Renate Jonker

Role of specific dietary amino acids in clinical conditions

In a variety of chronic and acute disease states, alterations in protein synthesis, breakdown and protein turnover rates occur that are related to the loss of body protein and skeletal muscle wasting. A key observation is the stimulation of protein breakdown in muscle and the stimulation of protein synthesis in the splanchnic area; mainly liver. An altered splanchnic extraction of amino acids as well as an anabolic resistance to dietary protein, related to stress, disuse and aging play a key role in the pathogenesis of muscle wasting in these conditions. To overcome these factors, specific dietary protein and amino acid diets have been introduced. The main focus of these diets is the quantity and quality of dietary proteins and whether a balanced mixture or solely dietary essential amino acids are required with or without higher intake levels of specific amino acids. Specifically in cancer patients, stimulated muscle protein synthesis has been obtained by increasing the amount of protein in a meal and by providing additional leucine. Also in other chronic diseases such as chronic obstructive pulmonary disease and cystic fibrosis, meals with specific dietary proteins and specific combinations of dietary essential amino acids are able to stimulate anabolism. In acute diseases, a special role for the amino acid arginine and its precursor citrulline as anabolic drivers has been observed. Thus, there is growing evidence that modifying the dietary amino acid composition of a meal will positively influence the net balance between muscle protein synthesis and breakdown, leading to muscle protein anabolism in a variety of chronic and acute disease states. Specific amino acids with anabolic potential are leucine, arginine and citrulline.

Hydrolyzed casein and whey protein meals comparably stimulate net whole-body protein synthesis in COPD patients with nutritional depletion without an additional effect of leucine co-ingestion

BACKGROUND & AIMS Muscle wasting commonly occurs in COPD, negatively affecting outcome. The aim was to examine the net whole-body protein synthesis response to two milk protein meals with comparable absorption rates (hydrolyzed casein (hCAS) vs. hydrolyzed whey (hWHEY)) and the effects of co-ingesting leucine. METHODS Twelve COPD patients (GOLD stage II-IV) with nutritional depletion, were studied following intake of a 15 g hCAS or hWHEY protein meal with or without leucine-co-ingestion, according to a double-blind randomized cross-over design. The isotopic tracers L-[ring-(2)H5]-Phenylalanine, L-[ring-(2)H2]-Tyrosine, L-[(2)H3]-3-Methylhistidine (given via continuous intravenous infusion), and L-[(15)N]-Phenylalanine (added to the protein meals) were used to measure endogenous whole-body protein breakdown (WbPB), whole-body protein synthesis (WbPS), net protein synthesis (NetPS), splanchnic extraction and myofibrillar protein breakdown (MPB). Analyses were done in arterialized-venous plasma by LC/MS/MS. RESULTS WbPS was greater after intake of the hCAS protein meal (P < 0.05) whereas the hWHEY protein meal reduced WbPB more (P < 0.01). NetPS was stimulated comparably, with a protein conversion rate greater than 70%. Addition of leucine did not modify the insulin, WbPB, WbPS or MPB response. CONCLUSIONS Hydrolyzed casein and whey protein meals comparably and efficiently stimulate whole-body protein anabolism in COPD patients with nutritional depletion without an additional effect of leucine co-ingestion. This trial was registered at clinicaltrials.gov as NCT01154400.

Effectiveness of essential amino acid supplementation in stimulating whole body net protein anabolism is comparable between COPD patients and healthy older adults

BACKGROUND The development of effective nutritional strategies in support of muscle growth for patients with chronic obstructive pulmonary disease (COPD) remains challenging. Dietary essential amino acids (EAAs) are the main driver of postprandial net protein anabolism. In agreement, EAA supplements in healthy older adults are more effective than supplements with the composition of complete proteins. In patients with COPD it is still unknown whether complete protein supplements can be substituted with only EAAs, and whether they are as effective as in healthy older adults. METHODS According to a double-blind randomized crossover design, we examined in 23 patients with moderate to very severe COPD (age: 65±2 years, FEV1: 40±2% of predicted) and 19 healthy age-matched subjects (age: 64±2 years), whether a free EAA mixture with a high proportion (40%) of leucine (EAA mixture) stimulated whole body net protein gain more than a similar mixture of balanced free EAAs and non-EAAs as present in whey protein (TAA mixture). Whole body net protein gain and splanchnic extraction of phenylalanine (PHE) were assessed by continuous IV infusion of L-[ring-2H5]-PHE and L-[ring-2H2]-tyrosine, and enteral intake of L-[15N]-PHE (added to the mixtures). RESULTS Besides an excellent positive linear relationship between PHE intake and net protein gain in both groups (r=0.84-0.91, P<0.001), net protein gain was 42% higher in healthy controls and 49% higher in COPD patients after intake of the EAA mixture compared to the TAA mixture (P<0.0001). These findings could not be attributed to the high LEU content, as in both groups net protein gain per gram EAA intake was lower for the EAA mixture (P<0.0001). Net protein gain was higher in COPD patients for both mixtures due to a 40% lower splanchnic extraction (P<0.0001), but was similarly related to dietary PHE (i.e. EAA) plasma appearance. CONCLUSIONS In COPD patients, similarly to healthy older adults, free EAA supplements stimulate whole body protein anabolism more than free amino acid supplements with the composition of complete proteins. Therefore, free EAA supplements may aid in the prevention and treatment of muscle wasting in this patient population.

Alterations in whole-body arginine metabolism in chronic obstructive pulmonary disease

BACKGROUND Chronic obstructive pulmonary disease (COPD) is a condition characterized by systemic low-grade inflammation that could increase the production of nitric oxide (NO), of which arginine is the sole precursor. Arginine is derived from the breakdown of protein and through the conversion of citrulline to arginine (de novo arginine production). OBJECTIVE Our objective was to study whole-body arginine and citrulline and related metabolism in stable COPD patients. DESIGN With the use of stable isotope methodology, we studied whole-body arginine and citrulline rates of appearance, de novo arginine (citrulline-to-arginine flux) and NO (arginine-to-citrulline flux) production, protein synthesis and breakdown rates, and plasma amino acid concentrations in a heterogeneous group of patients with moderate-to-severe COPD [n = 23, mean ± SE age: 65 ± 2 y, forced expiratory volume in 1 s (FEV1): 40% ± 2% of predicted], and a group of healthy older adults (n = 19, mean ± SE age: 64 ± 2 y, FEV1: 95% ± 4% of predicted). RESULTS Although plasma arginine and citrulline concentrations were comparable between COPD patients and controls, whole-body arginine (P = 0.015) and citrulline (P = 0.026) rates of appearance were higher in COPD patients and related to a 57% greater de novo arginine production (P < 0.0001). Despite a higher whole-body arginine clearance in COPD patients (P < 0.0001), we found no difference in NO production. CONCLUSION In stable patients with moderate-to-severe COPD, endogenous arginine production is upregulated to support a higher arginine utilization that is unrelated to whole-body NO production. This trial was registered at clinicaltrials.gov as NCT01173354 and NCT01172314.

A critical evaluation of the anabolic response after bolus or continuous feeding in COPD and healthy older adults

After bolus and continuous enteral feeding of the same protein, different digestion and absorption kinetics and anabolic responses are observed. Establishing which mode of feeding has the highest anabolic potential in patients with chronic obstructive pulmonary disease (COPD) may aid in the prevention of muscle wasting, but an important confounding factor is the duration of assessments after bolus feeding. We hypothesized that the anabolic response to bolus and continuous feeding in COPD patients is comparable when methodological issues are addressed. Twenty-one older adults (12 patients with stage II-IV COPD and 9 healthy controls) were studied after intake of a fast-absorbing hydrolyzed casein protein-carbohydrate mixture either as a single bolus or as small sips (crossover design). Whole body protein synthesis (PS), breakdown (PB), net PS (PS - PB) protein efficiency (netPSPE), net protein balance (phenylalanine (PHE) intake - PHE hydroxylation) protein efficiency (netBalPE), and splanchnic PHE extraction (SPEPHE) were assessed using stable isotope tracer methodology. Bolus feeding assessments were done at 90, 95, and 99% of the calculated duration of the anabolic response. At 99%, netBalPE was higher for sip feeding than bolus feeding in both groups (P<0.0001). Nevertheless, bolus feeding was associated with a lower SPEPHE (P<0.0001) and higher netPSPE (P<0.0001). At 90% compared with 99%, PS and netBalPE after bolus feeding was significantly overestimated. In conclusion, several factors complicate a comparison of the anabolic capacity of bolus and continuous feeding in acute studies, including the critical role of SPE calculation and assumptions, and the duration of postprandial assessments after bolus feeding.