Net Protein Catabolism Research Articles

The Effect of Glucagon on Protein Catabolism During Insulin Deficiency: Exchange of Amino Acids Across Skeletal Muscle and the Splanchnic Bed.

Transient insulin deprivation with concurrent hyperglucagonemia is a catabolic state that can occur in type 1 diabetes. To evaluate glucagon's catabolic effect in the setting of its glucogenic effect, we measured the regional exchanges of amino acid metabolites (amino-metabolites) across muscle and splanchnic beds in 16 healthy humans during either somatostatin followed by glucagon or saline infusion alone. Despite a twofold or greater increase in the regional exchange of amino-metabolites by glucagon, whole-body kinetics and concentrations of amino acids (AA) remained stable. Glucagon increased the splanchnic uptake of not only gluconeogenic but also essential (EAA) AA while increasing their release from the muscle bed. Regional tracer-based kinetics and 3-methylhistidine release indicate that EAA release from muscle is likely caused by reduced protein synthesis rather than increased protein degradation. Furthermore, many metabolites known to affect insulin action and metabolism were altered by hyperglucagonemia including increase in branched-chain AA and keto acids of leucine and isoleucine in arterial plasma. Further, an increase in arterial concentrations of α-aminoadipic acid arising from increased conversion from lysine in the splanchnic bed was noted. These results demonstrate that hyperglucagonemia during hypoinsulinemia increases net muscle protein catabolism and substantially increases the exchange of amino metabolites across splanchnic and muscle beds.

Magnitude of protein catabolic response in critically ill subjects is associated with multiple amino acid and lipolysis related metabolic disturbances

Rationale: The presence of net protein catabolism is well established in most ICU patients. However, it remains unclear whether the magnitude of this catabolic response is accompanied by disturbances in specific amino acid and glycerol pathways.

Hypercapnia-Driven Skeletal Muscle Dysfunction in an Animal Model of Pulmonary Emphysema Suggests a Complex Phenotype.

Patients with chronic pulmonary conditions such as chronic obstructive pulmonary disease (COPD) often develop skeletal muscle dysfunction, which is strongly and independently associated with poor outcomes including higher mortality. Some of these patients also develop chronic CO2 retention, or hypercapnia, which is also associated with worse prognosis. While muscle dysfunction in these settings involve reduction of muscle mass and disrupted fibers’ metabolism leading to suboptimal muscle work, mechanistic research in the field has been limited by the lack of adequate animal models. Over the last years, we have established a rodent model of COPD-induced skeletal muscle dysfunction that allowed a disaggregated interrogation of the cellular and physiological effects driven by COPD from the ones unique to hypercapnia. We found that while COPD and hypercapnia synergistically contribute to muscle atrophy, they are antagonistic processes regarding fibers respiratory capacity. We propose that AMP-activated protein kinase (AMPK) is a crucial regulator of CO2 signaling in hypercapnic muscles, which leads to both net protein catabolism and improved mitochondrial respiration to support a transition into a substrate-rich, fuel-efficient metabolic mode that allows muscle cells cope with the CO2 toxicity.

Adaptation to Amino Acid Kinetics and Urea Production in Adult Cats (Felis catus) Fed Below Their Protein Requirement (P09-008-19)

ObjectivesCats are obligate carnivores that evolved eating meat-based diets and have high requirements for amino acids (AA). However, little is known about how they regulate AA metabolism, especially at intakes below their requirement. This study was undertaken to examine the effect of dietary protein level above and below their requirement on urea production and AA metabolism in cats. MethodsCats (n = 18) were allocated to three treatments (7.5, 15, or 40% ME intake as crude protein), fed at maintenance for 3 wk, and then fitted with saphanous and cephalic vein catheters. On the following day, they received primed continuous infusions of [13C]bicarbonate, [1-13C]Leu and [15N2]urea from 0 to 120, 120 to 480 and 0 to 480 min, respectively. Cats were fed hourly during infusion and Leu entry rate from diet was calculated. Breath was sampled at 0, 100, 110, 120, 440, 460, and 480 min to measure 13CO2, with blood sampled at 0, 440, 460, and 480 min to measure 13C enrichments in Leu and ketoisocaproate, and [15N2]urea. ResultsValues for non-oxidative Leu disposal (NOLD, an indicator of protein synthesis), Leu rate of appearance in plasma (Ra, an indicator of protein degradation), Leu oxidation, and urea production rate (an indicator of net protein catabolism) are shown in Table 1. There were no differences in any measurements in cats fed at (15%) or below (7.5%) their requirement for protein. However, those fed with 7.5% of ME intake as crude protein had numerically lowest rates of whole body AA catabolism and oxidation, whereas, Leu Ra was numerically greatest. ConclusionsUsing Leu kinetics to trace AA metabolism, there did not seem to be a difference between cats fed at or below their requirement for protein. This may indicate that cats are able to adapt to dietary protein content more than what was previously believed. Funding SourcesMassey University Research Fund, and the McGeorge Research Fund Supporting Tables, Images and/or Graphs▪

Presence of early stage cancer does not impair the early protein metabolic response to major surgery.

BackgroundCombined bilateral mastectomy and reconstruction is a common major surgical procedure in women with breast cancer and in those with a family history of breast cancer. As this large surgical procedure induces muscle protein loss, a preserved anabolic response to nutrition is warranted for optimal recovery. It is unclear whether the presence of early stage cancer negatively affects the protein metabolic response to major surgery as this would mandate perioperative nutritional support.MethodsIn nine women with early stage (Stage II) breast malignancy and nine healthy women with a genetic predisposition to breast cancer undergoing the same large surgical procedure, we examined whether surgery influences the catabolic response to overnight fasting and the anabolic response to nutrition differently. Prior to and within 24 h after combined bilateral mastectomy and reconstruction surgery, whole body protein synthesis and breakdown rates were assessed after overnight fasting and after meal intake by stable isotope methodology to enable the calculation of net protein catabolism in the post‐absorptive state and net protein anabolic response to a meal.ResultsMajor surgery resulted in an up‐regulation of post‐absorptive protein synthesis and breakdown rates (P < 0.001) and lower net protein catabolism (P < 0.05) and was associated with insulin resistance and increased systemic inflammation (P < 0.01). Net anabolic response to the meal was reduced after surgery (P < 0.05) but higher in cancer (P < 0.05) indicative of a more preserved meal efficiency. The significant relationship between net protein anabolism and the amount of amino acids available in the circulation (R 2 = 0.85, P < 0.001) was independent of the presence of non‐cachectic early stage breast cancer or surgery.ConclusionsThe presence of early stage breast cancer does not enhance the normal catabolic response to major surgery or further attenuates the anabolic response to meal intake within 24 h after major surgery in patients with non‐cachectic breast cancer. This indicates that the acute anabolic potential to conventional feeding is maintained in non‐cachectic early stage breast cancer after major surgery.

Renal transplantation promptly restores excretory function but disturbed L-arginine metabolism persists in patients during the early period after surgery

The synthesis and whole body metabolism of L-arginine (Arg) are disturbed in renal diseases. Renal transplantation represents the best therapy in the end-stage of these diseases. In the present we compared alterations of plasma Arg and related compounds with renal excretory function in patients with end-stage renal disease, before and after kidney transplantation. Arg, asymmetric dimethylarginine (ADMA), citrulline (Cit), glutamine (Gln), ornithine (Orn), phenylalanine (Phe), tyrosine (Tyr), urea, creatinine, albumin, and nitrate were analyzed in patients before, immediately after (0-time) and 1, 2, 3, 7 and 14 days following living donors kidney transplantation. Healthy subjects were controls. Glomerular filtration rate (GFR) and amino acid molar ratios were calculated. Before transplantation creatinine, urea, Cit, Gln, ADMA, and nitrate were above, while GFR and Arg were below controls, confirming disturbed excretory and metabolic renal functions in patients with renal disease. Renal transplantation promptly normalized creatinine, urea, GFR, Cit, and nitrate. However, regardless of increased molar Phe/Tyr ratios, indicating increased net protein catabolism in peripheral tissues, low Arg and elevated ADMA concentrations persisted throughout the examined period. Alterations of other amino acids also suggest similarly disturbed Arg metabolism in patients after kidney transplantation. In conclusion, renal transplant promptly restored its excretory function, but increased net protein catabolism, disturbed Arg metabolism and endothelial dysfunction in entire body of these patients were not improved throughout the early period after the operation. That has to be considered in their therapy.

Unilateral nephrectomy causes an early abrupt decrease in plasma arginine and simultaneous reduction in glomerular filtration rate in living kidney donors

ObjectivesLiving donor kidney transplantation is regarded as beneficial to allograft recipients and not particularly detrimental to the donors. Recently we have documented a reduced glomerular filtration rate (GFR) in living kidney donors (LKDs). Considering kidneys as essential for l-arginine (Arg) metabolism, in the present study we analyzed plasma Arg and related compounds comparing them with the function of remaining kidney in LKDs after donation. Design and methodsWe analyzed GFR, plasma Arg, asymmetric dimethylarginine (ADMA), citrulline (Cit), glutamine (Gln), ornithine (Orn), phenylalanine (Phe), tyrosine (Tyr), thiobarbituric acid reactive substances (TBARS), urea, creatinine, nitrite, nitrate and their sum (NOx) in blood samples taken from LKDs before, immediately after (0-time) and 1, 2, 3, 7 and 14days following surgery. ResultsGradual and moderate creatinine increase and albumin decrease were associated with decreased GFR. An abrupt decrease in Arg occurred, staying below baseline level throughout the 14days. Also decreases in Gln, Cit, Orn, increase in Phe and TBARS, and unaltered ADMA, nitrite and NOx concentrations were obtained. Despite increased net protein catabolism (indicated by elevated Phe/Tyr ratios) lack of Arg, suggested by decreased molar Arg/Phe ratios, occurred. Decreased molar Arg/Gln suggests an early but transient decrease in Arg synthesis. ConclusionUnilateral nephrectomy causes an early abrupt decrease in plasma arginine and reduction in glomerular filtration rate in LKDs that was associated with increased net protein breakdown in the peripheral tissues and elevated oxidative damage, which has to be considered in their therapy.

Alkaline Salts to Counteract Bone Resorption and Protein Wasting Induced by High Salt Intake: Results of a Randomized Controlled Trial

High sodium chloride (NaCl) intake can induce low-grade metabolic acidosis (LGMA) and may thus influence bone and protein metabolism. We hypothesized that oral potassium bicarbonate (KHCO(3)) supplementation may compensate for NaCl-induced, LGMA-associated bone resorption and protein losses. Eight healthy male subjects participated in a randomized trial with a crossover design. Each of two study campaigns consisted of 5 d of dietary and environmental adaptation followed by 10 d of intervention and 1.5 d of recovery. In one study campaign, 90 mmol KHCO(3)/d were supplemented to counteract NaCl-induced LGMA, whereas the other campaign served as a control with only high NaCl intake. When KHCO(3) was ingested during high NaCl intake, postprandial buffer capacity ([HCO(3)(-)]) increased (P = 0.002). Concomitantly, urinary excretion of free potentially bioactive glucocorticoids [urinary free cortisol (UFF) and urinary free cortisone (UFE)] was reduced by 14% [∑(UFF,UFE); P = 0.024]. Urinary excretion of calcium and bone resorption marker N-terminal telopeptide of type I collagen was reduced by 12 and 8%, respectively (calcium, P = 0.047; N-terminal bone collagen telopeptide, P = 0.044). There was a trend of declining net protein catabolism when high NaCl was combined with KHCO(3) (P = 0.052). We conclude that during high salt intake, the KHCO(3)-induced postprandial shift to a more alkaline state reduces metabolic stress. This leads to decreased bone resorption and protein degradation, which in turn might initiate an anticatabolic state for the musculoskeletal system in the long run.

Protein-energy wasting and mortality in chronic kidney disease.

Protein-energy wasting (PEW) is common in patients with chronic kidney disease (CKD) and is associated with an increased death risk from cardiovascular diseases. However, while even minor renal dysfunction is an independent predictor of adverse cardiovascular prognosis, PEW becomes clinically manifest at an advanced stage, early before or during the dialytic stage. Mechanisms causing loss of muscle protein and fat are complex and not always associated with anorexia, but are linked to several abnormalities that stimulate protein degradation and/or decrease protein synthesis. In addition, data from experimental CKD indicate that uremia specifically blunts the regenerative potential in skeletal muscle, by acting on muscle stem cells. In this discussion recent findings regarding the mechanisms responsible for malnutrition and the increase in cardiovascular risk in CKD patients are discussed. During the course of CKD, the loss of kidney excretory and metabolic functions proceed together with the activation of pathways of endothelial damage, inflammation, acidosis, alterations in insulin signaling and anorexia which are likely to orchestrate net protein catabolism and the PEW syndrome.

Metabolic vs Nutrition Support

It is now generally accepted that early feeding post injury exerts a positive effect on outcome in the critically ill, despite the fact that many of these patients are well nourished or even overnourished on admission. One possible mechanism is that early feeding post injury may have a positive influence on the duration and intensity of the systemic inflammatory response, especially when coupled with intensive insulin therapy to maintain normoglycemia at <150 mg/dL. Current clinical nutrition guidelines recommend early enteral nutrition providing full nutrition requirements in the critically ill patient; however, in the first week post injury, exclusive enteral feeding is typically inadequate, particularly in protein. A potentially new and different therapeutic goal to modulate the systemic inflammatory response might be more effectively accomplished for the first week post injury by hypocaloric feedings (~9-18 kcal/kg or 50%-75% resting metabolic expenditure) principally as intravenous dextrose but with at least 1 g/kg protein as intravenous amino acids to provide early metabolic support. This proposed regime, along with intensive insulin therapy to maintain glucose homeostasis, should promote the protein synthetic component of the postinjury inflammatory response while reducing net protein catabolism. A formal trial of early metabolic support in the acutely injured should be safe, easy to execute, and potentially efficacious, with subsequent improvement in the inflammatory state and, it is hoped, clinical outcomes.

Consequences of head injury and static cold storage on hepatic function: ex vivo experiments using a model of isolated perfused rat liver

The purpose of the study was to evaluate the effect of head injury (HI) on the metabolic and energy functions of the liver and its consequences after cold storage. In male SD rats with HI, livers were isolated 4 days after injury and perfused either immediately (HI) or after 24 hours of cold preservation. Livers isolated from healthy rats were treated identically. The hepatic functions were explored with an isolated perfused liver model. Head injury induced a liver atrophy without significant difference in the intrahepatic energy level versus healthy rats. After cold storage, hepatic adenosine triphosphate and glycogen contents in HI rats were similar to those of healthy rats. The livers of the HI group that underwent cold preservation had a lower protein catabolism. The portal flow rate at the time of reperfusion was significantly increased in the HI group. In conclusion, static cold storage of livers harvested from HI rats revealed a net protein catabolism reduction and a modification of hepatic microcirculation.

Diabetes and Protein Metabolism

The celebrated Greek physician Aretaeus the Cappadocian some 1900 years ago described diabetes as a condition with “a melting down of the flesh and limbs into urine.” Remarkably, his observations are amazingly durable and accurate even by the standards of today with reference to type 1 diabetes. For example, insulin deprivation in type 1 diabetic patients causes a profound increase in catabolism, especially in skeletal muscle (1–4). Moreover, this net muscle protein catabolism is due to a net increase in protein breakdown rather than a decline in protein synthesis (1–4). In contrast, despite substantial alterations in glucose and lipid metabolism, the effect of type 2 diabetes on changes in protein metabolism is at best subtle, and results are inconsistent (5–8). A key difference is that in type 1 diabetic patients on insulin deprivation, muscle mass withers away (as demonstrated by profound cachexia in type 1 diabetic patients during the preinsulin era), whereas no such dramatic changes occur in type 2 diabetic patients with poor glycemic control. Withdrawal of treatment for 10 days in type 2 diabetic patients had little effect on amino acid levels or protein metabolism (8), although glucose metabolism is substantially altered; this may relate to differences in portal …

Calorie restriction accelerates the catabolism of lean body mass during 2 wk of bed rest

Background: Muscle inactivity and low energy intake commonly occur in persons with acute or chronic disease, in astronauts during space flight, and during aging.Objective: We used a crossover design to investigate the effects of the interactions of inactivity and calorie restriction on whole-body composition and protein kinetic regulation in 9 healthy volunteers.Design: Lean body mass (LBM) was measured by using dual-energy X-ray absorptionmetry before and at the end of 14-d periods of bed rest (B) and controlled ambulation (A) in patients receiving eucaloric (E) or hypocaloric (H) (≈80% of total energy expenditure) diets. Whole-body leucine kinetics were determined at the end of the 4 study periods by using a standard stable-isotope technique in the postabsorptive state and during a 3-h infusion of a 0.13 g · kg LBM−1 · h−1 amino acid mixture.Results: In the postabsorptive state, we found a significant (P = 0.04) bed rest × hypocaloric diet interaction for the rate of leucine oxidation, an index of net protein catabolism (A+E: 0.23 ± 0.01; B+E: 25 ± 0.01; A+H: 0.23 ± 0.01; B+H: 0.28 ± 0.01 μmol · min−1 · kg LBM−1). Bed rest significantly (P < 0.01) decreased amino acid–mediated stimulation of nonoxidative leucine disappearance, an index of protein synthesis (A+E: 35 ± 2%; B+E: 30 ± 2%; A+H: 41 ± 3%; B+H: 32 ± 2%). B+H decreased LBM by 1.10 ± 0.1 kg, which is significantly (P < 0.01) greater than the decrease seen with A+E, A+H, or B+E.Conclusion: Calorie restriction enhanced the catabolic response to inactivity by combining greater protein catabolism in the postabsorptive state with an impaired postprandial anabolic utilization of free amino acids.

Low postabsorptive net protein degradation in male cancer patients: Lack of sensitivity to regulatory amino acids?

Autophagic (lysosomal) and proteasomic protein degradation are important regulatory mechanisms in the homeostasis of muscle mass, that may be profoundly disturbed in cancer and other wasting syndromes. Due to the inhibiting effect of amino acids and insulin, net proteolysis is restricted to the fasted state, and in autophagy certain amino acids have been identified as 'regulatory' in the rat, including leucine, tyrosine, phenylalanine, methionine, and histidine (i.e. LYFMH). The present cross-sectional study assessed postabsorptive net protein catabolism in male cancer patients as well as in healthy male volunteers, to analyse its relation to such 'regulatory amino acids'. Postabsorptive amino acid exchange rates across the leg were determined in patients with gastrointestinal cancer (GIC, n=47) or renal cell carcinoma (RCC, n=15), age-matched (n=33), and young male control subjects (n=42). Both groups of cancer patients revealed a significantly lower postabsorptive net protein catabolism than control subjects. Furthermore, in the control subjects, the postabsorptive net protein catabolism was found to be inversely and significantly correlated with the arterial concentrations of the 8 amino acids YSHMFGI and L which include 5 of the 'regulatory amino acids'. Cancer patients, in contrast, revealed no such significant correlations. These results may indicate i) that postabsorptive net protein catabolism in skeletal muscle of healthy subjects may be sensitive to amino acids which reportedly regulate autophagy and ii) that such amino acid-sensitive mechanism of protein catabolism may be disturbed in cancer patients.

Atrophy and Impaired Muscle Protein Synthesis during Prolonged Inactivity and Stress

We recently demonstrated that 28-d bed rest in healthy volunteers results in a moderate loss of lean leg mass and strength. The objective of this study was to quantify changes in muscle protein kinetics, body composition, and strength during a clinical bed rest model reflecting both physical inactivity and the hormonal stress response to injury or illness. Muscle protein kinetics were calculated during a primed, continuous infusion (0.08 micromol/kg.min) of 13C6-phenylalanine on d 1 and 28 of bed rest. The setting for this study was the General Clinical Research Center at the University of Texas Medical Branch. Participants were healthy male volunteers (n = 6, 28 +/- 2 yr, 84 +/- 4 kg, 178 +/- 3 cm). During bed rest, hydrocortisone sodium succinate was administered iv (d 1 and 28) and orally (d 2-27) to reproduce plasma cortisol concentrations consistent with trauma or illness (approximately 22 microg/dl). We hypothesized that inactivity and hypercortisolemia would reduce lean muscle mass, leg extension strength, and muscle protein synthesis. Volunteers experienced a 28.4 +/- 4.4% loss of leg extension strength (P = 0.012) and a 3-fold greater loss of lean leg mass (1.4 +/- 0.1 kg) (P = 0.004) compared with our previous bed rest-only model. Net protein catabolism was primarily due to a reduction in muscle protein synthesis [fractional synthesis rate, 0.081 +/- 0.004 (d 1) vs. 0.054 +/- 0.007%/h (d 28); P = 0.023]. There was no change in muscle protein breakdown. Prolonged inactivity and hypercortisolemia represents a persistent catabolic stimulus that exacerbates strength and lean muscle loss via a chronic reduction in muscle protein synthesis.

Growth hormone therapy initiated before starvation ameliorates the catabolic state and enhances the protein-sparing effect of total parenteral nutrition.

The effect of 7 days of subcutaneously administered bovine growth hormone (bGH) (0.2 mg kg-1 day-1; n = 4) or an equivalent volume of 0.15 mol l-1 saline (n = 3) on protein metabolism was assessed in lambs. The catabolic response to 48 h of starvation and subsequent hypocaloric total parenteral nutrition (TPN) was measured using primed constant intravenous infusions of [15N]urea and [14C]leucine. Following 48 h of starvation and 7 h of TPN, bGH-treated animals had a significantly decreased rate of net protein catabolism compared with controls (mean(s.e.m.) 2.4(0.2) versus 3.2(0.3) g kg-1 day-1, P < 0.01). The mean(s.e.m.) rate of whole-body protein catabolism was also significantly decreased in bGH-treated animals at 10.9(0.3) g kg-1 day-1 compared with 12.9(0.7) g kg-1 day-1 in saline-treated controls (P < 0.05). In addition, the rates of net and whole-body protein catabolism decreased significantly (P < 0.05) during the period of hypocaloric parenteral feeding to mean(s.e.m.) values of 2.3(0.2) and 8.6(0.6) g kg-1 day-1 respectively in bGH-treated animals. By contrast, in saline-treated controls net and whole-body protein catabolism continued to increase during hypocaloric parenteral feeding. There was a significant decrease (P < 0.05) in the rate of [14C]leucine uptake in tissues of the gastrointestinal tract, heart and diaphragm in bGH-treated animals compared with controls. These results demonstrate that daily administration of growth hormone decreases the catabolic response to a metabolic stress, resulting in the conservation of protein in the heart, diaphragm, gastrointestinal tract and musculoskeletal system by a primary anticatabolic action. In addition, growth hormone therapy initiated before induction of the catabolic state enhances the protein-sparing effects of TPN. Further study is justified to determine whether growth hormone therapy initiated before elective or urgent surgery in the nutritionally depleted patient may have a role in reducing the severity of the postoperative catabolic state, particularly in the patient in whom a complicated course is anticipated.

Comparison of Peripheral Metabolic Effects of Insulin and Metformin Following Severe Burn Injury

Both insulin and metformin have been shown to attenuate hyperglycemia and reduce net muscle protein catabolism following burn injury. The purpose of this study was to compare the peripheral metabolic effects of insulin and metformin in severe burn patients. Six adult patients with burns greater than 40% of their body surface underwent metabolic evaluation utilizing isotopic dilution of phenylalanine, femoral arterial and venous blood sampling, and sequential biopsies of leg muscle. Following baseline measurements, insulin was infused into the femoral artery at 0.45 mIU/min 100 mL leg volume. Patients were then given metformin (850 mg every 8 hours) for seven days with repeat metabolic evaluation before and during intra-arterial infusion of insulin. Intra-arterial administration of insulin significantly increased insulin concentrations within the femoral vein, creating hyperinsulinemia localized to the extremity. Metformin had no significant effect on either peripheral glucose clearance or the rate of glucose oxidation. Furthermore, the availability of ATP and energy charge within muscle was not overtly affected by either insulin or metformin. Metformin did significantly increase the fractional synthetic rate of muscle protein which increased even further with insulin administration. Both metformin and insulin separately increased the rate of muscle protein synthesis as calculated using three compartment modeling. This study demonstrates a significant anabolic effect on muscle protein with metformin and a modest response with insulin. Findings also suggest that metformin and insulin may work synergistically to further improve muscle protein kinetics.

Antiglucocorticoid RU38486 reduces net protein catabolism in experimental acute renal failure

BackgroundIn acute renal failure, a pronounced net protein catabolism occurs that has long been associated with corticoid action. By competitively blocking the glucocorticoid receptor with the potent antiglucocorticoid RU 38486, the present study addressed the question to what extent does corticoid action specific to uremia cause the observed muscle degradation, and does inhibition of glucocorticoid action reduce the protein wasting?MethodsRU 38486 was administered in a dose of 50 mg/kg/24 h for 48 h after operation to fasted bilaterally nephrectomized (BNX) male adult Wistar rats and sham operated (SHAM) controls. Protein turnover was evaluated by high performance liquid chromatography (HPLC) of amino acid efflux in sera from isolated perfused hindquarters of animals treated with RU 38486 versus untreated controls.ResultsAdministration of RU 38486 reduces the total amino acid efflux (TAAE) by 18.6% in SHAM and 15.6% in BNX and efflux of the indicator of net protein turnover, phenylalanine (Phe) by 33.3% in SHAM and 13% in BNX animals as compared to the equally operated, but untreated animals. However, the significantly higher protein degradation observed in BNX (0.6 ± 0.2 nmol/min/g muscle) versus SHAM (0.2 ± 0.1 nmol/min/g muscle) rats, as demonstrated by the marker of myofribrillar proteolytic rate, 3-Methylhistidine (3 MH) remains unaffected by administration of RU 38486 (0.5 ± 0.1 v. 0.2 ± 0.1 nmol/min/g muscle in BNX v. SHAM).ConclusionRU 38486 does not act on changes of muscular protein turnover specific to uremia but reduces the effect of stress- stimulated elevated corticosterone secretion arising from surgery and fasting. A potentially beneficial effect against stress- induced catabolism in severe illness can be postulated that merits further study.

Branched-chain Ketoacyl Dehydrogenase Deficiency: Maple Syrup Disease.

Classic maple syrup disease can be managed to allow a benign neonatal course, normal growth, and low hospitalization rates. The majority of affected infants that are prospectively managed have good neurodevelopmental outcome; however, acute metabolic intoxication and neurologic deterioration can develop rapidly at any age. Each episode is associated with a risk for cerebral edema, cerebrovascular compromise, and brain herniation. High plasma leucine and, possibly, alpha-ketoisocaproate are the principal neurotoxins in maple syrup disease. Plasma levels rise rapidly in association with net protein catabolism provoked by common infections and injuries. Transient periods of maple syrup disease encephalopathy appear fully reversible, leaving no clinically detectable neurologic sequelae. In contrast, prolonged amino acid imbalance, particularly if occurring during the critical period of brain development, leads to neuronal hypoplasia, a paucity of synapses, and undermyelination. Stagnated maturation and inadequate nutritional maintenance of brain structure have lifelong neurologic and behavioral consequences. Core elements of effective long-term therapy include screening and identification of asymptomatic newborns, frequent plasma amino acid monitoring, careful attention to branched-chain amino acid nurtriture, prevention of cerebral essential amino acid deficiencies, adequate provision of essential omega-3 class fatty acids and micronutrients deficient in commercial formulas, methods for home monitoring of metabolic control, and a commitment to lifelong therapy. Recognizing the risk for acute leucine intoxication depends on anticipating effects of common childhood infection and physiologic stresses on whole body protein turnover. Successful management of metabolic decompensation is based on the use of home sick-day regimens, rapid availability of branched-chain amino acid-free hyperalimentation solutions for hospitalized children, prevention of hyponatremia in patients with leucinosis, and frequent adjustments of intravenous therapies guided by plasma amino acid levels and indices of metabolic and clinical response.

Effects of insulin-like growth factor on nitrogen balance during hypoxic exposure.

Acute exacerbations of chronic obstructive pulmonary disease (COPD) accompanied with hypoxaemia may induce net protein catabolism and hypoxaemia could be an important trigger of a systemic catabolic response. The aim of this study was to examine the anabolic effects of recombinant human insulin-like growth factor-I (IGF-1) in rats exposed to hypoxia. Although acute hypoxia is usually accompanied with a decrease in dietary intake, the usual nitrogen intake was maintained in this study. Sprague-Dawley rats were maintained by continuous infusion of solution for total parenteral nutrition for 6 days. The animals were then randomly assigned to a normoxic (N) or a hypoxic (H) group. During the last 3 days of the experiment N and H rats were randomised to receive either IGF-I or vehicle. Exposure to hypoxia caused a decrease in body-weight gain accompanied by a negative nitrogen balance, which was mainly due to increased urinary nitrogen excretion. No effect of recombinant human IGF-I treatment on body weight was observed during exposure to hypoxia, although nitrogen balance normalised. The co-infusion of recombinant human insulin-like growth factor-1 and total parenteral nutrition has a significant net anabolic effect, as demonstrated by nitrogen retention and reduction in urine protein excretion observed in rats. Insulin-like growth factor-1 may help to ameliorate the protein catabolism observed under hypoxic conditions.