Skeletal Muscle Amino Acid Research Articles

The Effect of Glutamine Supplementation in Patients Following Elective Surgery and Accidental Injury

The metabolic response to injury, whether a controlled elective surgical procedure or an accidental injury, is characterized by the breakdown of skeletal muscle protein and the translocation of the amino acids to visceral organs and the wound. At these sites, the substrate serves to enhance host defenses, and support vital organ function and wound repair. Glutamine (GLN) plays a major role in these processes, accounting for approximately one third of the translocated nitrogen. From available data, GLN-supplemented intravenous nutrition in patients undergoing elective surgery improves nitrogen balance, helps correct the decreased GLN concentration found in the free intracellular skeletal muscle amino acid pool and enhances net protein synthesis (particularly in skeletal muscle). Six randomized blind trials (two multicentered investigations) reported a decreased length in hospital stay in postoperative patients receiving GLN supplementation. After blunt trauma, GLN supplementation increased plasma concentrations, attenuated the immunosuppression commonly observed and decreased the rate of infection. Patients with burn injury have low GLN plasma and intramuscular concentrations; turnover and synthesis rate are accelerated, yet apparently inadequate to support normal concentrations. These data suggest that GLN supplementation has important effects in catabolic surgical patients, but the exact mechanisms to explain these events remain unknown, and more research is required to explain the apparent benefits of dietary GLN.

Regulation of Skeletal Muscle Amino Acid Metabolism during Exercise

The contribution of amino acid oxidation to total energy expenditure is negligible during short-term intense exercise and accounts for 3-6% of the total adenosine triphosphate supplied during prolonged exercise in humans. While not quantitatively important in terms of energy supply, the intermediary metabolism of several amino acids-notably glutamate, alanine, and the branched-chain amino acids-affects other metabolites, including the intermediates within the tricarboxylic acid (TCA) cycle. Glutamate appears to be a key substrate for the rapid increase in muscle TCA cycle intermediates (TCAI) that occurs at the onset of moderate to intense exercise, due to a rightward shift of the reaction catalyzed by alanine aminotransferase (glutamate + pyruvate <==> alanine + 2-oxoglutarate). The pool of muscle TCAI declines during prolonged exercise, and this has been attributed to an increase in leucine oxidation that relies on one of the TCAI. However, this mechanism does not appear to be quantitatively important due of the relatively low maximal activity of branched-chain oxoacid dehydrogenase, the key enzyme involved. It has been suggested that an increase in TCAI is necessary to attain high rates of aerobic energy production and that a decline in TCAI may be a causative factor in local muscle fatigue. These topics remain controversial, but recent evidence suggests that changes in TCAI during exercise are unrelated to oxidative energy provision in skeletal muscle.

Factors contributing to alterations in skeletal muscle and plasma amino acid profiles in patients with chronic obstructive pulmonary disease

There is increasing evidence of abnormal protein metabolism in patients with chronic obstructive pulmonary disease (COPD), as reflected by lower plasma branched-chain amino acid (BCAA) concentrations and different muscle amino acid (AA) patterns than in age-matched control subjects. We examined whether the low plasma BCAA concentrations in COPD reflect an imbalance between anabolic and catabolic processes as evidenced by a low fat-free mass (FFM) and alterations in the anabolic hormone insulin and whether discrepancies in muscle AA concentrations between studies are related to different patient characteristics. AA profiles in arterial plasma and quadriceps femoris muscle and insulin concentrations in venous plasma were analyzed in 28 postabsorptive COPD patients (14 with and 14 without macroscopic emphysema) and in 28 control subjects. FFM was measured by dual-energy X-ray absorptiometry. The lower sum of plasma BCAAs in the COPD group than in the control subjects was the result of a lower leucine concentration (P: < 0.001); no significant difference in valine and isoleucine was found between the groups. In the COPD group, the lower leucine concentrations were associated with low FFM (P: < 0.01). Compared with the control group, the muscle-to-plasma leucine gradient was higher in the COPD group (P: < 0.001) and was associated with a higher insulin concentration (P: < 0.01). Several muscle AA concentrations were higher or tended to be higher in the group without emphysema than in the control group, whereas nearly all AA concentrations were lower in the group with emphysema. Leucine metabolism is altered in COPD patients and is associated with low FFM and high insulin concentrations. There were striking differences in the skeletal muscle AA profile between the COPD subtypes.

Platelet-activating factor (PAF)-induced decreases in whole-body and skeletal muscle protein synthesis.

Platelet-activating factor (PAF) has been shown to reduce rat skeletal muscle amino acid uptake, which may restrict intracellular amino acid availability for protein synthesis and amino acid oxidation during endotoxemia. We investigated in rats the effect of PAF infusion on amino acid and protein metabolism by measuring (a) whole-body and tissue leucine kinetics; (b) plasma amino acid profile; and (c) muscle RNA activity (protein synthesis efficiency) and relative abundance of myofibrillar proteins. Fasted male Sprague-Dawley rats (250+/-20 g) were given a 4-h i.v. continuous infusion of L-(1-14C)-leucine to determine leucine kinetics during the infusion of PAF (2 microg/kg PAF as a priming i.v. bolus 1 h before a 4-h i.v. infusion of 2 microg/kg/h PAF) or vehicle. PAF infusion caused sustained hypotension, hyperglycemia, hematological alterations, and hyperlacticacidemia. Whole-body protein synthesis was decreased by 24% (P < 0.05) and leucine flux oxidized was increased by 23% (P < 0.05). Leucine flux was reduced, although not significantly (P = 0.07), in PAF-treated rats (n = 8) compared with controls (n = 8). PAF significantly decreased fractional protein synthesis in the rectus abdominus (33%), soleus (30%), and extensor digitorum longus (26%) muscles, but not in the liver. Plasma branched-chain amino acid levels decreased (approximately 30%, P < 0.05) in PAF-treated rats. Muscle RNA activity was 32% lower and myosin relative abundance declined whereas actin was unchanged in PAF-treated rats. PAF induced net protein catabolism as a result of elevated leucine oxidation at the expense of protein synthesis. PAF had the cumulative effects in the skeletal muscle of (a) attenuating amino acid uptake, (b) reducing protein synthesis efficiency, (c) decreasing fractional protein synthesis rate, and (d) decreasing myosin relative abundance. Thus, PAF may be an important mediator of decreased protein synthesis in skeletal muscle during endotoxic and septic shock.

Association of nonsense mutation of dystrophin gene with disruption of sarcoglycan complex in X-linked dilated cardiomyopathy

In a systematic analysis of inherited forms of cardiomyopathy, we previously identified a family with X-linked dilated cardiomyopathy characterised by a mutation in the rod region of dystrophin. We have now attempted to eludicate the genetic mechanism involved in this disease, as well as the role of dystrophin-associated glycoproteins. The affected dystrophin epitope, which lacks binding to the dys-1 antibody, was analysed by single-strand conformation polymorphism analysis, reverse-transcription PCR, and DNA sequencing. Effects on dystrophin-associated glycoproteins were studied by immunohistochemistry and western blotting. A translation-termination mutation (C4148T) in exon 29 of the dystrophin gene was found in all affected family members. Alternative splicing rescued the reading frame and led to the expression of a dystrophin molecule lacking 50 aminoacids both in cardiac and skeletal muscle. Immunohistochemical analysis of the dystrophin-associated proteins revealed a reduction of beta-sarcoglycan and delta-sarcoglycan in the sarcolemma of cardiac muscle but not skeletal muscle tissue. However, western blotting revealed similar amounts of sarcoglycan subunits in both tissues. The molecular mechanism of this subtype of X-linked cardiomyopathy may be explained by a conformational change in exon-29-deleted dystrophin, resulting in disruption of the sarcoglycan assembly in heart muscle but not skeletal muscle.

Effects on skeletal muscle amino acids and whole body nitrogen metabolism of total parenteral nutrition following laparoscopic cholecystectomy and given to healthy volunteers

Effects on skeletal muscle amino acids and whole body nitrogen metabolism of total parenteral nutrition following laparoscopic cholecystectomy and given to healthy volunteers

Oxidized amino acids in the urine of aging rats: potential markers for assessing oxidative stress in vivo.

Oxidative damage of proteins has been implicated in disease and aging. In vitro studies demonstrate that two unnatural amino acids, o,o'-dityrosine and o-tyrosine, are stable markers of protein oxidation. We have investigated the possibility that assaying these compounds in urine could provide a noninvasive way to determine levels of protein oxidation in vivo. Isotope dilution gas chromatography-mass spectrometry was used to quantify levels of o,o'-dityrosine and o-tyrosine in skeletal muscle and urine of aging rats subjected to two interventions: 1) dietary antioxidant supplementation and 2) exercise training. In both sedentary rats and exercise-trained rats, antioxidant therapy reduced levels of protein-bound o,o'-dityrosine in skeletal muscle. In contrast, antioxidant therapy or exercise training minimally affected o-tyrosine levels in this tissue. Levels of the oxidized amino acids in urine samples mirrored those of skeletal muscle proteins. Quantification of the levels of oxidized amino acids in urine may thus serve as a noninvasive measure of oxidative stress in vivo because they change in parallel with levels of protein-bound oxidized amino acids in skeletal muscle.

Counter-regulatory hormones and mechanisms in amino acid metabolism with special reference to the catabolic response in skeletal muscle.

There is evidence that both counter-regulatory hormones, in particular glucocorticoids, and cytokines influence amino acid and protein metabolism in skeletal muscle, and that these two groups of regulators interact in the development of muscle catabolism. Glucocorticoids stimulate muscle proteolysis during sepsis and also in other catabolic conditions. In addition, glucocorticoids regulate muscle glutamine metabolism, resulting in increased glutamine release and reduced glutamine concentrations in skeletal muscle. Glucocorticoids inhibit the glutamine transporter in skeletal muscle and stimulate glutamine synthetase activity. Proinflammatory cytokines, in particular tumor necrosis factor and interleukin-1, inhibit muscle amino acid transport by system A, and these cytokine effects are probably indirect. Most of the catabolic effects of tumor necrosis factor in skeletal muscle, including stimulated protein degradation and inhibited amino acid uptake, are mediated by glucocorticoids.

Testosterone injection stimulates net protein synthesis but not tissue amino acid transport

Testosterone administration (T) increases lean body mass and muscle protein synthesis. We investigated the effects of short-term T on leg muscle protein kinetics and transport of selected amino acids by use of a model based on arteriovenous sampling and muscle biopsy. Fractional synthesis (FSR) and breakdown (FBR) rates of skeletal muscle protein were also directly calculated. Seven healthy men were studied before and 5 days after intramuscular injection of 200 mg of testosterone enanthate. Protein synthesis increased twofold after injection (P < 0.05), whereas protein breakdown was unchanged. FSR and FBR calculations were in accordance, because FSR increased twofold (P < 0.05) without a concomitant change in FBR. Net balance between synthesis and breakdown became more positive with both methodologies (P < 0.05) and was not different from zero. T injection increased arteriovenous essential and nonessential nitrogen balance across the leg (P < 0.05) in the fasted state, without increasing amino acid transport. Thus T administration leads to an increased net protein synthesis and reutilization of intracellular amino acids in skeletal muscle.

Effects on skeletal muscle amino acids and whole bodynitrogen metabolism of total parenteral nutrition following laparoscopic cholecystectomy and given to healthy volunteers

In this descriptive study total parenteral nutrition (TPN) without glutamine was administered over 2 days to patients undergoing laparoscopic cholecystectomy ( n = 8) and to volunteers ( n = 8). Effects on muscle amino acids and nitrogen economy were studied. Muscle protein synthesis, determined by ribosome and polyribosome concentrations were measured in the patients. In both patients and volunteers the muscle amino acid patterns indicated muscle protein catabolism. Decreases in glutamine were seen in both groups (21.8 ± 4.6% in patients and 17.5 ± 5.4% in the volunteers). In both groups a negative nitrogen balance was seen (−4.1 ± 1.2 gram and −10.3 ± 2.4 gram respectively). The patients also showed decreased ribosome (by 13.7 ± 4.5%) and polyribosome concentration (by 17.4 ± 4.6%), indicating a decrease in muscle protein synthesis. No comparisons are made between the two groups since they are not comparable. However, it is concluded in these two descriptive studies, that during these conditions, TPN does not prevent muscle protein catabolism either during basal conditions or after a minor surgical trauma such as laparoscopic cholecystectomy.

The Increased Skeletal Muscle Protein Turnover of the Streptozotozin Diabetic Rat Is Associated with High Concentrations of Branched-Chain Amino Acids

Experimental streptozotozin-induced diabetes resulted in important changes in body weight which were associated with abnormalities in water and food intake. In addition, diabetic rats showed a clear muscle atrophy involving a decrease in both skeletal muscle size and protein content. This was accompanied by a marked loss of total carcass nitrogen. These changes were related to important alterations in protein turnover in skeletal muscle. Thus, the diabetic animals showed changes in the fractional protein rates of both synthesis (decreased by 37%) and degradation (increased by 140%). The increased protein degradation observed in the muscle of the diabetic animals was associated with important changes in the concentration of both circulating and muscle amino acids. Interestingly, the diabetic animals did not show important changes in either liver or kidney protein turnover rates, in spite of having a clear increase (over 50%) in kidney mass. In addition, and although the total amino acid concentration was not affected by the diabetic state, the chemically induced diabetic animals showed important elevations of branched-chain amino acids (leucine, isoleucine, and valine) in both blood and skeletal muscle. Similarly, important decreases in the blood concentrations of glutamate + glutamine, alanine, glycine, proline, serine, and threonine were also observed. These observations reinforce the idea of the association between muscle protein wasting, increased protein turnover, and alterations in branched-chain amino acids previously proposed by our group.

Defective glycolysis and catabolism of protein and amino acids in skeletal muscle during metabolic acidosis.

Defective glycolysis and catabolism of protein and amino acids in skeletal muscle during metabolic acidosis.

Regulation of glutamate dehydrogenase by branched-chain amino acids in skeletal muscle from rats and chicks

Little information is available regarding the regulation of glutamate dehydrogenase in skeletal muscle. We investigated the regulation of glutamate dehydrogenase by branched-chain amino acids (BCAA) in skeletal muscles from rats and chicks and determined the effects of metabolic acidosis on the activity and regulation of this enzyme by BCAA in rat skeletal muscle. Skeletal muscle mitochondria were prepared from normal rats and chicks and acidotic rats. Mitochondrial glutamate dehydrogenase activity was measured in the presence or absence of BCAA. Metabolic acidosis was induced by feeding rats 1.5% NH 4CI as drinking water. Glutamate dehydrogenase activity was stimulated by leucine ( P < 0.001) and isoleucine ( P < 0.05) in rat muscles and by leucine ( P < 0.05) in chick muscles in a concentration-dependent manner. Both leucine and isoleucine had their maximum effects at a concentration of 1 mM (45% by leucine and 27% by isoleucine in rat muscle; 36% by leucine in chick muscle). The maximum stimulatory effects of leucine and isoleucine in rat muscles were additive. Neither valine nor 2-oxoisocaproate had an effect on glutamate dehydrogenase activity in rat or chick muscles. In acidotic rats, the basal activity of skeletal muscle glutamate dehydrogenase was 1.8-fold ( P < 0.01) greater than in control rats; leucine, isoleucine, and valine significantly increased glutamate dehydrogenase activity (maximally 86, 55 and 33%, respectively; P < 0.05). We conclude that glutamate dehydrogenase activity in skeletal muscle from rats and chicks is regulated by BCAA, and that a species difference exists between rats and chicks. Metabolic acidosis increases the activity of glutamate dehydrogenase and its sensitivity to BCAA.

Effects of tumor necrosis factor alpha on skeletal muscle amino acid metabolism studied in-vivo.

The present study was performed to determine the chronology of the effects of a single 50 ug subcutaneous dose of TNF on food intake, weight gain, and skeletal muscle protein metabolism in normal rats. Earlier work demonstrated that a single subcutaneous dose of 50 ug of tumor necrosis factor alpha (TNF) significantly increased skeletal muscle protein synthesis and breakdown in the tumor bearing rat [1]. Some of the earlier work demonstrated that TNF can reduce food intake, weight gain and enhance muscle catabolism. Twenty-five male Sprague Dawley rats were randomized assigned to treatment or saline arms of the study. Rates of in vivo incorporation of L-1-14C-leucine into skeletal muscle were measured by the flooding dose technique. Rats were studied 6 and 60 hours after TNF or saline. Six hours after administration of the TNF, the total skeletal muscle amino acid concentration was significantly reduced by 20%. The greatest reductions were seen in lysine, arginine, and isoleucine (39-53%) followed by serine, tyrosine, ornithine, threonine and alanine (18-32%). Despite this drop in skeletal muscle amino acid concentrations, the rate of skeletal muscle protein synthesis was similar to the controls (12.2 +/- 4.1 vs 13.8 +/- 3.7 %/day, mean +/- sd, saline vs TNF treated, respectively). Dietary intake (8.2 +/- 0.5 vs 7.3 +/- 1.1 g/day) and weight gain (7.1 +/- 1.1 vs 9.1 +/- 3.8 g/day) were not affected by TNF administration. However, there was a significant increase in skeletal muscle protein synthesis rate in the TNF treated group after 60 hours (17.8 +/- 4.0 vs 12.2 +/- 4.1 %/day) but not after 6 hours (13.8 +/- 3.7 vs 13.7 +/- 3.3 %/day) compared to saline treated rats, respectively. TNF administration after 60 hours was not associated with an elevated skeletal muscle 3-methyl-histidine concentration or a reduced nitrogen balance. These data suggest that at a 50 ug subcutaneous dose of TNF, an early (6 hours) effect is to reduce skeletal muscle of amino acids without effecting either synthesis or breakdown. A later effect (60 hours) is to normalize skeletal muscle amino acid concentration and to increase skeletal muscle protein synthesis. This suggests that TNF may acutely alter amino acid transport as one of its modes of action.

Branched-chain alpha-keto acid dehydrogenase complex in rat skeletal muscle: regulation of the activity and gene expression by nutrition and physical exercise.

Branched-chain alpha-keto acid dehydrogenase complex is the rate-limiting enzyme in the catabolism of branched-chain amino acids in skeletal muscle. It is suggested that activation of this enzyme in the muscle during exercise plays an important role in the increased oxidation of branched-chain amino acids in the muscle. Evidence suggests that branched-chain alpha-keto acids, the substrates for the enzyme, regulate the activity state of the enzyme in the muscle during exercise through phosphorylation/dephosphorylation cycle of the enzyme protein. We propose a model for the mechanism of enzyme activation by exercise. In addition to this acute effect of exercise, we present evidence suggesting that exercise training modulates the enzyme activity and gene expression for the enzyme. Increases in the total activity as well as enzyme proteins by exercise training are suggested to be associated with mitochondrial biogenesis in the muscle.

Overnight branched-chain amino acid infusion causes sustained suppression of muscle proteolysis

Short-term (3 to 4 hours) infusion of branched-chain amino acids (BCAA) has been shown to suppress muscle protein breakdown. Whether these effects are sustained with chronic elevations of BCAA is not known. In the present study, we examined the effect of an overnight (16-hour) systemic BCAA infusion on whole-body and skeletal muscle amino acid metabolism, as assessed by simultaneously measured 3H-phenylalanine and 14C-leucine kinetics in eight normal volunteers; 10 overnight-fasted subjects studied during a 4-hour saline infusion served as controls. Overnight BCAA infusion increased plasma BCAA concentrations by fivefold to eightfold, and this was associated with a 20% to 60% decline in arterial concentrations of other amino acids. For Phe, this decline was mediated by a reduction in the systemic rate of appearance ([R a] 0.38 ± 0.03 v 0.60 ± 0.01 μmol/kg/min for BCAA and saline, respectively, P < .001). Endogenous Leu R a, calculated more indirectly as the difference between the total Leu R a and the unlabeled Leu infusion rate, did not differ between groups. In the forearm, overnight BCAA infusion resulted in a diminished net release of Phe (−3 ± 2 v −18 ± 4 [saline] nmol/min/100 mL, P < .02), and BCAA balance became markedly positive (751 ± 93 v −75 ± 30, P < .001). The diminished net forearm Phe release was accounted for by a decrease in local Phe R a ( P < .02). As with the systemic endogenous Leu R a, forearm Leu R a was not reproducibly affected by infused BCAA. These findings suggest a need for caution in the application of amino acid tracer kinetic methods when tracer and unlabeled tracee are infused simultaneously. In conclusion, overnight BCAA infusion caused a sustained decline in most plasma amino acids and in net forearm release of Phe, effects attributable to a sustained suppression of whole-body and muscle proteolysis.

Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle.

We have investigated the mechanisms of the anabolic effect of insulin on muscle protein metabolism in healthy volunteers, using stable isotopic tracers of amino acids. Calculations of muscle protein synthesis, breakdown, and amino acid transport were based on data obtained with the leg arteriovenous catheterization and muscle biopsy. Insulin was infused (0.15 mU/min per 100 ml leg) into the femoral artery to increase femoral venous insulin concentration (from 10 +/- 2 to 77 +/- 9 microU/ml) with minimal systemic perturbations. Tissue concentrations of free essential amino acids decreased (P < 0.05) after insulin. The fractional synthesis rate of muscle protein (precursor-product approach) increased (P < 0.01) after insulin from 0.0401 +/- 0.0072 to 0.0677 +/- 0.0101%/h. Consistent with this observation, rates of utilization for protein synthesis of intracellular phenylalanine and lysine (arteriovenous balance approach) also increased from 40 +/- 8 to 59 +/- 8 (P < 0.05) and from 219 +/- 21 to 298 +/- 37 (P < 0.08) nmol/min per 100 ml leg, respectively. Release from protein breakdown of phenylalanine, leucine, and lysine was not significantly modified by insulin. Local hyperinsulinemia increased (P < 0.05) the rates of inward transport of leucine, lysine, and alanine, from 164 +/- 22 to 200 +/- 25, from 126 +/- 11 to 221 +/- 30, and from 403 +/- 64 to 595 +/- 106 nmol/min per 100 ml leg, respectively. Transport of phenylalanine did not change significantly. We conclude that insulin promoted muscle anabolism, primarily by stimulating protein synthesis independently of any effect on transmembrane transport.

Transmembrane transport and intracellular kinetics of amino acids in human skeletal muscle

We have used stable isotopic tracers of amino acids to measure in vivo transmembrane transport of phenylalanine, leucine, lysine, alanine, and glutamine as well as the rates of intracellular amino acid appearance from proteolysis, de novo synthesis, and disappearance to protein synthesis in human skeletal muscle. Calculations were based on data obtained by the arteriovenous catheterization of the femoral vessels and muscle biopsy. We found that the fractional contribution of transport from the bloodstream to the total intracellular amino acid appearance depends on the individual amino acid, varying between 0.63 +/- 0.02 for phenylalanine and 0.22 +/- 0.02 for alanine. Rates of alanine and glutamine de novo synthesis were approximately eight and five times their rate of appearance from protein breakdown, respectively. The model-derived rate of protein synthesis was highly correlated with the same value calculated by means of the tracer incorporation technique. Furthermore, amino acid transport rates were in the range expected from literature values. Consequently, we conclude that our new model provides a valid means of quantifying the important aspects of protein synthesis, breakdown, and amino acid transport in human subjects.

Alanine metabolism in rats bearing the Yoshida AH-130 ascites hepatoma.

Rats bearing the Yoshida AH-130 ascites hepatoma, a cachectic rat tumour, showed signs of important muscle wasting with reduced muscle weights. This phenomenon was associated with a decreased rate of in vivo alanine oxidation as measured by the production of 14CO2 from [U-14C]alanine intragastrically administered. It was later found that the decreased amino acid oxidation was associated with a reduced uptake in skeletal muscle as measured in incubated soleus muscles, thus suggesting that the decreased in vivo oxidation is basically due to a reduced oxidation of the amino acid in skeletal muscle. The decrease in alanine oxidation in the tumour-bearing animals was also associated with higher circulating alanine concentrations in their blood. In addition, tumour-bearing rats presented a lower (26%) protein synthetic rate in skeletal muscle, as measured by the incorporation of [14C]phenylalanine into muscle protein. The addition of insulin to the incubation medium abolished the lower rate of protein synthesis, thus suggesting a greater response to this hormone by the muscle of tumour-bearing rats. In conjunction with a reduced protein synthesis, tumour-bearing rats showed a clearly enhanced rate of protein degradation in isolated skeletal muscles. The results presented confirm previous observations suggesting that the skeletal muscle of tumour bearing animals is in a profound negative nitrogen balance which partially accounts for the wasting observed in the tissue. In addition, the present study allows us to conclude that, in spite of the increased alanine utilization for both gluconeogenesis and tumour growth, the oxidation of alanine by the whole animal is decreased in the tumour-bearing rats. This seems to be associated with a decreased ability of skeletal muscle to handle this amino acid.

Extremity Metabolism in the Cachectic, VX-2 Carcinoma-Bearing Rabbit

The pathophysiology of skeletal muscle loss in cancer cachexia is poorly understood. Immature, male, New Zealand White rabbits (TBs; n = 11) were implanted with VX-2 carcinoma and various indices of systemic and limb metabolism were examined in comparison with pair-fed controls (PFCs; n = 9) and normal controls (NCs; n = 22) fed ad lib. The TBs became hypophagic and experienced reduced growth relative to both control groups ( P ⪡ 0.001). At 7 weeks (tumor burden 3-6% of body weight: no metastasis) the TBs had the following statistically significant differences from NCs: anemia, neutrophilic granulocytosis and thrombocytosis, hypercalcemia, hypoinsulinemia, elevated plasma triglycerides and altered plasma amino acids, increased hind limb effluxes of lactate and most amino acids. These alterations were not caused by hypophagin, since the PFCs were normal at 7 weeks with regard to all measured parameters except body weight and limb flow, both of which were reduced. The decrease in flow ( P < 0.05) apparently contributed to conservation of skeletal muscle amino acids in the PFCs. Young New Zealand White rabbits implanted with VX-2 carcinoma manifest tumor burden, wasting, and metabolic alterations qualitatively similar to those seen with many human cancers.