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Leucine Supplementation Increases Muscle Strength and Volume, Reduces Inflammation, and Affects Wellbeing in Adults and Adolescents with Cerebral Palsy.
Theis, N, Brown, MA, Wood, P, Waldron, M
The Journal of nutrition. 2021;(1):59-64
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Abstract
BACKGROUND Spastic cerebral palsy (CP) is characterized by muscle weakness owing, in part, to a blunted muscle protein synthetic response. This might be normalized by long-term leucine supplementation. OBJECTIVES The study assessed the effects of 10 wk leucine supplementation in adolescents and adults with CP. METHODS The study was a single-center randomized controlled trial. Twenty-four participants were randomly assigned to a control group (n = 12) or a leucine group (n = 12). l-Leucine (192 mg/kg body mass) was dissolved in water and administered daily for 10 wk. The primary outcome measures of elbow flexor muscle strength and muscle volume (measured by 3D ultrasound technique) and inflammation [C-reactive protein (CRP) concentration] were assessed before and after the 10 wk, alongside the secondary outcomes of body composition (measured by CP-specific skinfold assessment), metabolic rate (measured by indirect calorimetry), and wellbeing (measured by a self-reported daily questionnaire). Data were compared via a series of 2-factor mixed ANOVAs. RESULTS Twenty-one participants completed the intervention (control group: n = 11, mean ± SD age: 18.3 ± 2.8 y, body mass: 48.8 ± 11.9 kg, 45% male; leucine group: n = 10, age: 18.6 ± 1.7 y, body mass: 58.3 ± 20.2 kg, 70% male). After 10 wk, there was a 25.4% increase in strength (P = 0.019) and a 3.6% increase in muscle volume (P = 0.001) in the leucine group, with no changes in the control group. This was accompanied by a 59.1% reduction in CRP (P = 0.045) and improved perceptions of wellbeing (P = 0.006) in the leucine group. No changes in metabolism or body composition were observed in either group (P > 0.05). CONCLUSIONS Improvements in muscle strength and volume with leucine supplementation might provide important functional changes for adults and adolescents with CP and could be partly explained by reduced inflammation. The improved wellbeing highlights its capacity to improve the quality of daily living. This trial was registered at clinicaltrials.gov as NCT03668548.
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Protein-leucine ingestion activates a regenerative inflammo-myogenic transcriptome in skeletal muscle following intense endurance exercise.
Rowlands, DS, Nelson, AR, Raymond, F, Metairon, S, Mansourian, R, Clarke, J, Stellingwerff, T, Phillips, SM
Physiological genomics. 2016;(1):21-32
Abstract
Protein-leucine supplement ingestion following strenuous endurance exercise accentuates skeletal-muscle protein synthesis and adaptive molecular responses, but the underlying transcriptome is uncharacterized. In a randomized single-blind triple-crossover design, 12 trained men completed 100 min of high-intensity cycling then ingested 70/15/180/30 g protein-leucine-carbohydrate-fat (15LEU), 23/5/180/30 g (5LEU), or 0/0/274/30 g (CON) beverages during the first 90 min of a 240 min recovery period. Vastus lateralis muscle samples (30 and 240 min postexercise) underwent transcriptome analysis by microarray followed by bioinformatic analysis. Gene expression was regulated by protein-leucine in a dose-dependent manner affecting the inflammatory response and muscle growth and development. At 30 min, 15LEU and 5LEU vs. CON activated transcriptome networks with gene-set functions involving cell-cycle arrest (Z-score 2.0-2.7, P < 0.01), leukocyte maturation (1.7, P = 0.007), cell viability (2.4, P = 0.005), promyogenic networks encompassing myocyte differentiation and myogenin (MYOD1, MYOG), and a proteinaceous extracellular matrix, adhesion, and development program correlated with plasma lysine, arginine, tyrosine, taurine, glutamic acid, and asparagine concentrations. High protein-leucine dose (15LEU-5LEU) activated an IL-1I-centered proinflammatory network and leukocyte migration, differentiation, and survival functions (2.0-2.6, <0.001). By 240 min, the protein-leucine transcriptome was anti-inflammatory and promyogenic (IL-6, NF- β, SMAD, STAT3 network inhibition), with overrepresented functions including decreased leukocyte migration and connective tissue development (-1.8-2.4, P < 0.01), increased apoptosis of myeloid and muscle cells (2.2-3.0, P < 0.002), and cell metabolism (2.0-2.4, P < 0.01). The analysis suggests protein-leucine ingestion modulates inflammatory-myogenic regenerative processes during skeletal muscle recovery from endurance exercise. Further cellular and translational research is warranted to validate amino acid-mediated myeloid and myocellular mechanisms within skeletal-muscle functional plasticity.
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Formoterol, a highly β2-selective agonist, induces gender-dimorphic whole body leucine metabolism in humans.
Lee, P, Birzniece, V, Umpleby, AM, Poljak, A, Ho, KK
Metabolism: clinical and experimental. 2015;(4):506-12
Abstract
OBJECTIVE Formoterol is a β(2)-selective agonist that enhances protein anabolism in rodents. Whether formoterol imparts anabolic benefits in humans is unknown. The objective of the study was to investigate the effects of formoterol on whole body protein rates of turnover, oxidative loss and synthesis. DESIGN Open label intervention study. PATIENTS Fifteen healthy adults (8 men). MEASUREMENTS Volunteers were treated with oral formoterol 160 μg/day for one week. Changes in leucine turnover (LRa; index of protein breakdown), oxidation (Lox; irreversible protein loss) and incorporation into protein (LIP; index of protein synthesis) were assessed using the whole body 1-[(13)C]leucine turnover technique before/after treatment. RESULTS LRa, Lox and LIP correlated significantly with lean body mass (LBM). LRa, adjusted for LBM was significantly higher (P<0.05, 160±6 vs 109±3 μmol/min) in men but not fractional Lox and LIP (expressed as a proportion of LRa). Formoterol reduced LRa (-9±4%) in men but stimulated LRa (9±3%) in women. Formoterol significantly reduced (P<0.05) fractional Lox, an effect greater in women (-4±1 vs -1±1 %). It stimulated fractional LIP in women (∆4±1%, P<0.05) but not in men (∆1±1%). Formoterol induced an absolute anabolic effect that was greater in women (30 vs 8%). Heart rate, systolic and diastolic blood pressures were unaffected. CONCLUSION In a therapeutic dose, formoterol stimulates protein anabolism in humans. It induced gender-dimorphic effects on protein turnover and on the partitioning of amino acids from oxidative loss toward protein synthesis, effects that are greater in women than in men. Formoterol holds promise as a treatment for sarcopenia.
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Comparison of leucine and dispensable amino acid kinetics between Indian women with low or normal body mass indexes during pregnancy.
Kurpad, AV, Dwarkanath, P, Thomas, T, Mhaskar, A, Thomas, A, Mhaskar, R, Jahoor, F
The American journal of clinical nutrition. 2010;(2):320-9
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Abstract
BACKGROUND Evidence suggests that in women with a normal to high body mass index (BMI; in kg/m(2)), the extra amino acids needed during pregnancy are met through reduced oxidation. It is not known whether a woman with a low BMI can make this adaptation successfully. OBJECTIVE The objective was to measure and compare leucine kinetic parameters and alanine-nitrogen, glutamine amide-nitrogen, and glycine and cysteine fluxes in Indian women with a low and normal BMI in early and midpregnancy. DESIGN Fasted- and fed-state kinetics were measured by infusing 1-[(13)C]leucine, [(2)H(2)]cysteine, [(2)H(2)]glycine, [5-(15)N]glutamine, and [(15)N]alanine in groups of 10 women with a low BMI (<18.5) and 10 women with a normal BMI (18.5-25) in the first and second trimesters of pregnancy. RESULTS Leucine, glutamine, glycine, and cysteine fluxes were faster in women with a low BMI in both trimesters, but there was no difference in alanine flux between groups. This difference was explained in the first trimester by a higher proportion of fat-free mass in low-BMI women. Leucine oxidation and percentage of dietary leucine oxidized were higher in low-BMI women in both trimesters, but nonoxidative disposal was not different between groups. CONCLUSIONS Although they use dietary protein less efficiently, low-BMI women maintain net protein synthesis at the same rate as do normal-BMI women and produce similar quantities of labile nitrogen for the de novo synthesis of other dispensable amino acids such as glycine and cysteine. The extra amino acids required for increased maternal protein synthesis during pregnancy are provided by an overall decrease in amino acid catabolism in women with normal or low BMI.
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Impact of longitudinal plasma leucine levels on the intellectual outcome in patients with classic MSUD.
Hoffmann, B, Helbling, C, Schadewaldt, P, Wendel, U
Pediatric research. 2006;(1):17-20
Abstract
Maple syrup urine disease (MSUD) is an inherited deficiency of branched chain alpha-ketoacid dehydrogenase (BCKDH) activity impairing the degradation of the branched chain amino acids valine, leucine, and isoleucine. Classic MSUD may lead to severe neonatal encephalopathy including coma and impaired cognitive outcome in later life. Early start of dietary treatment and careful metabolic control may improve the outcome of patients with classic MSUD. The aim of this study was to investigate the impact of long-term metabolic control assessed by plasma leucine levels on cognitive outcome in patients with classic MSUD. Plasma leucine levels of 24 patients were obtained retrospectively for the first 6 y of life and yearly medians of mean plasma leucine levels were calculated. At the age of 6 y, IQ tests were performed. Yearly medians of mean plasma leucine levels yielded three homogeneous clusters (low, intermediate, high). Patients of the low cluster showed statistically significant higher IQ scores compared with those of those of intermediate and high clusters. Long-term plasma leucine levels are associated with impaired cognitive outcome in patients with classic MSUD. To achieve the best possible intellectual outcome for affected individuals, we recommend that in infants and preschool children the target range for plasma leucine should not exceed 200 micromol/L.
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Estrogen supplementation reduces whole body leucine and carbohydrate oxidation and increases lipid oxidation in men during endurance exercise.
Hamadeh, MJ, Devries, MC, Tarnopolsky, MA
The Journal of clinical endocrinology and metabolism. 2005;(6):3592-9
Abstract
Healthy active men exhibit higher rates of carbohydrate (CHO) and leucine oxidation and lower rates of lipid oxidation compared with their female counterparts both at rest and during moderate intensity endurance exercise. We postulated that this reduced dependence on amino acids as a fuel source in women was due to the female sex hormone estrogen. In a randomized, double-blind, placebo-controlled, cross-over design, we investigated the effect of supplementing 12 recreationally active men with estrogen on whole body substrate oxidation and leucine kinetics at rest and during moderate intensity endurance exercise. Subjects cycled for 90 min at an intensity of 65% maximum O(2) consumption after 8 d of either estrogen supplementation (2 mg 17beta-estradiol/d) or placebo (polycose). After a 2-wk washout period, they repeated the test after 8 d of the alternate treatment. On the test day, after a primed continuous infusion of l-[(13)C]leucine, O(2) consumption, CO(2) production, steady-state breath (13)CO(2), and plasma alpha-[(13)C]ketoisocaproate enrichments were measured at rest and at 60, 75, and 90 min during exercise in the postabsorptive state. Exercise increased energy expenditure more than 5-fold, CHO oxidation more than 6-fold, lipid oxidation more than 4-fold, and leucine oxidation 2.2-fold (all P < 0.0001), whereas it decreased the ratio of lipid to CHO oxidation by 50-70% (P = 0.003) compared with values at rest. Estrogen supplementation decreased respiratory exchange ratio during exercise (P = 0.03). Estrogen supplementation significantly decreased CHO oxidation by 5-16% (P = 0.04) and leucine oxidation by 16% (P = 0.01), whereas it significantly increased lipid oxidation by 22-44% (P = 0.024) at rest and during exercise. We conclude that estrogen influences fuel source selection at rest and during endurance exercise in recreationally active men, characterized by a reduced dependence on amino acids and CHO and an increased reliance on lipids as a fuel source.
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Insulin is protein-anabolic in chronic renal failure patients.
Lim, VS, Yarasheski, KE, Crowley, JR, Fangman, J, Flanigan, M
Journal of the American Society of Nephrology : JASN. 2003;(9):2297-304
Abstract
To examine the protein anabolic actions of insulin in chronic renal failure, the authors measured four sets of whole body leucine fluxes during insulin alone and insulin with amino acid infusion in nine uremic patients before hemodialysis (B-HD). Seven were restudied 8 wk after initiation of maintenance hemodialysis (HD). Six normal subjects served as control (N). All values ( micro mol/kg/h, mean +/- SEM) are presented in the sequence of B-HD, HD, and N, and only P < 0.05 are listed. During Flux 1 (baseline), D (leucine release from body protein degradation) were 114 +/- 7, 126 +/- 4, and 116 +/- 6, respectively. C (leucine oxidation rates) were 18 +/- 2, 17 +/- 2, and 21 +/- 3, respectively. S (leucine disappearance into body protein [index of protein synthesis]) were 96 +/- 6, 107 +/- 4, and 94 +/- 4, respectively, and balances (net leucine flux into protein [values were negative during fasting]) were -18 +/- 2, -17 +/- 2, and -21 +/- 3, respectively. During Flux 2 (low-dose insulin infusion), D were 89 +/- 3, 98 +/- 6, and 94 +/- 5, respectively; C were 12 +/- 1, 11 +/- 2, and 18 +/- 1, respectively (P = 0.02); S were 77 +/- 4, 87 +/- 5, and 76 +/- 5, respectively, and balances were -12 +/- 1, -11 +/- 2, and -18 +/- 1, respectively (P = 0.02). During Flux 3 (high-dose insulin infusion): D were 77 +/- 3, 82 +/- 7, and 84 +/- 5, respectively; C were 9 +/- 1, 8 +/- 1, and 14 +/- 1, respectively (P = 0.005); S were 68 +/- 4, 74 +/- 6, and 70 +/- 5, respectively, and balances were -9 +/- 1, -8 +/- 1, and -14 +/- 1, respectively (P = 0.005). In Flux 4 (insulin infused with amino acids): D were 73 +/- 3, 107 +/- 18, and 85 +/- 7, respectively; C were 35 +/- 4, 29 +/- 5, and 39 +/- 3, respectively; S were 105 +/- 5, 145 +/- 15, and 113 +/- 6, respectively (P = 0.02), and balances were 32 +/- 4, 38 +/- 5, and 27 +/- 3, respectively. These data show that B-HD and HD patients were as sensitive as normal subjects to the protein anabolic actions of insulin. Insulin alone reduced proteolysis and leucine oxidation, and insulin given with amino acids increased net protein synthesis.
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Epidural blockade modifies perioperative glucose production without affecting protein catabolism.
Lattermann, R, Carli, F, Wykes, L, Schricker, T
Anesthesiology. 2002;(2):374-81
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Abstract
BACKGROUND Epidural blockade with local anesthetic has been shown to blunt the increase in plasma glucose concentration during and after abdominal surgery. The aim of the study was to test the hypothesis that epidural blockade inhibits this hyperglycemic response by attenuating endogenous glucose production. The authors further examined if the modification of glucose production by epidural blockade has an impact on perioperative protein catabolism. METHODS Sixteen patients undergoing colorectal surgery received either general anesthesia and epidural blockade with local anesthetic (n = 8) or general anesthesia alone (control, n = 8). Glucose and protein kinetics were assessed by stable isotope tracer technique ([6,6-2H2]glucose, L-[1-13C]leucine) during and 2 h after surgery. Plasma concentrations of glucose, lactate, free fatty acids (FFA), cortisol, glucagon, and insulin were also determined. RESULTS Epidural blockade blunted the perioperative increase in the plasma concentration of glucose, cortisol, and glucagon when compared with the control group (P < 0.05). Plasma concentrations of lactate, FFA, and insulin did not change. Intra- and postoperative glucose production was lower in patients with epidural blockade than in control subjects (intraoperative, epidural blockade 8.2 +/- 1.9 vs. control 10.7 +/- 1.4 micromol x kg(-1) x min(-1), P < 0.05; postoperative, epidural blockade 8.5 +/- 1.8 vs. control 10.5 +/- 1.2 micromol x kg(-1) x min(-1), P < 0.05), whereas glucose clearance decreased to a comparable extent in both groups (P < 0.05). Protein breakdown (P < 0.05), protein synthesis (P < 0.05), and amino acid oxidation (P > 0.05) decreased with both anesthetic techniques. CONCLUSIONS Epidural blockade attenuates the hyperglycemic response to surgery through modification of glucose production. The perioperative suppression of protein metabolism was not influenced by epidural blockade.
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Growth hormone blunts protein oxidation and promotes protein turnover to a similar extent in abdominally obese and normal-weight women.
Buijs, MM, Romijn, JA, Burggraaf, J, De Kam, ML, Cohen, AF, Frölich, M, Stellaard, F, Meinders, AE, Pijl, H
The Journal of clinical endocrinology and metabolism. 2002;(12):5668-74
Abstract
Abdominally obese individuals have reduced 24-h plasma GH concentrations. Their normal plasma IGF-I levels may reflect GH hypersensitivity. Alternatively, obesity-associated hyposomatotropism may cause less biological effect in target tissues. We therefore determined whole-body responsiveness to the anabolic effects of GH in abdominally obese (OB) and normal weight (NW) premenopausal women. A 1-h iv infusion of GH or placebo was randomly administered to six NW (body mass index, 21.1 +/- 1.9 kg/m(2)) and six OB (body mass index, 35.5 +/- 1.5 kg/m(2)) women in a cross-over design. Endogenous insulin, glucagon and GH secretion was suppressed by infusion of somatostatin. Whole-body protein turnover was measured using a 10-h infusion of [(13)C]-leucine. GH administration induced a similar plasma GH peak in NW and OB women (49.8 +/- 10.4 vs. 45.1 +/- 5.6 mU/liter). GH, compared with placebo infusion, increased nonoxidative leucine disposal, P < 0.0001) and endogenous leucine appearance (R(a), P = 0.0004) but decreased leucine oxidation (P = 0.0051). All changes were similar in both groups. Accordingly, whole-body GH responsiveness, defined as the maximum response of nonoxidative leucine disposal, leucine R(a), and oxidation per unit of GH, was not different in OB and NW women (0.25 +/- 0.18 vs. 0.19 +/- 0.17 micro mol/kg.h, 0.21 +/- 0.23 vs. 0.13 +/- 0.17 micro mol/kg.h, and -0.10 +/- 0.08 vs. -0.08 +/- 0.05 micro mol/kg.h, respectively). These results indicated that whole-body tissue responsiveness to the net anabolic effect of GH is similar in OB and NW women. Hence, we inferred that hyposomatotropism may promote amino acid oxidation and blunt protein turnover in abdominal obesity. However, hyposomatotropism cannot account for all anomalous features of protein metabolism in abdominally obese humans.
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Effects of acute creatine monohydrate supplementation on leucine kinetics and mixed-muscle protein synthesis.
Parise, G, Mihic, S, MacLennan, D, Yarasheski, KE, Tarnopolsky, MA
Journal of applied physiology (Bethesda, Md. : 1985). 2001;(3):1041-7
Abstract
Creatine monohydrate (CrM) supplementation during resistance exercise training results in a greater increase in strength and fat-free mass than placebo. Whether this is solely due to an increase in intracellular water or whether there may be alterations in protein turnover is not clear at this point. We examined the effects of CrM supplementation on indexes of protein metabolism in young healthy men (n = 13) and women (n = 14). Subjects were randomly allocated to CrM (20 g/day for 5 days followed by 5 g/day for 3-4 days) or placebo (glucose polymers) and tested before and after the supplementation period under rigorous dietary and exercise controls. Muscle phosphocreatine, creatine, and total creatine were measured before and after supplementation. A primed-continuous intravenous infusion of L-[1-(13)C]leucine and mass spectrometry were used to measure mixed-muscle protein fractional synthetic rate and indexes of whole body leucine metabolism (nonoxidative leucine disposal), leucine oxidation, and plasma leucine rate of appearance. CrM supplementation increased muscle total creatine (+13.1%, P < 0.05) with a trend toward an increase in phosphocreatine (+8.8%, P = 0.09). CrM supplementation did not increase muscle fractional synthetic rate but reduced leucine oxidation (-19.6%) and plasma leucine rate of appearance (-7.5%, P < 0.05) in men, but not in women. CrM did not increase total body mass or fat-free mass. We conclude that short-term CrM supplementation may have anticatabolic actions in some proteins (in men), but CrM does not increase whole body or mixed-muscle protein synthesis.