Urinary 3-methylhistidine Excretion Research Articles

Glutamine and smooth muscle morphology of the gut in rats on total parenteral nutrition.

The purpose of this study was to assess the effects of addition of L-glutamine to an IV nutritional solution on the urinary excretion of 3-methylhistidine (3-MeH) and the morphology of the musculature of the gut in rats. Two experiments were run. In experiment 1 glutamine was added to a mildly hypocaloric IV solution which contained no other amino acids. For experiment 2 glutamine was added to an isocaloric balanced amino acid mixture. In both experiments L-alanine was added in equimolar amounts in place of the L-glutamine for the control groups. Providing glutamine in an IV diet without other amino acids significantly decreased urinary 3-MeH excretion (p less than 0.05). Electron microscopy and morphometric analysis of the jejunum showed an approximate 50% loss of musculature from the gut wall in alanine-treated animals. Glutamine supplementation of a balanced amino acid regime had no effect on urinary 3-MeH excretion or the musculature of the jejunum. We concluded that (1) glutamine is a preferred fuel for jejunal smooth muscle as well as for mucosal cells of the jejunum and (2) only when amino acids are limiting does exogenous glutamine prevent atrophy of the gut musculature.

Effects of Overfeeding in Children with Muscle Dystrophies

In muscle dystrophies as in other muscle-wasting diseases and states, a progressive loss of muscle protein occurs, probably as a result of an imbalance between muscle protein synthesis and degradation. In the present study we examined whether this progressive muscle wasting and reduced functional capacity so damaging to patients with muscular dystrophies, can be reduced or even reversed by nightly overfeeding with 1000 ml of Osmolite in addition to the voluntary daytime dietary intake. In the Duchenne muscle dystrophy (DMD) group (six patients) body weight increased significantly accompanied by a 14% increase in midarm muscle circumference with only minimal changes in triceps skin fold, indicating a relative build up of muscle mass. In the congenital muscular dystrophy (CMD) group (four patients) no changes occurred in body weight or any of the three anthropometric measurements performed. Baseline nitrogen balance was mildly positive in both groups and improved significantly in the DMD group during the 3-month experimental period of refeeding, with no changes in urinary 3-methylhistidine excretion, suggesting improved muscle protein synthesis with no change in muscle protein degradation. No changes were detected in hematological and biochemical parameters, liver function tests, pulmonary function tests, or a general activity index during the study period. Our results suggest that a reduced rate of protein synthesis rather than an increased rate of protein degradation occur in muscle dystrophies, and that overfeeding might offer promising nutritional effects, at least in DMD patients.

Barbiturate therapy reduces nitrogen excretion in acute head injury.

The effect of pentobarbital on nitrogen and energy metabolism was evaluated in seven severely head-injured patients (Glasgow Coma Scale 4.7 +/- 1.7) within the first week postinjury. Measured energy expenditure (% of predicted) was significantly lower in the pentobarbital group (n = 4) versus control (n = 3) (76 +/- 23% versus 132 +/- 28%, respectively, p less than 0.01). Similarly, 24-hour urinary nitrogen excretion was lower for the barbiturate group compared to control (11.2 +/- 4.0 gm versus 19.5 +/- 3.3 gm, respectively, p less than 0.01). No statistical difference was noted for urinary 3-methylhistidine excretion between the barbiturate and control groups (43 +/- 12 mcg/day versus 47 +/- 14 mcg/day, respectively, p = N.S.). Barbiturate therapy decreases measured energy expenditure and reduces nitrogen excretion without significantly altering 3-methylhistidine excretion in head-injured patients. The metabolic effects of pentobarbital may enable the ability to achieve energy and nitrogen equilibrium during metabolic support of acutely head-injured patients.

Effects of cimaterol, a β-adrenergic agonist, on protein metabolism in rats

Fractional accretion rates of total body 3-methylhistidine containing proteins (actin and myosin) were elevated 40% to 120% in rats fed a high-carbohydrate diet containing 10 or 100 ppm cimaterol for 1 week. Fractional degradation and fractional synthesis rates of these proteins were examined by measuring total body 3-methylhistidine content and urinary excretion of 3-methylhistidine. Consumption of the diet containing 100 ppm cimaterol for 1 week caused a 25% reduction in fractional degradation rates and a concomitant 32% increase in fractional synthesis rates of 3-methylhistidine containing proteins. Effects of cimaterol on fractional accretion, degradation, and synthesis rates of 3-methylhistidine containing proteins diminished after 1 week. Cimaterol failed to influence plasma insulin, triiodothyronine, or corticosterone concentrations. The dramatic increase in accretion of 3-methylhistidine containing proteins observed during the first week rats are fed diets containing cimaterol is caused by reciprocal action on protein degradation and synthesis.

EFFECT OF PEROPERATIVE NORMOTHERMIA ON POSTOPERATIVE PROTEIN METABOLISM IN ELDERLY PATIENTS UNDERGOING HIP ARTHROPLASTY

We have examined in elderly patients the effect of maintenance of normothermia during hip surgery on postoperative protein metabolism. In one group of six patients (warmed group) heat loss was minimized during surgery and in the recovery period by warming fresh gases, i.v. fluids and wrapping the exposed parts of the body with a warming blanket. In a second group of six patients (cold group), routine care was provided. General anaesthesia consisted of thiopentone, tubocurarine and halothane in both groups. Urinary excretion of urea nitrogen and 3-methylhistidine (3-MeH) after surgery was significantly lower in the warmed group compared with the cold group (P less than 0.05). There was little effect of normothermia on amino acid concentrations in plasma after surgery. Muscle glutamine concentration 4 days after surgery decreased by 50% in the cold group and 18% in the warmed group. Total body potassium (TBK), measured as an index of body cell mass, decreased significantly after surgery in both groups. However, 7 days after surgery the reduction in TBK in the cold group remained significantly lower than that of the warmed group (P less than 0.05). Maintenance of normothermia during hip surgery appeared to attenuate, but not eliminate, protein breakdown and nitrogen loss after surgery.

Effect of Administered Human Growth Hormone on Protein Metabolism in Septic Rats

The effect of administered human growth hormone (hGH) on protein metabolism in septic rats was investigated. Fifty-three male Wistar rates with SVC cannulation were divided into four groups. Group I (n = 10) underwent sham-operation. Sepsis was induced by cecal ligation in group II (n = 19), group III (n = 10), and group IV (n = 14). Isocaloric, isonitrogenous glucose/amino acids were infused for 4 days. hGH was administered in group III (100 mU/day) and group IV (200 mU/day) every day. Cumulative nitrogen balance (mg/kg) in group IV was significantly higher than in group II (p less than 0.01): group I, 1264 +/- 355; group II, 117 +/- 693; group III, 92 +/- 735; group IV, 1001 +/- 279. Cumulative urinary excretion of 3-methylhistidine (3-MH, mg/kg) did not differ between group II and group IV: group I, 6.2 +/- 0.9; group II, 12.0 +/- 2.2; group III, 13.4 +/- 2.9; group IV, 10.5 +/- 2.3. Serum albumin level in group IV (1.8 +/- 0.2 g/dl) was significantly higher than in group II (1.5 +/- 0.2 g/dl) (p less than 0.01). Blood urea nitrogen level in group IV (12.6 +/- 2.3 mg/dl) was significantly lower than in group II (18.8 +/- 7.4 mg/dl) (p less than 0.05). Although serum levels of glucose, insulin, triglyceride, and phospholipid were higher in sepsis groups than in sham-operated group, those levels did not differ among sepsis groups. Administration of hGH, 200 mU/day, resulted in marked nitrogen retention and had little effect on 3-MH excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Nitrogen-Sparing Effect of Epidural Administration of Local Anesthetics in Colon Surgery

A nitrogen-sparing effect of epidural anesthesia has been clearly demonstrated in gynecological and lower abdominal surgery. To determine if epidural anesthesia also has a protein-sparing effect during major upper or mid-abdominal surgery, postoperative nitrogen balance and 3-methylhistidine urinary excretion (an index of skeletal muscle protein catabolism) were measured for 6 days in 28 patients who had undergone colon resection for cancer with general anesthesia (N2O-O2-1% enflurane) either supplemented with low dose fentanyl plus intermittent systemic pentazocine for postoperative pain (n = 13), or the same general anesthetic plus epidural injection of either etidocaine 1% intraoperatively and bupivacaine 0.25% postoperatively (n = 8) or meperidine (n = 7) for 48 hr after skin incision. The cumulative 6-day nitrogen balance and the cumulative 3-methylhistidine urinary excretion were significantly less after epidural injection of etidocaine intraoperatively and bupivacaine postoperatively than in the two other groups. There was a significant correlation between the daily urinary excretion of 3-methylhistidine and the daily nitrogen balance in the three groups. This study suggests that in colon surgery, epidural analgesia with local anesthetics in the postoperative period improves nitrogen balance and this effect takes place partly in the muscle.

Pentobarbital Improves Nitrogen Retention in Sepsis

Pentobarbital therapy has been associated with decreased urinary nitrogen excretion and resting energy expenditure in stressed patients. The metabolic effects of pentobarbital in sepsis were investigated in 29 well-nourished rats who underwent superior vena caval cannulation, cecal ligation, and puncture. Animals were randomly assigned to receive either a continuous infusion of 20 mg/kg/day of pentobarbital combined with parenteral nutrition (n = 13) or parenteral nutrition alone (n = 16). Both groups received isocaloric, isonitrogenous parenteral nutrition postoperatively for 24 hr. Mean nitrogen balance (+/- SEM) was better in the pentobarbital group (+169 +/- 76 mg/kg/day vs -190 +/- 66 mg/kg/day, p less than 0.01). No significant differences between the pentobarbital and control groups were noted for urinary 3-methylhistidine excretion (9 +/- 0.7 micrograms/kg/day vs 11 +/- 0.6 micrograms/kg/day, respectively) or 24 hr survival (77% vs 69%, respectively). Pentobarbital improves nitrogen retention without decreasing urinary 3-methylhistidine excretion in septic rats.

Urinary 3-methylhistidine excretion increases with repeated weight training exercise

This investigation examines the effect of progressive resistance weight training exercise on urinary 3-methylhistidine (3-MH) excretions in untrained subjects. For 19 consecutive days, 11 males were fed a weight maintenance, lactovegetarian diet which contained the Recommended Dietary Allowance (0.8g.kg-1.d-1) for protein. No exercise was performed for the first 7 d of the study. Subjects were strength tested on day 8 and performed upper and lower body weight training exercises from days 9-19. Complete, 24-h urine collections were obtained from each subject on a daily basis. Samples were assayed for creatinine and 3-MH. Stable baseline 3-MH values were present during the pre-exercise control period. Significant increases in 3-MH occurred by study day 11, which was the third day of weight training exercise. This was true regardless of whether the data were expressed by daily excretions (microM.d-1; P less than 0.01), per unit of body weight (microM.kg-1.d-1; P less than 0.005), or per unit of creatinine excretion (microM.g Creat-1.d-1; P less than 0.001). Since urinary 3-MH is an index of actin and myosin catabolism, these data support the hypothesis that the rate of skeletal muscle degradation is increased during strength building exercises.

Reproducibility of urinary 3-methylhistidine excretion in human subjects consuming freely selected diets

Eight males and six females consumed their normal diet for 9 weeks, except for weeks 3 and 9 when they followed a self-selected diet free of 3-methylhistidine (3MH) for five subsequent weekdays (days 1 to 5). Timed 24-hours urine collections were obtained on days 3, 4, and 5 of these 3MH-free dietary periods and on one day during weeks 1 and 7. At the group level, no differences in 3MH excretion ( P > .05) between days 3, 4, and 5 in weeks 3 and 9 and between these weeks were observed. Reproducibility at the individual level was indicated by the within-subject coefficient of variation (CVw). CVw within weeks 3 and 9 was 2.5% and 5.1% for men and 4.8 and 8.0% for women. CVw between these weeks was highest when more than one measurement per week was performed. Relating 3MH to creatinine decreased the CVw between weeks. If muscle protein breakdown is to be measured at the individual level, a reasonably large biologic variation is to be taken into account and repeated measurements should be done to decrease the CVw.

Hydroxylysine excretion does not indicate collagen damage with downhill running in young men.

The purpose of this study was to determine whether urinary excretion of hydroxylysine (HO-Lys) is increased following prolonged, predominantly downhill running. Such an increase would be evidence of exercise-induced collagen damage. Each of ten young men performed a treadmill running test to determine VO2peak (an approximation of VO2max) followed by 60 min of intermittent running on -10% slope. Total urine excreted from 48 h pre-exercise to 96h post-exercise was collected in 8-h samples for measurement of HO-Lys. In addition, both urinary 3-methylhistidine (3-MeHis) excretion and serum creatine kinase (SCK) activity were measured as indicators of muscle tissue damage. In no sampling period was post-exercise HO-Lys excretion altered compared with pre-exercise (e.g., pre-exercise: 82.2 +/- 9.6 mumol.24 h-1, mean +/- SE; 51.0 +/- 3.7 mumol.g creatinine-1; post-exercise: 72.9 +/- 2.0 mumol.24 h-1; 47.0 +/- 1.5 mumol.g creatinine-1). SCK activity was increased (346%) 24 h post-exercise, but not immediately, 48 h, or 72 h post-exercise. 3-MeHis excretion was not altered following exercise. There were no strong associations between HO-Lys excretion and either of the markers of muscle damage. We concluded that no evidence of exercise-induced collagen damage was provided by urinary HO-Lys excretion.

Evaluation of urinary 3-methylhistidine excretion in infection by measurements of 1-methylhistidine and the creatinine ratios

When 3-methylhistidine (3MH) excretion is used as an indicator of myofibrillar protein catabolism, there are restricting factors, such as meat intake, incorrect 24-h urine collections, and a large interindividual variation in basal excretion. 1-Methylhistidine (1MH) was previously suggested as an indicator of meat intake. We studied the basal urinary excretion of 1MH and whether this was influenced by infection and we compared the use of 3MH vs the 3MH:creatinine ratio (3MH:Cr) in detecting changes during infection. The basal excretion of 1MH was 84.9 mumol/24 h and its creatinine molar ratio (1MH:Cr) was 7.4 x 10(-3) with no change during infection. Because 1MH:Cr was significantly increased in 4 of 14 patients, their 3MH values were considered influenced by meat intake and thus discarded. Among the remaining 10 patients, 9 showed a significant individual increase in 3MH:Cr during infection compared with only 4 in 3MH. This was due to a higher precision in 3MH:Cr despite the concomitant significant increase in urinary creatinine excretion.

Validity of 3-methylhistidine excretion as an indicator of skeletal muscle protein breakdown in humans

The urinary excretion of 3-methylhistidine (3MEH) in humans and animals has been used as a biologic marker for skeletal muscle protein breakdown. In rats, it has been recently suggested that there is a significant contribution of 3MEH in urine from the gastrointestinal tract due to the rapid turnover of protein in that tissue. To evaluate this point in humans, six patients with short bowel were evaluated. They were placed on three-day meat-free diets while 24-hour urine collections were obtained. The mean ± SEM 3MEH in the short-bowel group was 3.27 ± 0.34 μmol/kg/d and the mean ± SEM molar ratio of 3MEH to creatinine was 0.0212 ± 0.0012. These data were not significantly different from the control group at 95% confidence level. The results suggest that the contribution of the small intestine appears to be negligible, therefore urinary 3MEH should continue to be a valid index of skeletal muscle breakdown in man.

The origin of the increased urinary excretion of 3-methylhistidine in infection : [formula omitted], H. Stjernström, E. Andersson, J. Larsson. Departments of Infectious Diseases and Anesthesiology, University Hospital, Uppsala and Department of Surgery, University Hospital, Linköping, Sweden

The origin of the increased urinary excretion of 3-methylhistidine in infection : [formula omitted], H. Stjernström, E. Andersson, J. Larsson. Departments of Infectious Diseases and Anesthesiology, University Hospital, Uppsala and Department of Surgery, University Hospital, Linköping, Sweden

Hypogonadism in liver cirrhosis: Implication in altered amino acid metabolism in muscle

To investigate the relationship between hypogonadism and altered amino acid metabolism in patients with liver cirrhosis, we measured the basal levels of plasma testosterone, estradiol, and free amino acids, plus urinary 3-methylhistidine excretion, in 16 control and 19 cirrhotic patients. The concentration of plasma testosterone correlated significantly with that of plasma branched-chain amino acids, and inversely with urinary 3-methylhistidine excretion. This suggests that hypogonadism causes a disturbance in amino acid metabolism at least partly related to an augmented muscle protein turnover.

Urinary excretion of 3-methylhistidine as an index of protein nutrition in total parenteral nutrition.

In 39 healthy adult volunteers and nine patients receiving total parenteral nutrition (TPN), determinations were made of the urinary excretion of 3-methylhistidine (3-Mehis) to estimate the degree to which the urinary output of 3-Mehis reflects the status of protein nutrition. In 19 males and 10 females of the former group, measurements were made of the amount of 3-Mehis and of creatinine (Cr) in 24-hr urine samples. The urinary output of 3-Mehis was also measured in two subgroups of five healthy adult male subjects who were fed one of the two different diets prescribed: meat (M) and meat-free (F) diet. Furthermore, in one of these subgroups which was fed on F diet, the urinary output of 3-Mehis was measured both while the subject was kept at bed rest and while the subject was allowed to live a normal life. From these measurements the standard value was determined for the urine 3-Mehis level and the 3-Mehis/Cr ratio in 24-hr urine in healthy adult human subjects of both sexes. In nine patients maintained on TPN these indices of nutritional status were measured before and at 4 weeks of TPN. The time course of the indices was also investigated. The results obtained suggest that both the urinary output of 3-Mehis and the 3-Mehis/Cr ratio can provide a sensitive index of the status of protein nutrition.

Effects of moderate physical training on prednisone-induced protein wasting: A study of whole-body and bone protein metabolism

This study investigated the possibility of preventing prednisone-induced protein wasting by regular physical activity. Eight healthy untrained volunteers took prednisone (30 mg/d for nine days), once after a 4-week exercise program that consisted of jogging 2.5 miles four times a week, and once without exercise. Whole body protein turnover was measured from the 15N enrichment plateau of urinary ammonia during ingestion of 15N glycine at hourly intervals. Whole-body protein synthesis and breakdown were derived from nitrogen flux, nitrogen intake, and urinary nitrogen elimination. Muscle myofibrillar protein breakdown was explored by measuring urinary 3-methylhistidine excretion. Bone protein metabolism was studied by measuring serum bone GLA protein (BGP), a specific marker of bone protein synthesis, and urinary elimination of hydroxyproline, an index of bone resorption. Whole-body protein turnover was significantly increased by exercise and prednisone (+ 19% and + 17%, respectively); this effect was related to increased protein synthesis during exercise training (+ 27%, P < .01) and to increased protein breakdown during prednisone administration without exercise (+21%, P < .05). In contrast, values of protein turnover, synthesis, and breakdown were not different from control when the subjects took prednisone after training. Urinary excretion of 3-methylhistidine was decreased (−15%, P < .05) at the end of the prednisone administration period but was identical to the control value when the subjects took prednisone in association with exercise. In contrast, serum BGP was significantly decreased by prednisone, with or without exercise (−35%, P < .001). These data suggest that moderate exercise training can prevent, at least in part, the protein loss induced by prednisone. However, the prednisone-induced inhibition of bone synthesis does not appear to be affected by moderate exercise training.

Total parenteral nutrition in the newborn: impact of the quality of infused energy on nitrogen metabolism

To separate the respective influence of the level and source of infused energy on nitrogen metabolism, 32 studies were performed in 16 appropriate-for-gestational-age newborn infants (birth weight 2150 +/- 115 g, means +/- SEM). In a cross-over design, each patient received two 6-d periods of isocaloric and isonitrogenous (450 mg.kg-1.d-1) infusions, differing only by the source of calories (high or low fat intakes). Half of the patients were studied at 60 kcal.kg-1.d-1, the other half at 80 kcal.kg-1.d-1. Nitrogen balance, urinary 3-methylhistidine excretion, glycemia, and insulin were compared. The results suggest that for an intravenous energy intake ranging from 60 to 80 kcal.kg-1.d-1, glucose and fat provide an equivalent nitrogen sparing effect in the newborn infant. At an energy level covering maintenance requirements, it is the infant's clinical condition rather than the source of energy which affects most the magnitude of amino acids participation in energy metabolism.

Postoperative nasogastric tube feeding in patients with head and neck cancer: a prospective assessment of nutritional status and well-being

The effects of controlled continuous nasogastric tube feeding with a non-elemental liquid diet (Nutrison high energy) were studied 1 day before, and 1 week and 3 weeks after radical surgery mostly for cancer of the tongue or floor of the mouth in 20 patients. Since the actually administered 89% of a planned dose of 32 kcal/kg body weight/day given to the first eight patients (group A) proved inadequate to prevent a decrease of body fat mass, the energy dose given to 12 successive patients (group B) was increased. The administration of 95% of 43 kcal/kg body weight/day to group B patients appeared to be sufficient. A marked decrease of the 24 h urinary excretion of creatinine and 3-methylhistidine was observed at 1 week and still existed at 3 weeks after operation in both groups. The decrease was significant in group A amounting to some 40% for both metabolites. In group B creatinine excretion decreased by some 20% (n.s.) and 3-methylhistidine by some 35% (n.s). These findings suggest diminished muscle protein breakdown, even in the presence of an ample nutritional supply of energy and protein. A transient decrease of serum albumin, iron and zinc in all patients is likely not to be related to nutritional intake, but to surgery itself. Analysis of trace minerals and vitamins in blood and amino acids in serum and urine showed no deficiencies or amino acid imbalance. Assessment of the psychosocial impact of the nasogastric tube feeding regimen revealed gastro-intestinal complaints in a minority, and feelings of being deprived of the act of eating and drinking in the majority of patients.

Effect of ketoleucine treatment on atrophy of skeletal muscle

There is a net loss of skeletal muscle protein in muscle-wasting disorders including the muscular dystrophies and denervation atrophy. Regardless of the nature of the underlying defect, a treatment that could reduce the rate of muscle protein degradation may be of therapeutic value in these conditions. Ketoleucine (α-ketoisocaproic acid) has been reported to reduce the rate of protein degradation in skeletal muscle. To evaluate ketoleucine's therapeutic potential, we studied its effect on the muscle protein loss that follows denervation in rats. Maximum tolerated doses of ketoleucine were administered twice daily to rats after surgical denervation of one leg. Wet weights and noncollagen proteins of the soleus and extensor digitorum longus muscles were measured. The ketoleucine-treated animals failed to show significant decrease in muscle wasting, compared with nontreated denervated controls. Further, urinary 3-methylhistidine excretion, a putative measure of muscle breakdown, was not reduced in ketoleucine-treated animals. Our findings do not support the suggested therapeutic role for ketoleucine in muscle-wasting disease.