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.

Increased whole body hydroxyproline production as assessed by a new stable isotope technique is associated with hip and spine bone mineral loss in cystic fibrosis.

BACKGROUND & AIMS: Bone mineral loss, reduced lung function and impaired nutritional status are frequently present in children with Cystic Fibrosis (CF). Blood concentrations and urinary excretion of hydroxyproline (OH-PRO) have been used as markers of bone mineral status and lung function in CF. OBJECTIVE: To examine whether whole body hydroxyproline production, as assessed by a new stable isotope methodology, is increased in pediatric patients with CF and associated with bone mineral loss, lung function decline and impaired nutritional status. DESIGN: In a cross-sectional study in 15 pediatric patients with CF and 17 healthy young control subjects, whole body hydroxyproline production (Wb OH-PRO) was assessed in the postabsorptive state by primed-constant and continuous infusion of the stable isotope 2-D-OH-PRO for 3 h. Bone mineral density (BMD) of whole body, hip and spin, and body composition (fat mass and fat-free mass) were determined by dual-energy X-ray Absorptiometry (DXA). Plasma isotopic enrichments and OH-PRO concentrations were measured by LC/MS/MS. RESULTS: Higher values for WbOH-PRO production and plasma OH-PRO concentrations were found in pediatric CF patients than in the healthy young subjects (p < 0.001). WbOH-PRO production was significantly correlated with plasma OH-PRO concentrations in the CF (r: 0.70, p = 0.007) but not in the healthy group. WbOH-PRO production in CF was associated with low BMD values in hip (r = -0.61, p = 0.02) and spine (r = -0.59, p = 0.02) but not with whole body BMD, lung function or body composition. CONCLUSION: A new stable isotope approach revealed enhanced levels of whole body hydroxyproline production rate in pediatric patients with CF, indicative of enhanced whole body collagen breakdown. Increased levels for whole body hydroxyproline production in CF were associated with severe bone mineral loss in hip and spine but not with lung function decline or impaired nutritional status. Registration ClinicalTrials.gov = NCT01172301.

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.

Enhanced anabolic response to milk protein sip feeding in elderly subjects with COPD is associated with a reduced splanchnic extraction of multiple amino acids.

BACKGROUND & AIMS: We previously observed in elderly subjects with Chronic Obstructive Pulmonary Disease (COPD) an enhanced anabolic response to milk protein sip feeding, associated with reduced splanchnic extraction (SPE) of phenylalanine. Milk proteins are known for their high Branched-chain Amino Acids (BCAA) content, but no information is present about splanchnic extraction and metabolism of the individual BCAA in COPD. OBJECTIVE: To investigate whether BCAA metabolism and SPE of the individual BCAA are altered in COPD during milk protein sip feeding. DESIGN: In elderly subjects with COPD and in healthy age-matched elderly SPE, endogenous rate of appearance (Raendo) of the leucine (LEU), isoleucine (ILE) and valine (VAL) were measured before and during sip feeding of a Whey protein meal. To study the effect of aging, the healthy elderly were compared to a group of healthy young subjects. Stable isotopes of l-[(2)H(3)]-LEU, l-[1-(13)C]-ILE and l-[1-(13)C]-VAL were given on two separate test days orally or intravenously. Simultaneously, l-[ring-(2)H(5)]-phenylalanine (PHE) and l-[ring-(2)H(2)]-tyrosine (TYR) were given to determine the whole body protein breakdown (WbPB), synthesis (WbPS) and NetPS. RESULTS: SPE of all BCAA, TYR, and PHE (p < 0.01) were lower in the COPD group, and the increase in netPS during feeding was higher in the COPD group (P < 0.01) due to higher values for PS (P < 0.001). Raendo of all BCAA, PHE and TYR were higher in the COPD than the healthy elderly group (P < 0.05) before and during feeding (P < 0.001). Sip feeding resulted in a reduction of Raendo of PHE, ILE and VAL (P < 0.05). Postabsorptive Raendo was not different for any of the measured amino acids between the healthy elderly and young group, while sip feeding resulted in a reduction of Raendo of PHE. Only SPE of TYR was higher in the elderly (P < 0.05) and the increase in netPS during sip feeding was independent of aging. CONCLUSION: The enhanced anabolic response to milk protein sip feeding in normal-weight COPD patients is associated with a reduced splanchnic extraction of multiple amino acids including all branched-chain amino acids. Registration ClinicalTrials.gov = NCT01418469.

Glutathione and glutamate levels in the diaphragm of patients with chronic obstructive pulmonary disease.

Recently, decreased glutamate (Glu) and reduced glutathione (GSH) levels were reported in the quadriceps femoris of patients with chronic obstructive pulmonary disease (COPD). The aim of the present study was to investigate whether Glu and GSH levels are also modified in the diaphragm of these patients. Nine male COPD patients (forced expiratory volume in one second (FEV1) range 28-68% of the predicted value) and seven male patients with normal pulmonary function (mean +/- SD FEV1 86 +/- 3% pred) submitted to thoracotomy were included. Biopsy specimens were taken from the diaphragm (both groups) and the quadriceps femoris (COPD group alone) in order to assess fibre size, myosin heavy chain expression, GSH levels and amino acid profile. The COPD group was characterised by preserved fibre size, a higher proportion of type I fibres (mean +/- SEM 70 +/- 3 versus 26 +/- 4%), and higher Glu and GSH content in the diaphragm compared to the quadriceps muscle. However, Glu and GSH levels were similar in diaphragm from the COPD and control groups. Glu level correlated with GSH level in both muscles. No significant correlation was found between Glu or GSH level and fibre size or proportions. This study shows that glutamate and reduced glutathione levels are preserved in the diaphragm of chronic obstructive pulmonary disease patients. Alterations in glutamate and reduced glutathione metabolism are muscle-specific in chronic obstructive pulmonary disease, affecting the quadriceps femoris but not the diaphragm. Glutamate and reduced glutathione levels are strongly interrelated in both muscles, independent of fibre type distribution and fibre size.

Muscle wasting and changes in muscle protein metabolism in chronic obstructive pulmonary disease.

Loss of skeletal muscle mass is now recognised as an important feature of chronic obstructive pulmonary disease (COPD) which contributes to symptoms and influences prognosis. The changes in skeletal muscle remain poorly understood, largely because only a few studies have been performed to define the adaptations in whole body and muscle protein metabolism in COPD. The first sections of this review summarise background information about skeletal muscle wasting in COPD, and focuses on the studies concerned with amino acid profiles and protein synthesis and degradation rates. To aid interpretation some discussion of the techniques commonly used is included. A variety of different catabolic factors may determine whether chronic obstructive pulmonary disease patients become cachectic. The precise role for each one of these factors as well as the intracellular pathways activated in muscle as a result of chronic obstructive pulmonary disease are unknown and remain to be defined. Details of the actions of a range of different catabolic factors and potential mechanisms will be discussed.

Skeletal muscle fibre-type shifting and metabolic profile in patients with chronic obstructive pulmonary disease.

The aim of this study was to examine the nature of fibre-type redistribution in relation to fibre metabolic profile in the vastus lateralis in chronic obstructive pulmonary disease (COPD) and COPD subtypes. Fifteen COPD patients (eight with emphysema stratified by high-resolution computed tomography) and 15 healthy control subjects were studied. A combination of myofibrillar adenosine triphosphatase staining and immunohistochemistry was used to identify pure, as well as hybrid fibre types. For oxidative capacity, fibres were stained for cytochrome c oxidase and succinate dehydrogenase activities, and glycogen phosphorylase for glycolytic capacity. The proportion of type-I fibres in COPD patients was markedly lower (16% versus 42%), especially in emphysema, and the proportion of hybrid fibres was higher (29% versus 16%) compared to controls. The proportion of fibres staining positive for oxidative enzymes was lower in COPD patients, which correlated with the proportion of type-I fibres. In COPD oxidative capacity was lower within IIA fibres. The authors conclude that fibre-type transitions are involved in the fibre-type redistribution in chronic obstructive pulmonary disease. Low oxidative capacity is closely related to the proportion of type-I fibres, but an additional reduction of oxidative enzyme activity is present within IIA fibres. Fibre-type abnormalities may be aggravated in emphysema.