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 (FEVi: 53 +/- 15% predicted; age: 67 +/- 9 years and BMI: 24.5 +/- 3.3 kg/m(2)) 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-1 alpha 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. (C) 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved

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

Pulmonary inflammation-induced loss and subsequent recovery of skeletal muscle mass require functional poly-ubiquitin conjugation

Abstract Background Pulmonary inflammation in response to respiratory infections can evoke muscle wasting. Increased activity of the ubiquitin (Ub)-proteasome system (UPS) and the autophagy lysosome pathway (ALP) have been implicated in inflammation-induced muscle atrophy. Since poly-Ub conjugation is required for UPS-mediated proteolysis and has been implicated in the ALP, we assessed the effect of impaired ubiquitin conjugation on muscle atrophy and recovery following pulmonary inflammation, and compared activation and suppression of these proteolytic systems to protein synthesis regulation. Methods Pulmonary inflammation was induced in mice by an intratracheal instillation of LPS. Proteolysis (UPS and ALP) and synthesis signaling were examined in gastrocnemius muscle homogenates. Ub-conjugation-dependency of muscle atrophy and recovery was addressed using Ub-K48R (K48R) mice with attenuated poly-ubiquitin conjugation, and compared to UBWT control mice. Results Pulmonary inflammation caused a decrease in skeletal muscle mass which was accompanied by a rapid increase in expression of UPS and ALP constituents and reduction in protein synthesis signaling acutely after LPS. Muscle atrophy was attenuated in K48R mice, while ALP and protein synthesis signaling were not affected. Muscle mass recovery starting 72 h post LPS, correlated with reduced expression of UPS and ALP constituents and restoration of protein synthesis signaling. K48R mice however displayed impaired recovery of muscle mass. Conclusion Pulmonary inflammation-induced muscle atrophy is in part attributable to UPS-mediated proteolysis, as activation of ALP- and suppression of protein synthesis signaling occur independently of poly-Ub conjugation during muscle atrophy. Recovery of muscle mass following pulmonary inflammation involves inverse regulation of proteolysis and protein synthesis signaling, and requires a functional poly-Ub conjugation

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