High anabolic potential of essential amino acid mixtures in advanced nonsmall cell lung cancer.

BACKGROUND: Conventional nutritional supplements are not or only partly successful in inducing protein accretion in advanced cancer, suggesting an attenuated anabolic response. To prevent muscle wasting and its deleterious consequences, generating an anabolic response is crucial. Dietary essential amino acids (EAA) have anabolic properties in other wasting diseases; however, data in advanced cancer are lacking. PATIENTS AND METHODS: In 13 patients with advanced nonsmall-cell lung cancer (NSCLC) (stage III and IV) and 11 healthy age-matched subjects, we measured protein synthesis and breakdown of the whole body, and net protein anabolism (difference between protein synthesis and breakdown) after intake of 14 g of free EAA with high leucine levels (EAA/leucine) versus a balanced amino acid mixture containing both EAA and non-EAA as present in whey protein, according to a randomized, double-blind, crossover design. RESULTS: Protein synthesis and net protein anabolism were higher after intake of the EAA/leucine than the balanced amino acid mixture (P < 0.001), independent of presence of cancer. A highly significant linear relationship between net protein anabolism and the amount of EAA available in the systemic circulation (R(2): 0.85, P < 0.001) was found in both groups. The presence of muscle or recent weight loss, systemic inflammatory response, or length of survival did not influence this relationship. High leucine levels in the EAA/leucine mixture was of no anabolic benefit. CONCLUSIONS: There is no anabolic resistance or attenuated anabolic potential to intake of 14 g of EAA/leucine or balanced amino acid mixture in advanced (mainly stage III) NSCLC. The high anabolic potential of dietary EAA in cancer patients is independent of their nutritional status, systemic inflammatory response or disease trajectory, suggesting a key role of EAA in new nutritional approaches to prevent muscle loss, thereby improving outcome of patients with advanced cancer. CLINICALTRAILSGOV: NCT01172314.

New stable isotope method to measure protein digestibility and response to pancreatic enzyme intake in cystic fibrosis.

BACKGROUND & AIMS: Adequate protein intake and digestion are necessary to prevent muscle wasting in cystic fibrosis (CF). Accurate and easy-to-use methodology to quantify protein maldigestion is lacking in CF. OBJECTIVE: To measure protein digestibility and the response to pancreatic enzyme intake in CF by using a new stable isotope methodology. DESIGN: In 19 CF and 8 healthy subjects, protein digestibility was quantified during continuous (sip) feeding for 6 h by adding (15)N-labeled spirulina protein and L-[ring-(2)H5]phenylalanine (PHE) to the nutrition and measuring plasma ratio [(15)N]PHE to [(2)H5]PHE. Pancreatic enzymes were ingested after 2 h in CF and the response in protein digestibility was assessed. To exclude difference in mucosal function, postabsorptive whole-body citrulline (CIT) production rate was measured by L-[5-(13)C-5,5-(2)H2]-CIT pulse and blood samples were taken to analyze tracer-tracee ratios. RESULTS: Protein digestibility was severely reduced in the CF group (47% of healthy subjects; P < 0.001). Intake of pancreatic enzymes induced a slow increase in protein digestibility in CF until 90% of values obtained by healthy subjects. Maximal digestibility was reached at 100 min and maintained for 80 min. Stratification into CF children (n = 10) and adults showed comparable values for protein digestibility and similar kinetic responses to pancreatic enzyme intake. Whole-body citrulline production was elevated in CF indicating preserved mucosal function. CONCLUSION: Protein digestibility is severely compromised in patients with CF as measured by this novel and easy-to-use stable isotope approach. Pancreatic enzymes are able to normalize protein digestibility in CF, albeit with a severe delay. Registration ClinicalTrials.gov = NCT01494909.

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.

Acute tryptophan and serotonin depletion using an optimized tryptophan-free protein-carbohydrate mixture in the adult rat.

In contrast to humans, a tryptophan (TRP)-free amino acid (AA) mixture only leads to moderate depletion in plasma TRP levels in adult rats. In this study we evaluated the effects of an acute administration of a TRP-free protein-carbohydrate nutritional mixture in adult male Wistar rats. Plasma amino acid levels were examined at 2 and 4h starting after the first administration. Furthermore, the concentrations of amino acid, serotonin (5-HT), dopamine (DA) and their metabolite (5-hydroxyindolacetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC), respectively) were measured within the striatum, hippocampus and cortex. In the TRP depleted animals, the TRP/sigmaLNAA ratio (LNAA: large neutral amino acids) was substantial decreased at 2 and 4h after the first administration of the oral administration (by 71 and 78%, respectively). Four hours after treatment central TRP and 5-HT concentrations were decreased by 50%. Both peripheral and central TRP levels returned to basal values in the group treated with the nutritional mixture supplemented with TRP. Surprisingly, tyrosine levels were also reduced after oral administration of the protein-carbohydrate mixture without affecting central DA concentrations. In conclusion, the TRP-free protein-carbohydrate nutritional mixture appears to be an efficient tool to substantially reduce plasma and central TRP levels in adult rat.

Cognition following acute tryptophan depletion: difference between first-degree relatives of bipolar disorder patients and matched healthy control volunteers.

BACKGROUND: Serotonergic circuits have been proposed to mediate cognitive processes, particularly learning and memory. Cognitive impairment is often seen in bipolar disorders in relation to a possible lowered serotonergic turnover. METHODS: We investigated the effects of acute tryptophan depletion (ATD) on cognitive performance in healthy first-degree relatives of bipolar patients (FH) (N= 30) and matched controls (N= 15) in a placebo-controlled, double-blind cross-over design. Performance on planning, memory and attention tasks were assessed at baseline and 5 h after ATD. RESULTS: Following ATD, speed of information processing on the planning task was impaired in the FH group but not in the control group. FH subjects with a bipolar disorder type I relative (FH I) showed impairments in planning and memory, independent of ATD. In all subjects, ATD impaired long-term memory performance and speed of information processing. ATD did not affect short-term memory and focused and divided attention. CONCLUSIONS: The results suggest serotonergic vulnerability affecting frontal lobe areas in FH subjects, indicated by impaired planning. Biological vulnerability in FH I subjects is reflected in impaired planning and memory performance. In conclusion, the cognitive dysfunctions in FH subjects indicate an endophenotype constituting a possible biological marker in bipolar psychopathology. Serotonin appears to be involved in speed of information processing, verbal and visual memory and learning processes.