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

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

Sex Differences in the Brain: A Whole Body Perspective

Most writing on sexual differentiation of the mammalian brain (including our own) considers just two organs: the gonads and the brain. This perspective, which leaves out all other body parts, misleads us in several ways. First, there is accumulating evidence that all organs are sexually differentiated, and that sex differences in peripheral organs affect the brain. We demonstrate this by reviewing examples involving sex differences in muscles, adipose tissue, the liver, immune system, gut, kidneys, bladder, and placenta that affect the nervous system and behavior. The second consequence of ignoring other organs when considering neural sex differences is that we are likely to miss the fact that some brain sex differences develop to compensate for differences in the internal environment (i.e., because male and female brains operate in different bodies, sex differences are required to make output/function more similar in the two sexes). We also consider evidence that sex differences in sensory systems cause male and female brains to perceive different information about the world; the two sexes are also perceived by the world differently and therefore exposed to differences in experience via treatment by others. Although the topic of sex differences in the brain is often seen as much more emotionally charged than studies of sex differences in other organs, the dichotomy is largely false. By putting the brain firmly back in the body, sex differences in the brain are predictable and can be more completely understood

Biobanking in Molecular Biomarker Research for the Early Detection of Cancer

Although population-wide screening programs for several cancer types have been implemented in multiple countries, screening procedures are invasive, time-consuming and often perceived as a burden for patients. Molecular biomarkers measurable in non-invasively collected samples (liquid biopsies) could facilitate screening, as they could have incremental value on early diagnosis of cancer, but could also predict prognosis or monitor treatment response. Although the shift towards biomarkers from liquid biopsies for early cancer detection was initiated some time ago, there are many challenges that hamper the development of such biomarkers. One of these challenges is large-scale validation that requires large prospectively collected biobanks with liquid biopsies. Establishing those biobanks involves several considerations, such as standardization of sample collection, processing and storage within and between biobanks. In this perspective, we will elaborate on several issues that need to be contemplated in biobanking, both in general and for certain specimen types specifically, to be able to facilitate biomarker validation for early detection of cancer

A novel in vitro model for the assessment of postnatal myonuclear accretion

Background: Due to the post-mitotic nature of myonuclei, postnatal myogenesis is essential for skeletal muscle growth, repair, and regeneration. This process is facilitated by satellite cells through proliferation, differentiation, and subsequent fusion with a pre-existing muscle fiber (i.e., myonuclear accretion). Current knowledge of myogenesis is primarily based on the in vitro formation of syncytia from myoblasts, which represents aspects of developmental myogenesis, but may incompletely portray postnatal myogenesis. Therefore, we aimed to develop an in vitro model that better reflects postnatal myogenesis, to study the cell intrinsic and extrinsic processes and signaling involved in the regulation of postnatal myogenesis. Methods: Proliferating C2C12 myoblasts were trypsinized and co-cultured for 3 days with 5 days differentiated C2C12 myotubes. Postnatal myonuclear accretion was visually assessed by live cell time-lapse imaging and cell tracing by cell labeling with Vybrant® DiD and DiO. Furthermore, a Cre/LoxP-based cell system was developed to semi-quantitatively assess in vitro postnatal myonuclear accretion by the conditional expression of luciferase upon myoblast–myotube fusion. Luciferase activity was assessed luminometrically and corrected for total protein content. Results: Live cell time-lapse imaging, staining-based cell tracing, and recombination-dependent luciferase activity, showed the occurrence of postnatal myonuclear accretion in vitro. Treatment of co-cultures with the myogenic factor IGF-I (p  <  0.001) and the cytokines IL-13 (p  <  0.05) and IL-4 (p  <  0.001) increased postnatal myonuclear accretion, while the myogenic inhibitors cytochalasin D (p  <  0.001), myostatin (p  <  0.05), and TNFα (p  <  0.001) decreased postnatal myonuclear accretion. Furthermore, postnatal myonuclear accretion was increased upon recovery from electrical pulse stimulation-induced fiber damage (p  <  0.001) and LY29004-induced atrophy (p  <  0.001). Moreover, cell type-specific siRNA-mediated knockdown of myomaker in myoblasts (p  <  0.001), but not in myotubes, decreased postnatal myonuclear accretion. Conclusions: We developed a physiologically relevant, sensitive, high-throughput cell system for semi-quantitative assessment of in vitro postnatal myonuclear accretion, which can be used to mimic physiological myogenesis triggers, and can distinguish the cell type-specific roles of signals and responses in the regulation of postnatal myogenesis. As such, this method is suitable for both basal and translational research on the regulation of postnatal myogenesis, and will improve our understanding of muscle pathologies that result from impaired satellite cell number or function

Distinct responses of protein turnover regulatory pathways in hypoxia- and semistarvation-induced muscle atrophy

The balance of muscle protein synthesis and degradation determines skeletal muscle mass. We hypothesized that hypoxia-induced muscle atrophy and alterations in the regulation of muscle protein turnover include a hypoxia-specific component, in addition to the observed effects of reduction in food intake in response to hypoxia. Mice were subjected to normoxic, hypoxic (8% oxygen), or pair-fed conditions for 2, 4, and 21 days. Cell-autonomous effects of hypoxia on skeletal muscle were also assessed in differentiated C2C12 myotubes. Hypoxia induced an initial rapid loss of body and muscle weight, which remained decreased during chronic hypoxia and could only in part be explained by the hypoxia-induced reduction of food intake (semistarvation). Regulatory steps of protein synthesis (unfolded protein response and mammal target of rapamycin signaling) remained active in response to acute and sustained hypoxia but not to semistarvation. Activation of regulatory signals for protein degradation, including increased expression of Murf1, Atrogin-1, Bnip3, and Map1lc3b mRNAs, was observed in response to acute hypoxia and to a lesser extent following semistarvation. Conversely, the sustained elevation of Atrogin-1, Bnip3, and Map1lc3b mRNAs and the increased activity of their upstream transcriptional regulator Forkhead box O1 were specific to chronic hypoxia because they were not observed in response to reduced food intake. In conclusion, altered regulation of protein turnover during hypoxia-induced muscle atrophy resulted from an interaction of semistarvation and a hypoxia-specific component. The finding that food restriction but not hypoxia-induced semistarvation inhibited regulatory steps in protein synthesis suggests a hypoxia-specific impairment of the coordination between protein-synthesis signaling and protein-degradation signaling in skeletal muscl

Additional file 2: Figure S1. of Differential regulation of muscle protein turnover in response to emphysema and acute pulmonary inflammation

Similar pulmonary inflammation in control and emphysematous mice following IT-LPS instillation. Mice were intra-tracheally instilled with elastase to induce emphysema or vc, followed by a single bolus of LPS or vc. Lungs were lavaged to obtain BALfluid (n = 11 or 12/group), and cells isolated from the BALf were used to produce conditioned medium. NF-κB luciferase activity was measured in lysates prepared from C2C12 myotubes after stimulation with conditioned medium. (TIF 774 kb

Differential regulation of muscle protein turnover in response to emphysema and acute pulmonary inflammation

Abstract Background Exacerbations in COPD are often accompanied by pulmonary and systemic inflammation, and associated with increased susceptibility to and prevalence of weight loss and muscle wasting. Muscle mass loss during disease exacerbations may contribute to emphysema-associated muscle atrophy. However, whether pulmonary inflammation in presence of emphysema differentially affects skeletal muscle, including protein synthesis and degradation signaling pathways has not previously been addressed. The aims of this study were to 1) develop a mouse model of disease exacerbation-associated muscle wasting, 2) evaluate whether emphysema and muscle wasting can be monitored non-invasively and 3) assess alterations in muscle protein turnover regulation. Methods Emphysema was induced by three, weekly intra-tracheal (IT) elastase (E) or vehicle control (vc) instillations, followed by one single IT-LPS bolus (L) or vc instillation to mimic pulmonary inflammation-driven disease exacerbation. Consequently, four experimental groups were defined: vc/vc (‘C’), E/vc (‘E’), vc/LPS (‘L’), E/LPS (‘E + L’). Using micro cone-beam CT-scans, emphysema development and muscle mass changes were monitored, and correlated to muscle weight 48 h after LPS instillation. Protein turnover signaling was assessed in muscle tissue collected 24 h post LPS instillation. Results Micro-CT imaging correlated strongly with established invasive measurements of emphysema and muscle atrophy. Pulmonary inflammation following LPS instillation developed irrespective of emphysema and body and muscle weight were similarly reduced in the ‘L’ and ‘E + L’ groups. Accordingly, mRNA and protein expression levels of genes of the ubiquitin-proteasome pathway (UPS) and the autophagy-lysosomal pathway (ALP) were upregulated in skeletal muscle following IT-LPS (‘L’ and ‘E + L’). In contrast, mTOR signaling, which controls ALP and protein synthesis, was reduced by pulmonary inflammation (‘L’ and ‘E + L’) as well as emphysema as a single insult (‘E’) compared to control. Conclusion Changes in lung tissue density and muscle mass can be monitored non-invasively to evaluate emphysema and muscle atrophy longitudinally. Acute loss of muscle mass evoked by pulmonary inflammation is similar in control and emphysematous mice. Although muscle atrophy cues in response to pulmonary inflammation are not altered by emphysema, emphysema itself affects protein synthesis and ALP signaling, which may interfere with muscle mass recovery and impair maintenance of muscle mass in emphysema