Body Amino Acid Oxidation Research Articles

Clinical trial experiences with Physioneal™

The kidneys play an important role in maintaining the acid-base balance, as they excrete hydrogen ions and regenerate bicarbonate, thereby regulating intra- as well as extracellular pH, which are vital for normal cell function. In patients with renal failure, the inability of the kidneys to excrete an excess of hydrogen ions results in metabolic acidosis due to retention of acid degradation products, which has a detrimental effect on protein as well as amino acid turnover and leads to hypercatabolism1. In these patients, treatment with bicarbonate has been shown to improve nitrogen balance and decrease both whole body amino acid oxidation and protein degradation2. Metabolic acidosis also negatively affects cardiac, as well as bone, function. Consequently, one of the most important objectives of any dialysis therapy, including peritoneal dialysis (PD), is to correct acidosis. The correction of acidosis in PD is generally more stable than what can be achieved with intermittent hemodialysis3, and this may be one of the most important advantages of PD compared to hemodialysis. Historically, bicarbonate was the first buffer used in PD to correct uremic acidosis. However, the use of this buffer was soon discontinued due to its poor stability in the PD solution4. In a search for alternative buffering agents, bicarbonate was replaced by either lactate or acetate. Both buffers maintain effective acid-base balance as they react with hydrogen ions derived from carbonic acid, thereby regenerating bicarbonate. Acetate, however, was subsequently found to be associated with loss of ultrafiltration and sclerosing peritonitis5. Its use was abandoned in the 1980s, leaving lactate as the only buffer used in PD for many years.

Alterations in basal nutrient metabolism increase resting energy expenditure in sickle cell disease.

Basal rates of whole body protein, glucose, and lipid metabolism and resting energy expenditure (REE) were measured in eight African-American sickle cell disease (SCD) patients and in six African-American controls. Catheters were placed 1) in an antecubital vein for stable isotope infusion and 2) in a heated hand vein for arterialized venous blood. Breath and blood were collected during the last 30 min of the 2.5-h study, and REE was measured by indirect calorimetry. REE [128 +/- 5 vs. 111 +/- 1 kJ.kg fat-free mass (FFM)-1.day-1; P < 0.05 vs. controls] was 15% greater in the SCD patients. Whole body protein breakdown (5.0 +/- 0.3 vs. 3.8 +/- 0.2 mg.kg FFM-1.min-1; P < 0.05 vs. controls) and protein synthesis (4.4 +/- 0.3 vs. 3.2 +/- 0.2 mg.kg FFM-1.min-1; P < 0.05 vs. controls) were 32 and 38% greater, respectively, in the SCD patients, but whole body amino acid oxidation was similar (0.58 +/- 0.03 vs. 0.66 +/- 0.03 mg.kg FFM-1.min-1). Measures of whole body glucose and lipid metabolism were not significantly different between the groups. The additional energy required for the greater rates of whole body protein breakdown and synthesis caused by SCD contributes significantly to the observed increase in REE, suggesting that dietary energy and protein requirements are enhanced in SCD patients.

Recombinant growth hormone enhances muscle myosin heavy-chain mRNA accumulation and amino acid accrual in humans.

A potentially lethal complication of trauma, malignancy, and infection is a progressive erosion of muscle protein mass that is not readily reversed by nutritional support. Growth hormone is capable of improving total body nitrogen balance, but its role in myofibrillar protein synthesis in humans is unknown. The acute, in situ muscle protein response to an infusion of methionyl human growth hormone was investigated in the limbs of nutritionally depleted subjects during a period of intravenous refeeding. A 6-hr methionyl growth hormone infusion achieved steady-state serum levels comparable to normal physiologic peaks and was associated with a significant increase in limb amino acid uptake, without a change in body amino acid oxidation. Myosin heavy-chain mRNA levels, measured by quantitative dot blot hybridization, were also significantly elevated after growth hormone administration. The data indicate that methionyl growth hormone can induce intracellular amino acid accrual and increased levels of myofibrillar protein mRNA during hospitalized nutritional support and suggest growth hormone to be a potential therapy of lean body wasting.

Transport kinetics of amino acids across the resting human leg.

Flux rates of amino acids were measured across the leg after an overnight fast in resting human volunteers. A balanced amino acid solution was, after a primed infusion, continuously infused for 2 h at each of three step-wise and increasing rates corresponding to 8.3, 16.7, 33.2 mg N/kg per h that were equivalent to 0.2, 0.4, 0.8 g N/kg per d. Flux of amino acids across the leg was compared with the flux of glucose, glycerol, lactate, free fatty acids, and oxygen. The size of the muscular tissue pool of amino acids was measured. Whole body amino acid oxidation was estimated by means of the continuous infusion of a 14C-labeled mixture of amino acids. Arterial steady state levels were obtained for most amino acids within 30 to 45 min after the primed constant infusion. Leg flux of amino acids switched from a net efflux after an overnight fast to a balanced flux between infusion rates corresponding to 0.2-0.4 g N/kg per d. At 0.8 g N/kg per d essentially all amino acids showed uptake. The infusion of amino acids stimulated leg uptake of glucose and lactate production and decreased FFA release. Oxygen uptake and leg blood flow increased significantly with increased infusion of amino acids. There was significant variability in transport rate among individual amino acids. Branched chain amino acids showed rapid transport and methionine slow transport rate. Only small changes in the muscle tissue concentration of certain amino acids were registered after 6 h of amino acid infusion despite uptake for several hours. When amino acids were infused at a rate corresponding to 0.8 g N/kg per d, the leg uptake of amino acids was 6% and the simultaneous whole body oxidation of infused amino acids was approximately 10%. Net uptake of leucine across the leg per hour was 62% of the muscle pool of free leucine when amino acids were infused at a rate corresponding to 0.4 g N/kg per d. Multiple regression analysis showed that the arterial concentration of an amino acid was the most important factor for uptake, more so than insulin concentration and blood flow. It is concluded that leg exchange of amino acids is large enough to rapidly change the pool size of the amino acids in skeletal muscle, if not counter-regulated by changes in rates of protein synthesis and degradation. Estimates of the capacity for protein synthesis and transfer RNA acceptor sites in muscles agree in order of magnitude with the net uptake of amino acids at high infusion rates of amino acids. Therefore, measurements of the balance of tyrosine, phenylalanine, and particularly methionine at steady state may reflect net balance of proteins across skeletal muscles even in short-time experiments.

Leukocyte endogenous mediator alters protein dynamics in rats

Leukocyte endogenous mediator (LEM), a low-molecular-weight peptide synthesized by monocytic cells during phagocytosis, has been implicated as the host's initiator of the protein metabolic response to infection and inflammation. To determine whether administration of LEM would alter protein kinetics, appearance and oxidation of plasma tyrosine as well as the rates of protein synthesis in liver and skeletal muscle were determined in fasted rats that received a 30-hour continuous infusion of either physiologic saline, LEM, or heat-inactivated LEM. The LEM was obtained from rabbit peritoneal exudate and the treatment solutions supplied 2.8 × 10 8, cell equivalents 100 g of body weight (BW) per day. Endogenous tyrosine oxidation increased from 4.0 ± 0.4 μ mol 100 g , BW/h to 5.4 ± 0.7 μ mol 100 g , BW/h in animals infused with heat-inactivated LEM and to 7.5 ± 1.5 μ mol 100 g , BW/h in rats receiving LEM ( P < 0.01). Nonsecretory protein synthesis in the liver was greatest in rats administered LEM (2239 ± 325 mg/d) when compared with control groups receiving physiologic saline (1122 ± 195 mg/d) or heat-inactivated LEM (1374 ± 62 mg/d; P < 0.01), whereas skeletal protein synthetic rates were unchanged. Rates of muscle and collagen protein breakdown were estimated from the urinary excretion rate of N t-methylhistidine and hydroxyproline, respectively, and their excretion rose by 30% ( P < 0.05) and 42% ( P < 0.05) with LEM administration. These results suggest that administration of LEM stimulates a mobilization of amino acids from peripheral tissues to support increased visceral protein anabolism while whole body amino acid oxidation is also enhanced. Since similar effects follow fever and infection, these results suggest that LEM may play an underlying role in the protein metabolic response to infection and inflammation.