K. van Norren

Dietary supplementation with a specific combination of high protein, leucine, and fish oil improves muscle function and daily activity in tumour-bearing cachectic mice

Cancer cachexia is characterised by metabolic alterations leading to loss of adipose tissue and lean body mass and directly compromises physical performance and the quality of life of cancer patients. In a murine cancer cachectic model, the effects of dietary supplementation with a specific combination of high protein, leucine and fish oil on weight loss, muscle function and physical activity were investigated. Male CD2F1 mice, 6–7 weeks old, were divided into body weight-matched groups: (1) control, (2) tumour-bearing, and (3) tumour-bearing receiving experimental diets. Tumours were induced by s.c. inoculation with murine colon adenocarcinoma (C26) cells. Food intake, body mass, tumour size and 24 h-activity were monitored. Then, 20 days after tumour/vehicle inoculation, the animals were killed and muscle function was tested ex vivo. Tumour-bearing mice showed reduced carcass, muscle and fat mass compared with controls. EDL muscle performance and total daily activity were impaired in the tumour-bearing mice. Addition of single nutrients resulted in no or modest effects. However, supplementation of the diet with the all-in combination of high protein, leucine and fish oil significantly reduced loss of carcass, muscle and fat mass (loss in mass 45, 52 and 65% of TB-con, respectively (P<0.02)) and improved muscle performance (loss of max force reduced to 55–64% of TB-con (P<0.05)). Moreover, total daily activity normalised after intervention with the specific nutritional combination (50% of the reduction in activity of TB-con (P<0.05)). In conclusion, a nutritional combination of high protein, leucine and fish oil reduced cachectic symptoms and improved functional performance in cancer cachectic mice. Comparison of the nutritional combination with its individual modules revealed additive effects of the single components provided.

Direct effects of doxorubicin on skeletal muscle contribute to fatigue.

Chemotherapy-induced fatigue is a multidimensional symptom. Oxidative stress has been proposed as a working mechanism for anthracycline-induced cardiotoxicity. In this study, doxorubicin (DOX) was tested on skeletal muscle function. Doxorubicin induced impaired ex vivo skeletal muscle relaxation followed in time by contraction impediment, which could be explained by DOX-induced changes in Ca2+ responses of myotubes in vitro. The Ca2+ responses in skeletal muscle, however, could not be explained by oxidative stress.

Altered host-microbe interaction in HIV: a target for intervention with pro- and prebiotics.

The intestinal immune system is severely affected by HIV and circulating microbial products from the intestinal tract that provide an ongoing source of systemic inflammation and concomitant viral replication. In addition, HIV-infected individuals can have a deregulated immune response that may hamper the anti-viral capacity of the host. Various probiotic organisms and prebiotic agents have been shown to enhance intestinal epithelial barrier functions, reduce inflammation, and support effective Th-1 responses. As these characteristics may benefit HIV patients, this review aims to provide a theoretical framework for the development of probiotic and prebiotic interventions specifically for this population.

Beneficial immune modulatory effects of a specific nutritional combination in a murine model for cancer cachexia.

The majority of patients with advanced cancer are recognised by impaired immune competence influenced by several factors, including the type and stage of the tumour and the presence of cachexia. Recently, a specific nutritional combination containing fish oil, specific oligosaccharide mixture, high protein content and leucine has been developed aimed to support the immune system of cancer patients in order to reduce the frequency and severity of (infectious) complications. In a recently modified animal model cachexia is induced by inoculation of C26 tumour cells in mice. In a pre-cachectic state, no effect was observed on contact hypersensitivity, a validated in vivo method to measure Th1-mediated immune function, after adding the individual nutritional ingredients to the diet of tumour-bearing mice. However, the complete mixture resulted in significantly improved Th1 immunity. Moreover, in a cachectic state, the complete mixture reduced plasma levels of pro-inflammatory cytokines and beneficially affected ex vivo immune function. Accordingly, the combination of the nutritional ingredients is required to obtain a synergistic effect, leading to a reduced inflammatory state and improved immune competence. From this, it can be concluded that the specific nutritional combination has potential as immune-supporting nutritional intervention to reduce the risk of (infectious) complications in cancer patients.

Dose-dependent effects of leucine supplementation on preservation of muscle mass in cancer cachectic mice

Cancer cachexia, which is characterized by muscle wasting, is associated with increased morbidity and mortality. Because muscle protein synthesis may be increased and protein breakdown reduced by leucine supplementation, we used the C26 tumor-bearing cachectic mouse model to assess the effects of dietary supplementation with leucine on muscle weight and the markers of muscle protein breakdown (mRNA of atrogin and murf). Male CD2F1 mice were subcutaneously inoculated with tumor cells (tumor-bearing mice; TB) or were sham injected (control; C). They were fed standard diets or diets supplemented with leucine [1 gr (TB1Leu) or 8 gr (TB8Leu) supplemented leucine per kg feed]; TB and C received 8.7% Leu/g protein, TB1Leu received 9.6% Leu/g protein and TB8Leu received 14.6 Leu/g protein. After 21 days, the following were determined: body weights, plasma amino-acid concentrations, tumor size and muscle mass of the gastrocnemius (mG), tibialis anterior (mTA), extensor digitorum longus (mEDL) and soleus (mS) muscles. In tumor-bearing (TB) mice, carcass and skeletal muscle masses decreased, and levels of atrogin and murf mRNA in the mEDL increased. Muscle-mass loss was counteracted dose-dependently by leucine supplementation: relative to TB, the mass of the mG was +23% in TB8Leu, and +22% in mTA (p<0.05). However, leucine supplementation did not change atrogin and murf mRNA levels. Total plasma amino acid concentrations increased in TB, especially for taurine, lysine, arginine and alanine (p<0.05). Leucine supplementation attenuated the increase in total plasma amino-acid concentrations (p<0.05). Irrespective of changes in muscle protein breakdown markers, leucine supplementation reduced muscle wasting in tumor-bearing cachectic mice and attenuated changes in plasma amino acids.

Review article: the role of gastrointestinal hormones in the treatment of delayed gastric emptying in critically ill patients.

Delayed gastric emptying limits the administration of enteral nutrition, leading to malnutrition, which is associated with higher mortality and morbidity. Currently available prokinetics have limitations in terms of sustained efficacy and side effects.

Hypothalamic inflammation and food intake regulation during chronic illness.

Anorexia is a common symptom in chronic illness. It contributes to malnutrition and strongly affects survival and quality of life. A common denominator of many chronic diseases is an elevated inflammatory status, which is considered to play a pivotal role in the failure of food-intake regulating systems in the hypothalamus. In this review, we summarize findings on the role of hypothalamic inflammation on food intake regulation involving hypothalamic neuropeptide Y (NPY) and pro-opiomelanocortin (POMC). Furthermore, we outline the role of serotonin in the inability of these peptide based food-intake regulating systems to respond and adapt to changes in energy metabolism during chronic disease.

Increased hypothalamic serotonin turnover in inflammation-induced anorexia

BackgroundAnorexia can occur as a serious complication of disease. Increasing evidence suggests that inflammation plays a major role, along with a hypothalamic dysregulation characterized by locally elevated serotonin levels. The present study was undertaken to further explore the connections between peripheral inflammation, anorexia and hypothalamic serotonin metabolism and signaling pathways. First, we investigated the response of two hypothalamic neuronal cell lines to TNFα, IL-6 and LPS. Next, we studied transcriptomic changes and serotonergic activity in the hypothalamus of mice after intraperitoneal injection with TNFα, IL-6 or a combination of TNFα and IL-6.ResultsIn vitro, we showed that hypothalamic neurons responded to inflammatory mediators by releasing cytokines. This inflammatory response was associated with an increased serotonin release. Mice injected with TNFα and IL-6 showed decreased food intake, associated with altered expression of inflammation-related genes in the hypothalamus. In addition, hypothalamic serotonin turnover showed to be elevated in treated mice.ConclusionsOverall, our results underline that peripheral inflammation reaches the hypothalamus where it affects hypothalamic serotoninergic metabolism. These hypothalamic changes in serotonin pathways are associated with decreased food intake, providing evidence for a role of serotonin in inflammation-induced anorexia.

A fast and accurate method to measure both oxidative stress and vitality in a single organ slice.

Increased oxidative stress does not necessarily cause an organ to suffer from oxidative damage, since antioxidant systems to protect organs are present. However, when a decrease in the vitality of an organ coincides with an increase in oxidative stress, increased oxidative damage is likely. A sequential method for the measurement of both energy status and oxidative stress in the same sample has been developed. The novelty of this method lies in the combination of efficiency and accuracy. Nucleotides and malondialdehyde (MDA) of 80 different samples can be released in a perchloric environment with ultrasonic treatment instead of homogenization. Malondialdehyde concentration can be measured after complexing with 2,4-dinitrophenylhydrazine without any homogenization, solvent phase extraction, and centrifugation steps. Yields of both malondialdehyde and nucleotides were similar to those of the homogenization procedure. Detection limit was 141 fmol for MDA and 22.5 pmol for the nucleotides. Furthermore, the stability of the malondialdehyde-2,4-dinitrophenylhydrazine complex after 3 weeks at -20 degrees C is excellent 99.7% (+/-5.6). Nucleotides are stable for the same time period. Spiking of samples with MDA and nucleotides showed good recoveries (102.5% (+/-5.0) and 99.8% (+/-7.9), respectively). The present data show an accurate method to measure both the energy status and the oxidative stress in a single organ slice with a minimum of effort and time.

OP026: Intensive Exercise Hampers the Postprandial Citrulline Bioavailability Following Casein Bolus Feeding

Rationale: Metabolic stress like surgery and intensive exercise have been reported to increase intestinal permeability. It is not known whether intensive exercise also influences gut metabolic functioning. The effects of intensive exercise on intestinal permeability, postprandial amino acid (AA) bioavailability and intestinal enterocyte metabolic mass were determined in the human intervention study Protege.