Poor tolerability of thalidomide in end-stage oesophageal cancer.

Oesophageal cancer cachexia is a significant clinical problem, resulting in excessive morbidity and mortality. In a pilot study, 10 patients with cachexia due to advanced cancer of the oesophagus gained weight, including lean tissue, after 14-day treatment with thalidomide. Here, we present randomised placebo controlled trial data over a 6-week period to test the hypothesis that thalidomide is superior to placebo in terms of weight gain in patients with cachexia caused by oesophageal cancer. Thalidomide, 200 mg daily, or an identical placebo was given to patients with advanced oesophageal cancer. Total body weight and lean body mass were assessed in addition to drug tolerability and performance indices. Thirty-four patients were recruited. Of these, six given thalidomide and 16 given placebo completed the protocol; all withdrawals were due to adverse drug reactions or complications of disease. Thalidomide showed no benefit over placebo in participants who completed the protocol. These data suggest that thalidomide is poorly tolerated in patients with advanced cancer of the oesophagus and may not ameliorate the progression of cachexia. In the absence of hard supportive evidence, off-licence treatment with thalidomide should be used with great caution as an adjunct to nutritional support in patients with advanced cancer.

Resistance exercise enhances mTOR and MAPK signalling in human muscle over that seen at rest after bolus protein ingestion.

AIM: Feeding protein after resistance exercise enhances the magnitude and duration of myofibrillar protein synthesis (MPS) over that induced by feeding alone. We hypothesized that the underlying mechanism for this would be a greater and prolonged phosphorylation of signalling involved in protein translation. METHODS: Seven healthy young males performed unilateral resistance exercise followed immediately by the ingestion of 25 g of whey protein to maximally stimulate MPS in a rested and exercised leg. RESULTS: Phosphorylation of p70 ribosomal protein S6 kinase (p70S6K) was elevated (P<0.05) above fasted at 1 h at rest whereas it was elevated at 1, 3 and 5 h after exercise with protein ingestion and displayed a similar post-exercise time course to that shown by MPS. Extracellular regulated kinase1/2 (ERK1/2) and p90 ribosomal S6 kinase (p90RSK) phosphorylation were unaltered after protein ingestion at rest but were elevated (P < 0.05) above fasted early in recovery (1 h) and were greater for the exercised-fed leg than feeding alone (main effect; P < 0.01). Eukaryotic elongation factor 2 (eEF2) phosphorylation was also less (main effect; P<0.05) in the exercised-fed leg than in the rested leg suggesting greater activity after exercise. Eukaryotic initiation 4E binding protein-1 (4EBP-1) phosphorylation was increased (P<0.05) above fasted to the same extent in both conditions. CONCLUSION: Our data suggest that resistance exercise followed by protein feeding stimulates MPS over that induced by feeding alone in part by enhancing the phosphorylation of select proteins within the mammalian target of rapamycin (p70S6K, eEF2) and by activating proteins within the mitogen-activated protein kinase (ERK1/2, p90RSK) signalling.

Facts, noise and wishful thinking: muscle protein turnover in aging and human disuse atrophy.

Surprisingly little is known about the mechanisms of muscle atrophy with aging and disuse in human beings, in contrast to rodents, from which much has been extrapolated to explain the human condition. However, this extrapolation is likely unwarranted because the time course, extent of wasting, muscle fiber involvement and alterations of muscle protein turnover are all quite different in rodent and human muscle. Furthermore, there is little evidence that static indices of protein turnover represent dynamic changes and may be misleading. With disuse there are reductions in the rate of muscle protein synthesis (MPS) large enough to explain the atrophic loss of muscle protein without a concomitant increase in proteolysis. In aging, there is no evidence that there are marked alterations in basal muscle protein turnover in healthy individuals but instead the ability to maintain muscle after feeding is compromised. This anabolic resistance is evident with physical inactivity, which exacerbates the inability to maintain muscle mass with aging. The main conclusion of this review is that in uncomplicated, non-inflammatory disuse atrophy, the facilitative change causing loss of muscle mass is a depression of MPS, exacerbated by anabolic resistance during feeding, with possible adaptive depressions, rather than increases, of muscle proteolysis.

Alterations of protein turnover underlying disuse atrophy in human skeletal muscle.

Unloading-induced atrophy is a relatively uncomplicated form of muscle loss, dependent almost solely on the loss of mechanical input, whereas in disease states associated with inflammation (cancer cachexia, AIDS, burns, sepsis, and uremia), there is a procatabolic hormonal and cytokine environment. It is therefore predictable that muscle loss mainly due to disuse alone would be governed by mechanisms somewhat differently from those in inflammatory states. We suggest that in vivo measurements made in human subjects using arterial-venous balance, tracer dilution, and tracer incorporation are dynamic and thus robust by comparison with static measurements of mRNA abundance and protein expression and/or phosphorylation in human muscle. In addition, measurements made with cultured cells or in animal models, all of which have often been used to infer alterations of protein turnover, appear to be different from results obtained in immobilized human muscle in vivo. In vivo measurements of human muscle protein turnover in disuse show that the primary variable that changes facilitating the loss of muscle mass is protein synthesis, which is reduced in both the postabsorptive and postprandial states; muscle proteolysis itself appears not to be elevated. The depressed postprandial protein synthetic response (a phenomenon we term "anabolic resistance") may even be accompanied by a diminished suppression of proteolysis. We therefore propose that most of the loss of muscle mass during disuse atrophy can be accounted for by a depression in the rate of protein synthesis. Thus the normal diurnal fasted-to-fed cycle of protein balance is disrupted and, by default, proteolysis becomes dominant but is not enhanced.

Cyclic stretch reduces myofibrillar protein synthesis despite increases in FAK and anabolic signalling in L6 cells.

Muscle protein synthesis is increased after exercise, but evidence is now accruing that during muscular activity it is suppressed. In life, muscles are subjected to shortening forces due to contraction, but may also be subject to stretching forces during lengthening. It would be biologically inefficient if contraction and stretch have different effects on muscle protein turnover, but little is known about the metabolic effects of stretch. To investigate this, we assessed myofibrillar and sarcoplasmic protein synthesis (MPS, SPS, respectively) by incorporation of [1-13C]proline (using gas chromatography-mass spectrometry) and anabolic signalling (by phospho-immunoblotting and kinase assays) in cultured L6 skeletal muscle cells during 30 min of cyclic stretch and over 30 min intervals for up to 120 min afterwards. SPS was unaffected, whereas MPS was suppressed by 40 +/- 0.03% during stretch, before returning to basal rates by 90-20 min afterwards. Paradoxically, stretch stimulated anabolic signalling with peak values after 2-30 min: e.g. focal adhesion kinase (FAK Tyr576/577; +28 +/- 6%), protein kinase B activity (Akt; +113 +/- 31%), p70S6K1 (ribosomal S6 kinase Thr389; 25 +/- 5%), 4E binding protein 1 (4EBP1 Thr37/46; 14 +/- 3%), eukaryotic elongation factor 2 (eEF2 Thr56; -47 +/- 4%), extracellular regulated protein kinase 1/2 (ERK1/2 Tyr202/204; +65% +/- 9%), eukaryotic initiation factor 2alpha (eIF2alpha Ser51; -20 +/- 5%, P < 0.05) and eukaryotic initiation factor 4E (eIF4E Ser209; +33 +/- 10%, P < 0.05). After stretch, except for Akt activity, stimulatory phosphorylations were sustained: e.g. FAK (+26 +/- 11%) for > or =30 min, eEF2 for > or =60 min (peak -45 +/- 4%), 4EBP1 for > or =90 min (+33 +/- 5%), and p70S6K1 remained elevated throughout (peak +64 +/- 7%). Adenosine monophosphate-activated protein kinase (AMPK) phosphorylation was unchanged throughout. We report for the first time that acute cyclic stretch specifically suppresses MPS, despite increases in activity/phosphorylation of elements thought to increase anabolism.

Disassociation between the effects of amino acids and insulin on signaling, ubiquitin ligases, and protein turnover in human muscle.

We determined the effects of intravenous infusion of amino acids (AA) at serum insulin of 5, 30, 72, and 167 mU/l on anabolic signaling, expression of ubiquitin-proteasome components, and protein turnover in muscles of healthy young men. Tripling AA availability at 5 mU/l insulin doubled incorporation of [1-(13)C]leucine [i.e., muscle protein synthesis (MPS), P < 0.01] without affecting the rate of leg protein breakdown (LPB; appearance of d(5)-phenylalanine). While keeping AA availability constant, increasing insulin to 30 mU/l halved LPB (P < 0.05) without further inhibition at higher doses, whereas rates of MPS were identical to that at 5 mU/l insulin. The phosphorylation of PKB Ser(473) and p70(S6k) Thr(389) increased concomitantly with insulin, but whereas raising insulin to 30 mU/l increased the phosphorylation of mTOR Ser(2448), 4E-BP1 Thr(37/46), or GSK3beta Ser(9) and decreased that of eEF2 Thr(56), higher insulin doses to 72 and 167 mU/l did not augment these latter responses. MAFbx and proteasome C2 subunit proteins declined as insulin increased, with MuRF-1 expression largely unchanged. Thus increasing AA and insulin availability causes changes in anabolic signaling and amounts of enzymes of the ubiquitin-proteasome pathway, which cannot be easily reconciled with observed effects on MPS or LPB.

Rheumatoid cachexia: a clinical perspective.

Rheumatoid cachexia is under-recognized in clinical practice. The loss of lean body tissue, which characterizes cachexia, is often compensated for by gain in body fat-so called 'cachectic obesity'-so that 85% or more RA patients have a normal BMI. Severe cachexia with loss of weight leads to increased morbidity and premature mortality but loss of muscle bulk with a normal BMI also associates with poor clinical outcomes. Increasing BMI, even into the obese range, is associated with less joint damage and reduced mortality. Measurement of body composition using DXA and other techniques is feasible but the results must be interpreted with care. Newer techniques such as whole-body MRI will help define with more confidence the mass and distribution of fat and muscle and help elucidate the relationships between body composition and outcomes. Cachexia shows little response to diet alone but progressive resistance training and anti-TNF therapies show promise in tackling this potentially disabling extra-articular feature of RA.

Exercise- and nutrient-controlled mechanisms involved in maintenance of the musculoskeletal mass.

The mechanisms of maintenance of the protein mass of muscle and associated connective tissue and bone are becoming more accessible as a result of the use of a combination of well-established techniques for measurement of protein turnover and measurement of protein expression and phosphorylation state of signalling molecules involved in anabolic and catabolic responses. Amino acids, hormones and physical activity appear to be the major short-term physiological regulators of muscle mass, mainly through their actions on protein synthesis and breakdown, on a time scale of minutes to hours, with duration of changes in gene expression up to weeks. Amino acids are the main components in the diet regulating protein turnover, having marked effects in stimulating muscle protein synthesis and with almost no effect on muscle protein breakdown. Branched-chain amino acids, and in particular leucine, simulate protein synthesis via signalling pathways involving mTOR (mammalian target of rapamycin) in a dose-response manner. Insulin has little effect on protein synthesis in human muscle, but it has a marked inhibitory effect on protein breakdown. The amino acid simulation of anabolism is not dependent on the presence of insulin, IGF-1 (insulin-like growth factor-1) or growth hormone. Exercise not only stimulates protein synthesis in muscle, but also in tendon; and disuse atrophy is accompanied by marked decreases of both muscle and tendon collagen protein synthesis. Bone collagen synthesis appears to be nutritionally regulated by the availability of amino acids, but not lipid or glucose.

Collagen synthesis in human musculoskeletal tissues and skin.

We have developed a direct method for the measurement of human musculoskeletal collagen synthesis on the basis of the incorporation of stable isotope-labeled proline or leucine into protein and have used it to measure the rate of synthesis of collagen in tendon, ligament, muscle, and skin. In postabsorptive, healthy young men (28 +/- 6 yr) synthetic rates for tendon, ligament, muscle, and skin collagen were 0.046 +/- 0.005, 0.040 +/- 0.006, 0.016 +/- 0.002, and 0.037 +/- 0.003%/h, respectively (means +/- SD). In postabsorptive, healthy elderly men (70 +/- 6 yr) the rate of skeletal muscle collagen synthesis is greater than in the young (0.023 +/- 0.002%/h, P < 0.05 vs. young). The rates of synthesis of tendon and ligament collagen are similar to those of mixed skeletal muscle protein in the postabsorptive state, whereas the rate for muscle collagen synthesis is much lower in both young and elderly men. After nutrient provision, collagen synthesis was unaltered in tendon and skeletal muscle, remaining at postabsorptive values (young: tendon, 0.045 +/- 0.008%/h; muscle, 0.016 +/- 0.003%/h; elderly: muscle, 0.024 +/- 0.003%/h). These results demonstrate that the rate of human musculoskeletal tissue collagen synthesis can be directly and robustly measured using stable isotope methodology.

Metabolic activity and collagen turnover in human tendon in response to physical activity.

Connective tissue of the human tendon plays an important role in force transmission. The extracellular matrix turnover of tendon is influenced by physical activity. Blood flow, oxygen demand, and the level of collagen synthesis and matrix metalloproteinases increase with mechanical loading. Gene transcription and especially post-translational modifications of proteins of the extracellular matrix are enhanced following exercise. Conversely, inactivity markedly decreases collagen turnover. Training leads to a chronically increased collagen turnover, and dependent on the type of collagen also to some degree of net collagen synthesis. These changes modify the biomechanical properties of the tissue (for example, viscoelastic characteristics) as well as the structural properties of the in collagen (for example, cross-sectional area). Mechanical loading of human tendon does result in a marked interstitial increase in growth factors that are known potentially to stimulate synthesis of collagen and other extracellular matrix proteins. Taken together, human tendon tissue mounts a vigorous acute and chronic response to mechanical loading in terms of metabolic-circulatory changes as well as of extracellular matrix formation. These changes may contribute to training-induced adaptation of biomechanical properties consisting of altered resistance to loading and enhanced tolerance to strenuous exercise. Understanding of such changes is a pre-requisite in the development of measures aimed at prevention of overuse tendon injuries occurring during sport, work or leisure-related activities.

Selective activation of AMPK-PGC-1alpha or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation.

Endurance training induces a partial fast-to-slow muscle phenotype transformation and mitochondrial biogenesis but no growth. In contrast, resistance training mainly stimulates muscle protein synthesis resulting in hypertrophy. The aim of this study was to identify signaling events that may mediate the specific adaptations to these types of exercise. Isolated rat muscles were electrically stimulated with either high frequency (HFS; 6x10 repetitions of 3 s-bursts at 100 Hz to mimic resistance training) or low frequency (LFS; 3 h at 10 Hz to mimic endurance training). HFS significantly increased myofibrillar and sarcoplasmic protein synthesis 3 h after stimulation 5.3- and 2.7-fold, respectively. LFS had no significant effect on protein synthesis 3 h after stimulation but increased UCP3 mRNA 11.7-fold, whereas HFS had no significant effect on UCP3 mRNA. Only LFS increased AMPK phosphorylation significantly at Thr172 by approximately 2-fold and increased PGC-1alpha protein to 1.3 times of control. LFS had no effect on PKB phosphorylation but reduced TSC2 phosphorylation at Thr1462 and deactivated translational regulators. In contrast, HFS acutely increased phosphorylation of PKB at Ser473 5.3-fold and the phosphorylation of TSC2, mTOR, GSK-3beta at PKB-sensitive sites. HFS also caused a prolonged activation of the translational regulators p70 S6k, 4E-BP1, eIF-2B, and eEF2. These data suggest that a specific signaling response to LFS is a specific activation of the AMPK-PGC-1alpha signaling pathway which may explain some endurance training adaptations. HFS selectively activates the PKB-TSC2-mTOR cascade causing a prolonged activation of translational regulators, which is consistent with increased protein synthesis and muscle growth. We term this behavior the "AMPK-PKB switch." We hypothesize that the AMPK-PKB switch is a mechanism that partially mediates specific adaptations to endurance and resistance training, respectively.

Protein synthesis rates in human muscles: neither anatomical location nor fibre-type composition are major determinants.

In many animals the rate of protein synthesis is higher in slow-twitch, oxidative than fast-twitch, glycolytic muscles. To discover if muscles in the human body also show such differences, we measured [13C]leucine incorporation into proteins of anatomically distinct muscles of markedly different fibre-type composition (vastus lateralis, triceps, soleus) after an overnight fast and during infusion of a mixed amino acid solution (75 mg amino acids kg(-1) h(-1)) in nine healthy, young men. Type-1 fibres contributed 83 +/- 4% (mean +/-s.e.m.) of total fibres in soleus, 59 +/- 3% in vastus lateralis and 22 +/- 2% in triceps. The basal myofibrillar and sarcoplasmic protein fractional synthetic rates (FSR, % h(-1)) were 0.034 +/- 0.001 and 0.064 +/- 0.001 (soleus), 0.031 +/- 0.001 and 0.060 +/- 0.001 (vastus), and 0.027 +/- 0.001 and 0.055 +/- 0.001 (triceps). During amino acid infusion, myofibrillar protein FSR increased to 3-fold, and sarcoplasmic to 2-fold basal values (P < 0.001). The differences between muscles, although significant statistically (triceps versus soleus and vastus lateralis, P < 0.05), were within approximately 15%, biologically probably insignificant. The rates of collagen synthesis were not affected by amino acid infusion and varied by < 5% between muscles and experimental conditions.

Bidirectional substrate fluxes through the system N (SNAT5) glutamine transporter may determine net glutamine flux in rat liver.

System N (SNAT3 and SNAT5) amino acid transporters are key mediators of glutamine transport across the plasma membrane of mammalian cell types, including hepatocytes and astrocytes. We demonstrate that SNAT5 shows simultaneous bidirectional glutamine fluxes when overexpressed in Xenopus oocytes. Influx and efflux are both apparently Na+ dependent but, since they are not directly coupled, the carrier is capable of mediating net amino acid movement across the cell membrane. The apparent Km values for glutamine influx and efflux are similar (approximately 1 mm) and the transporter behaviour is consistent with a kinetic model in which re-orientation of the carrier from outside- to inside-facing conformations (either empty or substrate loaded) is the limiting step in the transport cycle. In perfused rat liver, the observed relationship between influent (portal) glutamine concentration and net hepatic glutamine flux may be described by a simple kinetic model, assuming the balance between influx and efflux through System N determines net flux, where under physiological conditions efflux is generally saturated owing to high intracellular glutamine concentration. SNAT5 shows a more periportal mRNA distribution than SNAT3 in rat liver, indicating that SNAT5 may have particular importance for modulation of net hepatic glutamine flux.

Claims for the anabolic effects of growth hormone: a case of the emperor's new clothes?

This review examines the evidence that growth hormone has metabolic effects in adult human beings. The conclusion is that growth hormone does indeed have powerful effects on fat and carbohydrate metabolism, and in particular promotes the metabolic use of adipose tissue triacylglycerol. However, there is no proof that net protein retention is promoted in adults, except possibly of connective tissue. The overexaggeration of the effects of growth hormone in muscle building is effectively promoting its abuse and thereby encouraging athletes and elderly men to expose themselves to increased risk of disease for little benefit.

Effects of ageing and human whole body and muscle protein turnover.

Prevalence of sarcopenia is up to 60% of those individuals over 80 years of age and is associated with increased disability. The causes behind the age-related loss of muscle are difficult to discern. Measurements of protein synthesis/breakdown and net protein balance are important, and further methodological development is warranted. Whole body protein turnover is changed only little - if at all - with ageing, when corrected for fat free mass of the individuals. Discrepancies in reports are often related to inconsistent recordings of energy intake especially protein and variation in subject, gender and physical activity level. Ageing is associated with reduced sensitivity toward amino acids, increased first pass uptake in a splanchnic region and a reduced postprandial stimulation of protein synthesis. Physical activity and amino acids are additive in effect also in elderly individuals, and timing of training and protein intake is crucial, in that early intake of amino acids is advantageous with regards to stimulation of protein synthesis.

Sequential extracts of human bone show differing collagen synthetic rates.

Type I collagen is the major bone protein. Little is known quantitatively about human bone collagen synthesis in vivo, despite its importance for the understanding of bone formation and turnover. Our aim was to develop a method that could be used for the physiological and pathophysiological investigation of human bone collagen synthesis. We have carried out preliminary studies in patients undergoing hip replacement and in pigs to validate the use of the flooding dose method using (13)C- or (15)N-labelled proline and we have now refined our techniques to allow them to be used in a normal clinical or physiological setting. The results show that the application of a flooding dose causes bone free-proline labelling to equilibrate with that of blood in pigs and human beings, so that only 150 mg of bone will provide enough sample to prepare and measure the labelling of three fractions of bone collagen (dissolved in NaCl, acetic acid and pepsin/acetic acid) which have the same relative labelling (1.0:0.43:0.1) as measured by GC-combustion-isotope ratio MS. The rates of incorporation were substantially faster than in skeletal muscle samples taken at the same time. The results suggest that different fractions of human bone collagen turnover at markedly higher rates than had been previously considered. This approach should allow us to discover how growth and development, food, activity and drugs affect bone collagen turnover and to measure the effects on it of ageing and bone disease.

Fat utilization during exercise: adaptation to a fat-rich diet increases utilization of plasma fatty acids and very low density lipoprotein-triacylglycerol in humans.

1. This study was carried out to test the hypothesis that the greater fat oxidation observed during exercise after adaptation to a high-fat diet is due to an increased uptake of fat originating from the bloodstream. 2. Of 13 male untrained subjects, seven consumed a fat-rich diet (62 % fat, 21 % carbohydrate) and six consumed a carbohydrate-rich diet (20 % fat, 65 % carbohydrate). After 7 weeks of training and diet, 60 min of bicycle exercise was performed at 68 +/- 1 % of maximum oxygen uptake. During exercise [1-(13)C]palmitate was infused, arterial and venous femoral blood samples were collected, and blood flow was determined by the thermodilution technique. Muscle biopsy samples were taken from the vastus lateralis muscle before and after exercise. 3. During exercise, the respiratory exchange ratio was significantly lower in subjects consuming the fat-rich diet (0.86 +/- 0.01, mean +/- S.E.M.) than in those consuming the carbohydrate-rich diet (0.93 +/- 0.02). The leg fatty acid (FA) uptake (183 +/- 37 vs. 105 +/- 28 micromol min(-1)) and very low density lipoprotein-triacylglycerol (VLDL-TG) uptake (132 +/- 26 vs. 16 +/- 21 micromol min(-1)) were both higher (each P < 0.05) in the subjects consuming the fat-rich diet. Whole-body plasma FA oxidation (determined by comparison of (13)CO(2) production and blood palmitate labelling) was 55-65 % of total lipid oxidation, and was higher after the fat-rich diet than after the carbohydrate-rich diet (13.5 +/- 1.2 vs. 8.9 +/- 1.1 micromol min(-1) kg(-1); P < 0.05). Muscle glycogen breakdown was significantly lower in the subjects taking the fat-rich diet than those taking the carbohydrate-rich diet (2.6 +/- 0.5 vs. 4.8 +/- 0.5 mmol (kg dry weight)(-1) min(-1), respectively; P < 0.05), whereas leg glucose uptake was similar (1.07 +/- 0.13 vs. 1.15 +/- 0.13 mmol min(-1)). 4. In conclusion, plasma VLDL-TG appears to be an important substrate source during aerobic exercise, and in combination with the higher plasma FA uptake it accounts for the increased fat oxidation observed during exercise after fat diet adaptation. The decreased carbohydrate oxidation was apparently due to muscle glycogen sparing and not to diminished plasma glucose uptake.

Interaction between glutamine availability and metabolism of glycogen, tricarboxylic acid cycle intermediates and glutathione.

After exhaustive exercise, intravenous or oral glutamine promoted skeletal muscle glycogen storage. However, when glutamine was ingested with glucose polymer, whole-body carbohydrate storage was elevated, the most likely site being liver and not muscle, possibly due to increased glucosamine formation. The rate of tricarboxylic acid (TCA) cycle flux and hence oxidative metabolism may be limited by the availability of TCA intermediates. There is some evidence that intramuscular glutamate normally provides alpha-ketoglutarate to the mitochondrion. We hypothesized that glutamine might be a more efficient anaplerotic precursor than endogenous glutamate alone. Indeed, a greater expansion of the sum of muscle citrate, malate, fumarate and succinate concentrations was observed at the start of exercise (70% VO2(max)) after oral glutamine than when placebo or ornithine alpha-ketoglutarate was given. However, neither endurance time nor the extent of phosphocreatine depletion or lactate accumulation during the exercise was altered, suggesting either that TCA intermediates were not limiting for energy production or that the severity of exercise was insufficient for the limitation to be operational. We have also shown that in the perfused working rat heart, there is a substantial fall in intramuscular glutamine and alpha-ketoglutarate, especially after ischemia. Glutamine (but not glutamate, alpha-ketoglutarate or aspartate) was able to rescue the performance of the postischemic heart. This ability appears to be connected to the ability to sustain intracardiac ATP, phosphocreatine and glutathione.