptive and pathological alterations in adipose and skeletal muscle tissue following cigarette smoke exposure using in vivo and in vitro models. Mice were exposed to cigarette smoke or air for 72 days and the pre-adipose cell line 3T3-L1 was utilized as an in vitro model. Cigarette smoke exposure decreased body weight, and the proportional loss in fat mass was more pronounced than the lean mass loss. Cigarette smoke exposure reduced adipocyte size and increased adipocyte numbers. Adipose macrophage numbers and associated cytokine levels, including interleukin-1ß, interleukine-6 and tumor necrosis factor-α were elevated in smoke-exposed mice. Muscle strength and protein synthesis signaling were decreased after smoke exposure; however, muscle mass was not changed. In vitro studies demonstrated that lipolysis and fatty acid oxidation were upregulated in cigarette smoke-exposed pre-adipocytes. In conclusion, cigarette smoke exposure induces a loss of whole-body fat mass and adipose atrophy, which is likely due to enhanced lipolysis.

Effect of targeted nutrient supplementation on physical activity and health-related quality of life in COPD: study protocol for the randomised controlled NUTRECOVER trial.

INTRODUCTION: Physical and mental health are often affected in chronic obstructive pulmonary disease (COPD) adversely affecting disease course and quality of life. Abnormalities in whole body and cellular energy metabolism, dietary and plasma nutrient status and intestinal permeability have been well established in these patients as systemic determinants of functional decline and underexplored treatable traits. The aim of this study is to investigate the efficacy of 1 year targeted nutrient supplementation on physical activity level and health-related quality of life in patients with COPD. METHODS AND ANALYSIS: This study is a single-centre randomised, placebo-controlled, double-blind trial in 166 patients with COPD recruited from multiple hospitals in the Netherlands. The intervention group will receive a multinutrient supplement, including vitamin D, tryptophan, long-chain polyunsaturated fatty acids and prebiotic dietary fibres as main components (94 kCal per daily dose). The control group will receive an isocaloric isonitrogenous placebo. Both groups will ingest one portion per day for at least 12 months and will additionally receive counselling on healthy lifestyle and medical adherence over the course of the study. Coprimary outcomes are physical activity assessed by triaxial accelerometry and health-related quality of life measured by the EuroQol-5 dimensions questionnaire. Secondary outcomes are cognitive function, psychological well-being, physical performance, patient-reported outcomes and the metabolic profile assessed by body composition, systemic inflammation, plasma nutrient levels, intestinal integrity and microbiome composition. Outcomes will be measured at baseline and after 12 months of supplementation. In case patients are hospitalised for a COPD exacerbation, a subset outcome panel will be measured during a 4-week recovery period after hospitalisation. ETHICS AND DISSEMINATION: This study was approved by the local Ethics Committee of Maastricht University. Subjects will be included after written informed consent is provided. Study outcomes will be disseminated through presentations at (inter)national conferences and through peer-reviewed journals. TRIAL REGISTRATION: NCT03807310.

Nutrition as a modifiable factor in the onset and progression of pulmonary function impairment in COPD: a systematic review.

CONTEXT: Chronic obstructive lung disease (COPD) is a progressive lung disease characterized by persistent airflow limitation. An increasing amount of evidence suggests an effect of dietary quality on the risk of COPD in the general population and pulmonary function decline in patients with COPD. OBJECTIVE: The association of dietary intake and nutrient status with COPD risk and onset, as well as pulmonary function decline (change in forced expiratory volume in 1 second, forced vital capacity, or the ratio of the former to the latter) in patients with COPD was investigated in this systematic review. DATA SOURCES: The PubMed database was searched by combining terms of pulmonary function or COPD with diet, nutrient status, or nutritional supplementation. DATA EXTRACTION: Original studies and systematic reviews and meta-analyses were included. Articles obtained were independently screened for relevance on the bases of title and abstract by 2 researchers. Eventually, 89 articles were included in the analysis. RESULTS: The unhealthy Western-style diet is associated with an increased risk of COPD and an accelerated decline of pulmonary function. Intake of fruit, vegetables, dietary fibers, vitamins C and E, polyphenols, and ß-carotene were individually associated with lower COPD risk, whereas consumption of processed meat was associated with higher COPD risk. Data on the effect of dietary quality on pulmonary function decline in patients with COPD are limited and inconsistent. Strong evidence for beneficial effects on pulmonary function decline was found only for vitamin D supplementation. CONCLUSION: Considering the increasing burden of COPD, more attention should be given to dietary quality as a modifiable factor in disease development and progression in patients with COPD. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42021240183.

Working memory training efficacy in COPD: the randomised, double-blind, placebo-controlled Cogtrain trial.

BACKGROUND: Cognitive impairment is highly prevalent in COPD and is associated with a sedentary lifestyle, unhealthy diet and increased cognitive stress susceptibility. Enhancement of cognitive performance by working memory training (WMT) may reverse these effects. Therefore, this study aimed to investigate the efficacy of WMT in COPD on cognitive performance, healthy lifestyle behaviours and cognitive stress susceptibility. METHODS: The double-blind randomised, placebo-controlled Cogtrain trial consisted of a 12-week training phase comprising 30 active or sham WMT sessions, followed by a second 12-week maintenance phase with 12 sessions. Measurements took place at baseline and after the first and second phases. The primary outcome was cognitive performance. Secondary outcomes were the recall of prespecified healthy lifestyle goals, physical capacity and activity, dietary quality and cognitive stress susceptibility. Motivation towards exercising and healthy eating and psychological wellbeing were exploratory outcomes. RESULTS: Sixty-four patients with moderate COPD (45% male, aged 66.2±7.2 years, median forced expiratory volume in 1 s 60.6% predicted) were randomised. WMT significantly increased patients' performance on the trained tasks in the first phase, which remained stable in the second phase. Of the 17 cognitive outcome measures, only one measure of memory improved after the first phase and one measure of reaction time after the second phase. This intervention did not influence physical capacity and activity, recall of prespecified healthy lifestyle goals, psychological wellbeing or cognitive stress susceptibility. CONCLUSION: WMT improved performance on the trained tasks but not overall cognitive performance, healthy lifestyle behaviours or cognitive stress susceptibility in patients with COPD.

Towards Personalized Management of Sarcopenia in COPD.

The awareness of the presence and consequences of sarcopenia has significantly increased over the past decade. Sarcopenia is defined as gradual loss of muscle mass and strength and ultimately loss of physical performance associated with aging and chronic disease. The prevalence of sarcopenia is higher in chronic obstructive pulmonary disease (COPD) compared to age-matched controls. Current literature suggests that next to physical inactivity, COPD-specific alterations in physiological processes contribute to accelerated development of sarcopenia. Sarcopenia in COPD can be assessed according to current guidelines, but during physical performance testing, ventilatory limitation should be considered. Treatment of muscle impairment can halt or even reverse sarcopenia, despite respiratory impairment. Exercise training and protein supplementation are currently at the basis of sarcopenia treatment. Furthermore, effective current and new interventions targeting the pulmonary system (eg, smoking cessation, bronchodilators and lung volume reduction surgery) may also facilitate muscle maintenance. Better understanding of disease-specific pathophysiological mechanisms involved in the accelerated development of sarcopenia in COPD will provide new leads to refine nutritional, exercise and physical activity interventions and develop pharmacological co-interventions.

Cognitive performance in relation to metabolic disturbances in patients with COPD.

BACKGROUND & AIMS: Cognitive impairment (CI) and metabolic abnormalities, including the metabolic syndrome (MetS) and sarcopenia, are more prevalent in COPD patients compared to controls without diagnosed lung disease. Because earlier studies have shown these metabolic abnormalities may affect cognitive performance, this study investigated whether cognitive performance is more impaired in subgroups of COPD patients with MetS or sarcopenia. METHODS: Cognitive performance patterns of 170 COPD patients referred for pulmonary rehabilitation (53.5% male, 63.4 ± 9.4 years, FEV1 54.5 ± 22.7% predicted) were compared between COPD subgroups stratified by presence of MetS and sarcopenia. Cognitive performance was assessed using a detailed neuropsychological test battery, which measured psychomotor speed (Stroop Color-Word Test, Concept Shifting Test, Letter-Digit Substitution Test), planning (Behavioral Assessment of the Dysexecutive Syndrome), working memory (Visual-Verbal Learning Test, Digit Span), verbal memory (Visual-Verbal Learning Test) and cognitive flexibility (Stroop Color-Word Test, Concept Shifting Test). MetS was determined according to the NCEP ATP-III criteria. Sarcopenia was determined based on decreased appendicular lean mass by dual-energy x-ray absorptiometry and impaired physical performance by 6-min walking distance. RESULTS: MetS was observed in 54.7% and sarcopenia in 30.0% of COPD patients. The prevalence of general CI was not different between patients with and without MetS (30.4% and 39.0%, respectively) or those with and without sarcopenia (34.0% and 34.5%, respectively, both p > 0.05). Domain-specific cognitive performance was not different between metabolic subgroups, but those with sarcopenia displayed a lower prevalence of CI on verbal memory than those without (21.7% and 29.7%, respectively, p = 0.011). Only the digit span (working memory) subtest was significantly different between metabolic subgroups, in favor of those without MetS (p = 0.017). CONCLUSION: Cognitive performance was not affected more in COPD patients with sarcopenia or MetS.

Role of acute exacerbations in skeletal muscle impairment in COPD.

Introduction: Muscle impairments are prevalent in COPD and have adverse clinical implications in terms of physical performance capacity, disease burden, quality of life and even mortality. During acute exacerbations of COPD (AECOPDs) the respiratory symptoms worsen and this might also apply to the muscle impairments. Areas covered: This report includes a review of both clinical and pre-clinical peer-reviewed literature of the past 20 years found in PubMed providing a comprehensive view on the role of AECOPD in muscle dysfunction in COPD, the putative underlying mechanisms and the treatment perspectives. Expert opinion: The contribution of AECOPD and its recurrent nature to muscle impairment in COPD cannot be ignored and can be attributed to the acutely intensifying and converging disease-related drivers of muscle deterioration, in particular disuse, systemic inflammation and corticosteroid treatment. The search for novel treatment options should focus on the AECOPD-enhanced drivers of muscle dysfunction as well as on the underlying, mainly catabolic, mechanisms. Considering the impact of AECOPD on muscle function, and that of muscle impairment on the recurrence of exacerbations, counteracting muscle deterioration in AECOPD provides an unprecedented therapeutic opportunity.

Iron deficiency-induced loss of skeletal muscle mitochondrial proteins and respiratory capacity; the role of mitophagy and secretion of mitochondria-containing vesicles.

Iron homeostasis is essential for mitochondrial function, and iron deficiency has been associated with skeletal muscle weakness and decreased exercise capacity in patients with different chronic disorders. We hypothesized that iron deficiency-induced loss of skeletal muscle mitochondria is caused by increased mitochondrial clearance. To study this, C2C12 myotubes were subjected to the iron chelator deferiprone. Mitochondrial parameters and key constituents of mitophagy pathways were studied in presence or absence of pharmacological autophagy inhibition or knockdown of mitophagy-related proteins. Furthermore, it was explored if mitochondria were present in extracellular vesicles (EV). Iron chelation resulted in an increase in BCL2/Adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and BNIP3-like gene and protein levels, and the appearance of mitochondria encapsulated by lysosome-like vesicular structures in myotubes. Moreover, mitochondria were secreted via EV. These changes were associated with cellular mitochondrial impairments. These impairments were unaltered by autophagy inhibition, knockdown of mitophagy-related proteins BNIP3 and BNIP3L, or knockdown of their upstream regulator hypoxia-inducible factor 1 alpha. In conclusion, mitophagy is not essential for development of iron deficiency-induced reductions in mitochondrial proteins or respiratory capacity. The secretion of mitochondria-containing EV could present an additional pathway via which mitochondria can be cleared from iron chelation-exposed myotubes.

Recovery of muscle mass and muscle oxidative phenotype following disuse does not require GSK-3 inactivation.

BACKGROUND: Physical inactivity contributes to muscle wasting and reductions in mitochondrial oxidative phenotype (OXPHEN), reducing physical performance and quality of life during aging and in chronic disease. Previously, it was shown that inactivation of glycogen synthase kinase (GSK)-3ß stimulates muscle protein accretion, myogenesis, and mitochondrial biogenesis. Additionally, GSK-3ß is inactivated during recovery of disuse-induced muscle atrophy. AIM: Therefore, we hypothesize that GSK-3 inhibition is required for reloading-induced recovery of skeletal muscle mass and OXPHEN. METHODS: Wild-type (WT) and whole-body constitutively active (C.A.) Ser21/9 GSK-3α/ß knock-in mice were subjected to a 14-day hind-limb suspension/14-day reloading protocol. Soleus muscle mass, fiber cross-sectional area (CSA), OXPHEN (abundance of sub-units of oxidative phosphorylation (OXPHOS) complexes and fiber-type composition), as well as expression levels of their main regulators (respectively protein synthesis/degradation, myogenesis and peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) signaling) were monitored. RESULTS: Subtle but consistent differences suggesting suppression of protein turnover signaling and decreased expression of several OXPHOS sub-units and PGC-1α signaling constituents were observed at baseline in C.A. GSK-3 versus WT mice. Although soleus mass recovery during reloading occurred more rapidly in C.A. GSK-3 mice, this was not accompanied by a parallel increased CSA. The OXPHEN response to reloading was not distinct between C.A. GSK-3 and WT mice. No consistent or significant differences in reloading-induced changes in the regulatory steps of protein turnover, myogenesis or muscle OXPHEN were observed in C.A. GSK-3 compared to WT muscle. CONCLUSION: This study indicates that GSK-3 inactivation is dispensable for reloading-induced recovery of muscle mass and OXPHEN.

Pulmonary inflammation-induced alterations in key regulators of mitophagy and mitochondrial biogenesis in murine skeletal muscle.

BACKGROUND: Both mitophagy, a selective mechanism for clearance of mitochondria, and mitochondrial biogenesis are key processes determining mitochondrial content and oxidative capacity of the musculature. Abnormalities in these processes could therefore contribute to deterioration of peripheral muscle oxidative capacity as observed in e.g. chronic obstructive pulmonary disease. Although it has been suggested that inflammatory mediators can modulate both mitophagy and mitochondrial biogenesis, it is unknown whether acute pulmonary inflammation affects these processes in oxidative and glycolytic skeletal muscle in vivo. Therefore, we hypothesised that molecular signalling patterns of mitochondrial breakdown and biogenesis temporally shift towards increased breakdown and decreased biogenesis in the skeletal muscle of mice exposed to one single bolus of IT-LPS, as a model for acute lung injury and pulmonary inflammation. METHODS: We investigated multiple important constituents and molecular regulators of mitochondrial breakdown, biogenesis, dynamics, and mitochondrial content in skeletal muscle over time in a murine (FVB/N background) model of acute pulmonary- and systemic inflammation induced by a single bolus of intra-tracheally (IT)-instilled lipopolysaccharide (LPS). Moreover, we compared the expression of these constituents between gastrocnemius and soleus muscle. RESULTS: Both in soleus and gastrocnemius muscle, IT-LPS instillation resulted in molecular patterns indicative of activation of mitophagy. This coincided with modulation of mRNA transcript abundance of genes involved in mitochondrial fusion and fission as well as an initial decrease and subsequent recovery of transcript levels of key proteins involved in the molecular regulation of mitochondrial biogenesis. Moreover, no solid differences in markers for mitochondrial content were found. CONCLUSIONS: These data suggest that one bolus of IT-LPS results in a temporal modulation of mitochondrial clearance and biogenesis in both oxidative and glycolytic skeletal muscle, which is insufficient to result in a reduction of mitochondrial content.

Resveratrol and metabolic health in COPD: A proof-of-concept randomized controlled trial.

BACKGROUND: Patients with COPD are often characterized by disturbed metabolic health which is reflected in altered body composition. Current studies in healthy subjects suggest that resveratrol improves metabolic health by enhancing muscle mitochondrial function and adipose tissue morphology. The primary objective was to investigate the effect of four weeks resveratrol supplementation on muscle mitochondrial function in patients with COPD. Secondary objectives were to investigate the effect of resveratrol on adipose tissue inflammatory and metabolic gene expression, systemic inflammation and body composition in patients with COPD. METHODS: In a double-blind randomized placebo-controlled proof-of-concept study, 21 COPD patients (FEV1: 53 ± 15% predicted; age: 67 ± 9 years and BMI: 24.5 ± 3.3 kg/m2) received resveratrol (150 mg/day) or placebo for four weeks. Before and after intervention, blood samples, quadriceps muscle and subcutaneous abdominal fat biopsies were obtained for metabolic and inflammatory profiling. Body composition was assessed by dual energy X-ray absorptiometry. RESULTS: Muscle mitochondrial biogenesis regulators AMPK, SIRT1 and PGC-1α as well as mitochondrial respiration, Oxphos complexes, oxidative enzyme activities and kynurenine aminotransferases were not improved by resveratrol. Plasma high-sensitive C-reactive protein and kynurenine did not change after resveratrol supplementation. Adipose tissue inflammatory markers were unaffected by resveratrol, while markers of glycolysis and lipolysis were significantly increased compared to placebo supplementation. Body weight decreased after resveratrol supplementation (resveratrol -0.95 ± 1.01 kg vs placebo -0.16 ± 0.66 kg, p = 0.049) due to a reduction in lean mass (resveratrol -1.79 ± 1.67 kg vs 0.37 ± 0.86 kg, p = 0.026). CONCLUSION: We do not confirm previously reported positive effects of resveratrol on skeletal muscle mitochondrial function in patients with COPD, but show an unexpected decline in lean mass. CLINICAL TRIAL REGISTRY: Clinicaltrials.gov NCT02245932.

Clinical outcome and cost-effectiveness of a 1-year nutritional intervention programme in COPD patients with low muscle mass: The randomized controlled NUTRAIN trial.

BACKGROUND AND AIMS: The efficacy of nutritional intervention to enhance short- and long-term outcomes of pulmonary rehabilitation in COPD is still unclear, hence this paper aims to investigate the clinical outcome and cost-effectiveness of a 12-month nutritional intervention strategy in muscle-wasted COPD patients. METHODS: Prior to a 4-month pulmonary rehabilitation programme, 81 muscle-wasted COPD patients (51% males, aged 62.5 ± 0.9 years) with moderate airflow obstruction (FEV1 55.1 ± 2.2% predicted) and impaired exercise capacity (Wmax 63.5 ± 2.4% predicted) were randomized to 3 portions of nutritional supplementation per day (enriched with leucine, vitamin D and polyunsaturated fatty acids) [NUTRITION] or PLACEBO (phase 1). In the unblinded 8-month maintenance phase (phase 2), both groups received structured feedback on their physical activity level assessed by accelerometry. NUTRITION additionally received 1 portion of supplemental nutrition per day and motivational interviewing-based nutritional counselling. A 3-month follow-up (phase 3) was included. RESULTS: After 12 months, physical capacity measured by quadriceps muscle strength and cycle endurance time were not different, but physical activity was higher in NUTRITION than in PLACEBO (Δ1030 steps/day, p = 0.025). Plasma levels of the enriched nutrients (p < 0.001) were higher in NUTRITION than PLACEBO. Trends towards weight gain in NUTRITION and weight loss in PLACEBO led to a significant between-group difference after 12 months (Δ1.54 kg, p = 0.041). The HADS anxiety and depression scores improved in NUTRITION only (Δ-1.92 points, p = 0.037). Generic quality of life (EQ-5D) was decreased in PLACEBO but not in NUTRITION (between-group difference after 15 months 0.072 points, p = 0.009). Overall motivation towards exercising and healthy eating was high and did not change significantly after 12 months; only amotivation towards healthy eating yielded a significant between-group difference (Δ1.022 points, p = 0.015). The cost per quality-adjusted life-year after 15 months was EUR 16,750. CONCLUSIONS: Nutritional intervention in muscle-wasted patients with moderate COPD does not enhance long-term outcome of exercise training on physical capacity but ameliorates plasma levels of the supplemented nutrients, total body weight, physical activity and generic health status, at an acceptable increase of costs for patients with high disease burden.

Skeletal muscle unloading results in increased mitophagy and decreased mitochondrial biogenesis regulation.

INTRODUCTION: Physical inactivity significantly contributes to loss of muscle mass and performance in bed-bound patients. Loss of skeletal muscle mitochondrial content has been well-established in muscle unloading models, but the underlying molecular mechanism remains unclear. We hypothesized that apparent unloading-induced loss of muscle mitochondrial content is preceded by increased mitophagy- and decreased mitochondrial biogenesis-signaling during the early stages of unloading. METHODS: We analyzed a comprehensive set of molecular markers involved in mitochondrial-autophagy, -biogenesis, -dynamics, and -content, in the gastrocnemius muscle of C57BL/6J mice subjected to 0- and 3-days hind limb suspension, and in biopsies from human vastus lateralis muscle obtained before and after 7 days of one-leg immobilization. RESULTS: In both mice and men, short-term skeletal muscle unloading results in molecular marker patterns indicative of increased receptor-mediated mitophagy and decreased mitochondrial biogenesis regulation, before apparent loss of mitochondrial content. DISCUSSION: These results emphasize the early-onset of skeletal muscle disuse-induced mitochondrial remodeling.

Impaired Skeletal Muscle Kynurenine Metabolism in Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND: Loss of peripheral muscle oxidative phenotype, cognitive impairment, and depression are well-recognized systemic manifestations of chronic obstructive pulmonary disease (COPD). Kynurenine (KYN), known to be associated with disturbed mental health, can be metabolized in muscle by kynurenine aminotransferases (KAT) 1-4. These KATs are regulated by peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1α (PGC1α). We hypothesize that impaired PGC1α signaling in COPD is associated with reduced muscle KAT expression and increased KYN plasma levels. METHODS: Retrospective collected and metabolically phenotyped muscle tissue and blood obtained from 29 well-characterized COPD patients and 15 healthy controls were analyzed. KYN was measured in plasma and KAT1-4 expression and major constituents of PGC1α signaling were assessed in quadriceps muscle biopsies. RESULTS: Circulating KYN levels were increased in COPD. Furthermore, both gene and protein expression levels of KAT4 were reduced in muscle tissue from COPD patients. Finally, in the whole group (even when controlled for airflow obstruction) and in each subgroup separately, KAT4 gene expression correlated significantly with constituents of the PGC1α signaling pathway. CONCLUSIONS: These data support our hypothesis that KYN plasma levels are elevated in COPD through impaired KYN clearance in muscle. Our findings show a pathway via which exercise training and/or nutritional modulation may improve physical and mental health in COPD patients.

Distinct skeletal muscle molecular responses to pulmonary rehabilitation in chronic obstructive pulmonary disease: a cluster analysis.

BACKGROUND: Pulmonary rehabilitation (PR) is a cornerstone in the management of chronic obstructive pulmonary disease (COPD), targeting skeletal muscle to improve functional performance. However, there is substantial inter-individual variability in the effect of PR on functional performance, which cannot be fully accounted for by generic phenotypic factors. We performed an unbiased integrative analysis of the skeletal muscle molecular responses to PR in COPD patients and comprehensively characterized their baseline pulmonary and physical function, body composition, blood profile, comorbidities, and medication use. METHODS: Musculus vastus lateralis biopsies were obtained from 51 COPD patients (age 64 ± 1 years, sex 73% men, FEV1 , 34 (26-41) %pred.) before and after 4 weeks high-intensity supervised in-patient PR. Muscle molecular markers were grouped by network-constrained clustering, and their relative changes in expression values-assessed by qPCR and western blot-were reduced to process scores by principal component analysis. Patients were subsequently clustered based on these process scores. Pre-PR and post-PR functional performance was assessed by incremental cycle ergometry and 6 min walking test (6MWT). RESULTS: Eight molecular processes were discerned by network-constrained hierarchical clustering of the skeletal muscle molecular rehabilitation responses. Based on the resulting process scores, four clusters of patients were identified by hierarchical cluster analysis. Two major patient clusters differed in PR-induced autophagy (P < 0.001), myogenesis (P = 0.014), glucocorticoid signalling (P < 0.001), and oxidative metabolism regulation (P < 0.001), with Cluster 1 (C1; n = 29) overall displaying a more pronounced change in marker expression than Cluster 2 (C2; n = 16). General baseline characteristics did not differ between clusters. Following PR, both 6 min walking distance (+26.5 ± 8.3 m, P = 0.003) and peak load on the cycle ergometer test (+9.7 ± 1.9 W, P < 0.001) were improved. However, the functional improvement was more pronounced in C1, as a higher percentage of patients exceeded the minimal clinically important difference in peak workload (61 vs. 21%, P = 0.022) and both peak workload and 6 min walking test (52 vs. 8%, P = 0.008) upon PR. CONCLUSIONS: We identified patient groups with distinct skeletal muscle molecular responses to rehabilitation, associated with differences in functional improvements upon PR.

Psychological co-morbidities in COPD: Targeting systemic inflammation, a benefit for both?

COPD is a chronic lung disease characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities. Furthermore, COPD is often characterized by extrapulmonary manifestations and comorbidities worsening COPD progression and quality of life. A neglected comorbidity in COPD management is mental health impairment defined by anxiety, depression and cognitive problems. This paper summarizes the evidence for impaired mental health in COPD and focuses on current pharmacological intervention strategies. In addition, possible mechanisms in impaired mental health in COPD are discussed with a central role for inflammation. Many comorbidities are associated with multi-organ-associated systemic inflammation in COPD. Considering the accumulative evidence for a major role of systemic inflammation in the development of neurological disorders, it can be hypothesized that COPD-associated systemic inflammation also affects the function of the brain and is an interesting therapeutic target for nutra- and pharmaceuticals.

Cognitive impairment in chronic obstructive pulmonary disease: disease burden, determinants and possible future interventions.

Introduction: Cognitive impairment (CI) is an important but an under-recognized extra-pulmonary feature of chronic obstructive pulmonary disease (COPD). It is related to the burden of disability, worse health outcomes, and impaired self-management. Areas covered: CI includes deterioration of a wide range of cognitive functions, such as memory and various executive functions. Risk of hospitalization might be higher in patients with COPD compared to those without, with CI negatively impacting the wellbeing of patients with COPD. Disease-specific factors such as hypoxemia and inflammation, lifestyle factors such as dietary insufficiencies and lack of physical activity, and comorbidities such as obstructive sleep apnea and depression are likely to synergistically contribute to the development of CI in COPD. Tailored interventions can possibly improve CI in COPD, but this needs further investigation. Expert commentary: Further research is warranted involving the optimization of neuropsychological testing for screening and outcome assessment, longitudinal studies to investigate the development of CI in COPD over time, and randomized clinical trials to test the feasibility and efficacy of promising interventions.

The effect of acute and 7-days dietary nitrate on mechanical efficiency, exercise performance and cardiac biomarkers in patients with chronic obstructive pulmonary disease.

BACKGROUND & AIMS: Many COPD patients have a reduced exercise capacity and mechanical efficiency and are at increased cardiometabolic risk. This study aimed to assess acute and 7-days effects of dietary nitrate on mechanical efficiency, exercise performance and cardiac biomarkers in patients with COPD. METHODS: This double-blind, randomized cross-over placebo controlled trial included 20 mild-to-moderate COPD patients (66.6 ± 7.5 years) with moderate exercise impairments and decreased mechanical efficiency, normal BMI (26 ± 3 kg/m2) but high prevalence of abdominal obesity (83.3%). Subjects were randomly allocated to the treatment order of 7 days sodium nitrate ingestion (∼8 mmol/day) and 7 days placebo (NaCl solution) or vice versa, separated by a washout period. Before (Day-1) and after (Day-7) both intervention periods resting metabolic rate and the metabolic response during submaximal cycle ergometry, cycling endurance time, plasma nitrate and nitrite levels, cardiac plasma biomarkers (e.g. cardiac troponin T, Nt-proBNP and creatinine kinase) and blood pressure were measured. Subsequently, gross, net and delta mechanical efficiency were calculated. RESULTS: Plasma nitrate and nitrite concentrations increased at Day-1 and Day-7 after sodium nitrate but not after placebo ingestion. Systolic and diastolic blood pressure did not change following nitrate ingestion. Furthermore, no differences were observed in gross, net, and delta mechanical efficiency during submaximal exercise, cycling endurance time and cardiac biomarkers between nitrate and placebo on Day-1 and Day-7. Meta-analysis of all available studies in COPD also showed no beneficial effect of beetroot juice on systolic and diastolic blood pressure. CONCLUSION: Acute as well as 7-days sodium nitrate supplementation does not modulate mechanical efficiency, blood pressure or cardiac biomarkers in mild-to-moderate COPD patients.