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Effects of high versus standard essential amino acid intakes on whole-body protein turnover and mixed muscle protein synthesis during energy deficit: A randomized, crossover study.
Gwin, JA, Church, DD, Hatch-McChesney, A, Howard, EE, Carrigan, CT, Murphy, NE, Wilson, MA, Margolis, LM, Carbone, JW, Wolfe, RR, et al
Clinical nutrition (Edinburgh, Scotland). 2021;(3):767-777
Abstract
BACKGROUND & AIMS Consuming 0.10-0.14 g essential amino acids (EAA)/kg/dose (0.25-0.30 g protein/kg/dose) maximally stimulates muscle protein synthesis (MPS) during energy balance. Whether consuming EAA beyond that amount enhances MPS and whole-body anabolism following energy deficit is unknown. The aims of this study were to determine the effects of standard and high EAA ingestion on mixed MPS and whole-body protein turnover following energy deficit. DESIGN Nineteen males (mean ± SD; 23 ± 5 y; 25.4 ± 2.7 kg/m2) completed a randomized, double-blind crossover study consisting of two, 5-d energy deficits (-30 ± 4% of total energy requirements), separated by 14-d. Following each energy deficit, mixed MPS and whole-body protein synthesis (PS), breakdown (PB), and net balance (NET) were determined at rest and post-resistance exercise (RE) using primed, constant L-[2H5]-phenylalanine and L-[2H2]-tyrosine infusions. Beverages providing standard (0.1 g/kg, 7.87 ± 0.87 g) or high (0.3 g/kg, 23.5 ± 2.54 g) EAA were consumed post-RE. Circulating EAA were measured. RESULTS Postabsorptive mixed MPS (%/h) at rest was not different (P = 0.67) between treatments. Independent of EAA, postprandial mixed MPS at rest (standard EAA, 0.055 ± 0.01; high EAA, 0.061 ± 0.02) and post-RE (standard EAA, 0.055 ± 0.01; high EAA, 0.065 ± 0.02) were greater than postabsorptive mixed MPS at rest (P = 0.02 and P = 0.01, respectively). Change in (Δ postabsorptive) whole-body (g/180 min) PS and PB was greater for high than standard EAA [mean treatment difference (95% CI), 3.4 (2.3, 4.4); P = 0.001 and -15.6 (-17.8, -13.5); P = 0.001, respectively]. NET was more positive for high than standard EAA [19.0 (17.3, 20.7); P = 0.001]. EAA concentrations were greater in high than standard EAA (P = 0.001). CONCLUSIONS These data demonstrate that high compared to standard EAA ingestion enhances whole-body protein status during underfeeding. However, the effects of consuming high and standard EAA on mixed MPS are the same during energy deficit. CLINICAL TRIAL REGISTRY NCT03372928, https://clinicaltrials.gov.
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Daily Consumption of a Specially Formulated Essential Amino Acid-Based Dietary Supplement Improves Physical Performance in Older Adults With Low Physical Functioning.
Azhar, G, Wei, JY, Schutzler, SE, Coker, K, Gibson, RV, Kirby, MF, Ferrando, AA, Wolfe, RR
The journals of gerontology. Series A, Biological sciences and medical sciences. 2021;(7):1184-1191
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Abstract
We have investigated the hypothesis that nutritional supplementation of the diet in low-physical-functioning older individuals with a specially formulated composition based on essential amino acids (EAAs) would improve physical function as compared to supplementation with the same amount of whey protein. A third group of comparable volunteers were given nutrition education but no supplementation of the diet. After 6 weeks of whey protein supplementation (n = 32), there was no effect on the distance walked in 6 minutes, but the distance walked improved significantly from the pre-value after 12 weeks of whey supplementation. EAA consumption (n = 28) significantly improved walking distance at both 6 and 12 weeks. The distance walked at 12 weeks (419.0 ± 25.0 m) was 35.4 m greater than the pre-value of 384.0 ± 23.0 m (p < .001). The increase in distance walked by the EAA group was also significantly greater than that in the whey group at both 6 and 12 weeks (p < .01). In contrast, a decrease in distance walked was observed in the control group (n = 32) (not statistically significant, NS). EAA supplementation also improved grip strength and leg strength, and decreased body weight and fat mass. Plasma low-density lipoprotein concentration was significantly reduced in the EAA group, as well as the concentration of macrophage migration inhibitory factor. There were no adverse responses in any groups, and compliance was greater than 95% in all individuals consuming supplements. We conclude that dietary supplementation with an EAA-based composition may be a beneficial therapy in older individuals with low physical functional capacity. Clinical Trials Registration Number: This study was registered with ClinicalTrials.gov: NCT03424265-"Nutritional interventions in heart failure."
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A collagen hydrolysate/milk protein-blend stimulates muscle anabolism equivalently to an isoenergetic milk protein-blend containing a greater quantity of essential amino acids in older men.
Brook, MS, Scaife, P, Bass, JJ, Cegielski, J, Watanabe, S, Wilkinson, DJ, Smith, K, Phillips, BE, Atherton, PJ
Clinical nutrition (Edinburgh, Scotland). 2021;(6):4456-4464
Abstract
BACKGROUND & AIMS Nutritional composition is key for skeletal muscle maintenance into older age. Yet the acute effects of collagen protein blended with other protein sources, in relation to skeletal muscle anabolism, are ill-defined. We investigated human muscle protein synthesis (MPS) responses to a 20 g blend of collagen protein hydrolysate + milk protein (CP+MP, 125 ml) oral nutritional supplement (ONS) vs. 20 g non-blended milk protein source (MP, 200 ml) ONS, in older adults. METHODS Healthy older men (N = 8, 71±1 y, BMI: 27±1 kg·m-2) underwent a randomized trial of 20 g protein, from either a CP+MP blend (Fresubin®3.2 kcal DRINK), or a kcal-matched (higher in essential amino acids (EAA) ONS of MP alone. Vastus lateralis (VL) MPS and plasma AA were determined using stable isotope-tracer mass spectrometry; anabolic signaling was quantified via immuno-blotting in VL biopsies taken at baseline and 2/4 h after ONS feeding. Plasma insulin was measured via enzyme-linked immunosorbent assay (ELISA). Measures were taken at rest, after the feed (FED) and after the feed + exercise (FED-EX) conditions (unilateral leg exercise, 6 × 8, 75% 1-RM). RESULTS MP resulted in a greater increase in plasma leucine (MP mean: 152 ± 6 μM, CP+MP mean: 113 ± 4 μM (Feed P < 0.001) and EAA (MP mean: 917 ± 25 μM, CP+MP mean: 786 ± 15 μM (Feed P < 0.01) than CP+MP. CP + MP increased plasma glycine (peak 385 ± 57 μM (P < 0.05)), proline (peak 323 ± 29 μM (P < 0.01)) and non-essential amino acids (NEAA) (peak 1621 ± 107 μM (P < 0.01)) with MP showing no increase. Plasma insulin increased in both trials (CP+MP: 58 ± 10 mU/mL (P < 0.01), MP: 42 ± 6 mU/mL (P < 0.01), with peak insulin greater with CP+MP vs. MP (P < 0.01). MPS demonstrated equivalent increases in response to CP+MP and MP under both FED (MP: 0.039 ± 0.005%/h to 0.081 ± 0.014%/h (P < 0.05), CP+MP: 0.042 ± 0.004%/h to 0.085 ± 0.007%/h (P < 0.05)) and FED-EX (MP: 0.039 ± 0.005%/h to 0.093 ± 0.013%/h (P < 0.01), CP+MP: 0.042 ± 0.004%/h to 0.105 ± 0.015%/h, (P < 0.01)) conditions. FED muscle p-mTOR fold-change from baseline increased to a greater extent with CP+MP vs. MP (P < 0.05), whilst FED-EX muscle p-eEF2 fold-change from baseline decreased to a greater extent with CP+MP vs. MP (P < 0.05); otherwise anabolic signaling responses were indistinguishable. CONCLUSION Fresubin®3.2 kcal DRINK, which contains a 20 g mixed blend of CP+MP, resulted in equivalent MPS responses to MP alone. Fresubin® 3.2 Kcal DRINK may provide a suitable alternative to MP for use in older adults and a convenient way to supplement calories and protein to improve patient adherence and mitigate muscle mass loss.
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High-intensity interval training and essential amino acid supplementation: Effects on muscle characteristics and whole-body protein turnover.
Hirsch, KR, Greenwalt, CE, Saylor, HE, Gould, LM, Harrison, CH, Brewer, GJ, Blue, MNM, Ferrando, AA, Huffman, KM, Mayer-Davis, EJ, et al
Physiological reports. 2021;(1):e14655
Abstract
The purpose of this study was to compare the independent and combined effects of high-intensity interval training (HIIT) and essential amino acids (EAA) on lean mass, muscle characteristics of the quadriceps, and 24-hr whole-body protein turnover (WBPT) in overweight and obese adults. An exploratory aim was to evaluate potential modulatory effects of sex. Sixty-six adults (50% female; Age: 36.7 ± 6.0 yrs; %BF: 36.0 ± 7.8%) were assigned to 8 wks of: (a) HIIT, 2 days/wk; (b) EAA supplementation, 3.6 g twice daily; (c) HIIT + EAA; or (d) control. At baseline, 4 wks, and 8 wks, total body, thigh LM and muscle characteristics were measured via dual-energy x-ray absorptiometry and B-mode ultrasound, respectively. In a subsample, changes in WBPT was measured using [N15 ]alanine. Differences between groups were assessed using linear mixed models adjusted for baseline values, followed by 95% confidence intervals on adjusted mean change scores (Δ). HIIT and HIIT + EAA improved thigh LM (Δ: +0.17 ± 0.05 kg [0.08, 0.27]; +0.22 ± 0.05 kg [0.12,0.31]) and vastus lateralis cross-sectional area (Δ: +2.73 ± 0.52 cm2 [1.69,3.77]; +2.64 ± 0.53 cm2 [1.58,3.70]), volume (Δ: +54.50 ± 11.69 cm3 [31.07, 77.92]; +62.39 ± 12.05 cm3 [38.26, 86.52]), and quality (Δ: -5.46 ± 2.68a.u. [-10.84, -0.09]; -7.97 ± 2.76a.u.[-13.49, -2.45]). Protein synthesis, breakdown, and flux were greater with HIIT + EAA and EAA compared to HIIT (p < .05). Sex differences were minimal. Compared to women, men tended to respond more to HIIT, with or without EAA. For women, responses were greater with HIIT + EAA than HIIT. In overweight and obese adults, 8 weeks of HIIT, with or without EAA, improved thigh LM size and quality; EAA may enhance muscular adaptation via increases in protein turnover, supporting greater improvements in muscular size and quality.
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The Effect of Leucine-Enriched Essential Amino Acid Supplementation on Anabolic and Catabolic Signaling in Human Skeletal Muscle after Acute Resistance Exercise: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Comparison Trial.
Takegaki, J, Sase, K, Yasuda, J, Shindo, D, Kato, H, Toyoda, S, Yamada, T, Shinohara, Y, Fujita, S
Nutrients. 2020;(8)
Abstract
Resistance exercise transiently activates anabolic and catabolic systems in skeletal muscle. Leucine-enriched essential amino acids (LEAAs) are reported to stimulate the muscle anabolic response at a lower dose than whey protein. However, little is known regarding the effect of LEAA supplementation on the resistance exercise-induced responses of the anabolic and catabolic systems. Here, we conducted a randomized, double-blind, placebo-controlled, parallel-group comparison trial to investigate the effect of LEAA supplementation on mechanistic target of rapamycin complex 1 (mTORC1), the ubiquitin-proteasome system and inflammatory cytokines after a single bout of resistance exercise in young men. A total of 20 healthy young male subjects were supplemented with either 5 g of LEAA or placebo, and then they performed 10 reps in three sets of leg extensions and leg curls (70% one-repetition maximum). LEAA supplementation augmented the phosphorylation of mTORSer2448 (+77.1%, p < 0.05), p70S6KThr389 (+1067.4%, p < 0.05), rpS6Ser240/244 (+171.3%, p < 0.05) and 4EBP1Thr37/46 (+33.4%, p < 0.05) after resistance exercise. However, LEAA supplementation did not change the response of the ubiquitinated proteins, MuRF-1 and Atrogin-1 expression. Additionally, the mRNA expression of IL-1β and IL-6 did not change. These data indicated that LEAA supplementation augments the effect of resistance exercise by enhancing mTORC1 signal activation after exercise.
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Effect of essential amino acid supplementation and aerobic exercise on insulin sensitivity in healthy older adults: A randomized clinical trial.
Randolph, AC, Markofski, MM, Rasmussen, BB, Volpi, E
Clinical nutrition (Edinburgh, Scotland). 2020;(5):1371-1378
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BACKGROUND & AIMS The combination of prolonged essential amino acid (EAA) supplementation and aerobic exercise training (Ex) improves muscle protein metabolism, strength and function in healthy older adults. However, excess EAA intake may worsen insulin sensitivity. Here we report the effects of EAA supplementation (EAA, n = 11), placebo (PLA, n = 10), aerobic exercise with placebo (Ex + PLA, n = 11) or Ex with EAA supplementation (Ex + EAA, n = 10) for 22 weeks on insulin sensitivity in non-diabetic older adults. METHODS A 2 × 2 design with block randomization and double blinding for supplement or placebo was used. Subjects ingested EAA (15 g) or placebo daily. Exercising subjects participated in supervised progressive vigorous treadmill walking 3 times weekly. Measures of insulin sensitivity by oral glucose tolerance testing were collected at baseline and 22 weeks. Dietary intakes of protein and specific amino acids were determined in a subset of subjects. RESULTS Overall, exercise improved insulin sensitivity, while EAA supplementation had no effect. In the dietary subset, post-intervention insulin sensitivity did not correlate significantly with the total intake of EAA, anti-angiogenic amino acids (cysteine, methionine), or branched-chain amino acids (isoleucine, leucine, valine). CONCLUSIONS Overall, we conclude that in healthy older adults with moderate protein intake, EAA supplementation is metabolically safe as it does not decrease insulin sensitivity regardless of its combination with aerobic exercise. Thus, daily protein intake should be controlled for when modeling insulin sensitivity. Future studies should explore the role of increased blood flow as a potential explanatory factor for the observed interaction between aerobic exercise and supplementation. CLINICAL TRIAL REGISTRATION NUMBER NCT00872911.
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Amino Acid Plasma Profiles from a Prolonged-Release Protein Substitute for Phenylketonuria: A Randomized, Single-Dose, Four-Way Crossover Trial in Healthy Volunteers.
Scheinin, M, Barassi, A, Junnila, J, Lovró, Z, Reiner, G, Sarkkinen, E, MacDonald, A
Nutrients. 2020;(6)
Abstract
Several disorders of amino acid (AA) metabolism are treated with a protein-restricted diet supplemented with specific AA mixtures. Delivery kinetics impacts AA absorption and plasma concentration profiles. We assessed plasma profiles after ingestion of an AA mixture engineered to prolong AA absorption with Physiomimic TechnologyTM (Test) in a randomized, single-dose, four-way crossover trial in healthy volunteers (Trial Registration: ISRCTN11016729). In a two-step hypothesis, the primary endpoints were (i) significant reduction in peak plasma concentrations (Cmax) of essential amino acids (EAAs) while (ii) maintaining EAA bioavailability (AUC0-300 min) compared to a free AA mixture (Reference). Secondary endpoints included effects on plasma profiles of other AA groups and effects on several metabolic markers. Thirty subjects completed the study. Both co-primary endpoints were met: Cmax for EAAs was 27% lower with the Test product compared to the Reference product (ratio, 0.726, p < 0.0001); overall plasma EAA levels from the two AA mixtures was within the pre-specified bioequivalence range (AUC0-300min ratio, 0.890 (95% CI: 0.865, 0.915)). These findings were supported by the results of secondary endpoints. Prolongation of AA absorption was associated with modulation of several metabolic markers. It will be important to understand whether this can improve the long-term management of disorders of AA metabolism.
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The Degree of Aminoacidemia after Dairy Protein Ingestion Does Not Modulate the Postexercise Anabolic Response in Young Men: A Randomized Controlled Trial.
Chan, AH, D'Souza, RF, Beals, JW, Zeng, N, Prodhan, U, Fanning, AC, Poppitt, SD, Li, Z, Burd, NA, Cameron-Smith, D, et al
The Journal of nutrition. 2019;(9):1511-1522
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BACKGROUND Resistance exercise and dietary protein stimulate muscle protein synthesis (MPS). The rate at which proteins are digested and absorbed into circulation alters peak plasma amino acid concentrations and may modulate postexercise MPS. A novel mineral modified milk protein concentrate (mMPC), with identical amino acid composition to standard milk protein concentrate (MPC), was formulated to induce rapid aminoacidemia. OBJECTIVES The aim of this study was to determine whether rapid aminoacidemia and greater peak essential amino acid (EAA) concentrations induced by mMPC would stimulate greater postresistance exercise MPS, anabolic signaling, and ribosome biogenesis compared to standard dairy proteins, which induce a small but sustained plasma essential aminoacidemia. METHODS Thirty healthy young men (22.5 ± 3.0 y; BMI 23.8 ± 2.7 kg/m2) received primed constant infusions of l-[ring-13C6]-phenylalanine and completed 3 sets of leg presses and leg extensions at 80% of 1 repetition. Afterwards, participants were randomly assigned in a double-blind fashion to consume 25 g mMPC, MPC, or calcium caseinate (CAS). Vastus lateralis biopsies were collected at rest, and 2 and 4 h post exercise. RESULTS Plasma EAA concentrations, including leucine, were 19.2-26.6% greater in the mMPC group 45-90 min post ingestion than in MPC and CAS groups (P < 0.001). Myofibrillar fractional synthetic rate from baseline to 4 h was increased by 82.6 ± 64.8%, 137.8 ± 72.1%, and 140.6 ± 52.4% in the MPC, mMPC, and CAS groups, respectively, with no difference between groups (P = 0.548). Phosphorylation of anabolic signaling targets (P70S6KThr389, P70S6KThr421/Ser424, RPS6Ser235/236, RPS6Ser240/244, P90RSKSer380, 4EBP1) were elevated by <3-fold at both 2 and 4 h post exercise in all groups (P < 0.05). CONCLUSIONS The amplitude of plasma leucine and EAA concentrations does not modulate the anabolic response to resistance exercise after ingestion of 25 g dairy protein in young men. This trial was registered at http://www.anzctr.org.au/ as ACTRN12617000393358.
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Effects of 12 Weeks of Essential Amino Acids (EAA)-Based Multi-Ingredient Nutritional Supplementation on Muscle Mass, Muscle Strength, Muscle Power and Fatigue in Healthy Elderly Subjects: A Randomized Controlled Double-Blind Study.
Negro, M, Perna, S, Spadaccini, D, Castelli, L, Calanni, L, Barbero, M, Cescon, C, Rondanelli, M, D'Antona, G
The journal of nutrition, health & aging. 2019;(5):414-424
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OBJECTIVE To counteract muscle mass, muscle strength and power loss during aging, and to study age-related change of neuromuscular manifestation of fatigue in relation to nutritional supplementation. DESIGN randomized controlled double-blind study. SETTING Twice-daily consumption for 12 weeks of an Essential Amino Acids (EAA)-based multi-ingredient nutritional supplement containing EAA, creatine, vitamin D and Muscle Restore Complex®. PARTICIPANTS 38 healthy elderly subjects (8 male, 30 female; age: 68.91±4.60 years; body weight: 69.40±15.58 kg; height: 1.60±0.09 m) were randomized and allocated in supplement (SUPP) or placebo (PLA) group. Mean Measurements: Vitamin D blood level; Appendicular Lean Mass (ALM); Visceral Adipose Tissue (VAT); Maximal Voluntary Contraction (MVC) and Peak Power (PP); myoelectric descriptors of fatigue: Fractal Dimension and Conduction Velocity initial values (FD iv, CV iv), their rates of change (FD slopes, CV slopes) and the Time to perform the Task (TtT). Mean Results: Significant changes were found in SUPP compared to baseline: Vitamin D (+8.73 ng/ml; p<0.001); ALM (+0.34 kg; p<0.001); VAT (-76.25 g; p<0.001); MVC (+0.52 kg; p<0.001); PP (+4.82 W; p<0.001). Between group analysis (SUPP Vs. PLA) showed improvements: vitamin D blood levels (+11,72 ng/ml; p<0.001); Legs FFM (+443.7 g; p<0.05); ALM (+0.53 kg; p<0.05); MVC (+1.38 kg; p<0.05); PP (+9.87 W; p<0.05). No statistical changes were found for FD iv, CV iv, FD and CV slopes and TtT, either compared to baseline or between groups. Significant correlations between mean differences in SUPP group were also found. CONCLUSION The study demonstrates that in healthy elderly subjects an EAA-based multi-ingredient nutritional supplementation of 12 weeks is not effective to change myoelectric manifestation of fatigue and TtT failure but can positively affect muscle mass, muscle strength, muscle power and VAT, counterbalancing more than one year of age-related loss of muscle mass and strength.
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Leucine-enriched essential amino acid supplementation in mechanically ventilated trauma patients: a feasibility study.
Wandrag, L, Brett, SJ, Frost, GS, To, M, Loubo, EA, Jackson, NC, Umpleby, AM, Bountziouka, V, Hickson, M
Trials. 2019;(1):561
Abstract
BACKGROUND Critically ill patients lose up to 2% of muscle mass per day. We assessed the feasibility of administering a leucine-enriched essential amino acid (L-EAA) supplement to mechanically ventilated trauma patients with the aim of assessing the effect on skeletal muscle mass and function. METHODS A randomised feasibility study was performed over six months in intensive care (ICU). Patients received 5 g L-EAA five times per day in addition to standard feed (L-EAA group) or standard feed only (control group) for up to 14 days. C-reactive protein, albumin, IL-6, IL-10, urinary 3-MH, nitrogen balance, protein turnover ([1-13C] leucine infusion), muscle depth change (ultrasound), functional change (Katz and Barthel indices) and muscle strength Medical Research Council (MRC) sum score to assess ICU Acquired Weakness were measured sequentially. RESULTS Eight patients (9.5% of screened patients) were recruited over six months. L-EAA doses were provided on 91/124 (73%) occasions. Inflammatory and urinary marker data were collected; serial muscle depth measurements were lacking due to short length of stay. Protein turnover studies were performed on five occasions. MRC sum score could not be performed as patients were not able to respond to the screening questions. The Katz and Barthel indices did not change. L-EAA delivery was achievable, but meaningful functional and muscle mass outcome measures require careful consideration in the design of a future randomised controlled trial. CONCLUSION L-EAA was practical to provide, but we found significant barriers to recruitment and measurement of the chosen outcomes which would need to be addressed in the design of a future, large randomised controlled trial. TRIAL REGISTRATION ISRCTN Registry, ISRCTN79066838 . Registered on 25 July 2012.