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Dispensable Amino Acids, except Glutamine and Proline, Are Ideal Nitrogen Sources for Protein Synthesis in the Presence of Adequate Indispensable Amino Acids in Adult Men.
Cooper, L, Ball, RO, Pencharz, PB, Sakai, R, Elango, R
The Journal of nutrition. 2020;(9):2398-2404
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Abstract
BACKGROUND Nutritionally, there is a dietary requirement for indispensable amino acids (IAAs) but also a requirement for nitrogen (N) intake for the de novo synthesis of the dispensable amino acids (DAAs). It has been suggested that there might be a dietary requirement for specific DAAs. OBJECTIVES Experiment 1 tested whether 9 of the DAAs (Ala, Arg, Asn, Asp, Gln, Glu, Gly, Pro, Ser) are ideal N sources using the indicator amino acid oxidation (IAAO) technique. Experiment 2 examined whether there is a dietary requirement for Glu in adult men. METHODS Seven healthy men (aged 20-24 y) participated in 11 or 2 test diet intakes, in experiment 1 and 2, respectively, in a repeated measures design. In experiment 1, a base diet consisting of the IAA provided at the RDA was compared with test intakes with the base diet plus addition of individual DAAs to meet a 50:50 ratio of IAA:DAA on an N basis. In experiment 2, the diets corresponded to the amino acid pattern present in egg protein, in which all Glu and Gln was present as Glu, or removed, with Ser used to make the diets isonitrogenous. On each study day the IAAO protocol with l-[1-13C]phenylalanine was used to measure whole-body protein synthesis. RESULTS In experiment 1, repeated measures ANOVA with post hoc multiple comparisons showed that 7 of the 9 DAAs (Ala, Arg, Asn, Asp, Glu, Gly, Ser) decreased IAAO significantly (P < 0.05) compared with base IAA diet, the exceptions being Gln and Pro. In experiment 2, a paired t test did not find significant (P > 0.05) differences in the IAAO in response to removal and replacement of Glu intake. CONCLUSIONS The results suggest that in healthy men most DAAs are ideal N sources for protein synthesis, in the presence of adequate IAAs, and that endogenous synthesis of Glu is sufficient.Registered clinicaltrials.gov identifier: NCT02009917.
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The Anabolic Response to Dietary Protein Is Not Limited by the Maximal Stimulation of Protein Synthesis in Healthy Older Adults: A Randomized Crossover Trial.
Park, S, Jang, J, Choi, MD, Shin, YA, Schutzler, S, Azhar, G, Ferrando, AA, Wolfe, RR, Kim, IY
Nutrients. 2020;(11)
Abstract
We have recently demonstrated in young adults that an anabolic response with mixed meal protein intake above ~35 g/meal, previously recognized as an "optimal" protein dose, was further stimulated. However, it is unknown if this applies to older adults. We therefore examined anabolic response to a mixed meal containing either 35 g (MOD, moderate amount of protein) or 70 g (HIGH, high amount of protein) in a randomized cross-over metabolic study in older adults (n = 8). Primed continuous infusions of L-[2H5] phenylalanine and L-[2H2]tyrosine were performed to determine whole-body protein kinetics and muscle protein fractional synthesis rate (MPS) in basal fasted and fed states. Whole-body protein kinetics (NB, net protein balance; PS, protein synthesis; PB, protein breakdown) and MPS was expressed as changes from the baseline post-absorptive state. Consistent with our previous findings in young adults, both feedings resulted in a positive NB, with HIGH being more positive than MOD. Furthermore, NB (expressed as g protein∙240 min) increased linearly with an increasing amount of protein intake, expressed relative to lean body mass. The positive NB was achieved due mainly to the suppression of PB in both MOD and to a greater extent HIGH, while PS was only increased in HIGH. Consistent with the whole-body data, MPS was significantly higher in HIGH than MOD. Plasma concentrations of essential amino acids and insulin were greater in HIGH vs. MOD. We conclude that in the context of mixed meals, whole-body anabolic response linearly increases with increasing protein intake primarily through the suppression of PB, and MPS was further stimulated with protein intake above the previously considered "optimal" protein dose in older adults.
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Impact of 3-week citrulline supplementation on postprandial protein metabolism in malnourished older patients: The Ciproage randomized controlled trial.
Bouillanne, O, Melchior, JC, Faure, C, Paul, M, Canouï-Poitrine, F, Boirie, Y, Chevenne, D, Forasassi, C, Guery, E, Herbaud, S, et al
Clinical nutrition (Edinburgh, Scotland). 2019;(2):564-574
Abstract
BACKGROUND Citrulline (CIT), is not extracted by the splanchnic area, can stimulate muscle protein synthesis and could potentially find clinical applications in conditions involving low amino acid (AA) intake, such as in malnourished older subjects. OBJECTIVE Our purpose was to research the effects of CIT supplementation on protein metabolism in particular on non-oxidative leucine disposal (NOLD, primary endpoint), and splanchnic extraction of amino acids in malnourished older patients. DESIGN This prospective randomized multicenter study determined whole-body and liver protein synthesis, splanchnic protein metabolism and appendicular skeletal muscle mass (ASMM) in 24 malnourished older patients [80-92 years; 18 women and 6 men] in inpatient rehabilitation units. All received an oral dose of 10 g of CIT or an equimolar mixture of six non-essential amino acids (NEAAs), as isonitrogenous placebo, for 3 weeks. RESULTS NOLD and albumin fractional synthesis rates were not different between the NEAA and CIT groups. Splanchnic extraction of dietary amino acid tended to decrease (p = 0.09) in the CIT group (45.2%) compared with the NEAA group (60.3%). Total differences in AA and NEAA area under the curves between fed-state and postabsorptive-state were significantly higher in the CIT than in the NEAA group. There were no significant differences for body mass index, fat mass (FM), lean mass (LM) or ASMM in the whole population except for a tendential decrease in FM for the citrulline group (p = 0.089). Compared with Day 1, lean mass and ASMM significantly increased (respectively p = 0.016 and p = 0.018) at Day 20 in CIT-treated women (mean respective increase of 1.7 kg and 1.1 kg), and fat mass significantly decreased (p = 0.001) at Day 20 in CIT-group women (mean decrease of 1.3 kg). CONCLUSIONS Our results demonstrate that CIT supplementation has no effect on whole-body protein synthesis or liver protein synthesis in malnourished older subjects. However, CIT supplementation was associated with a higher systemic AA availability. In the subgroup of women, CIT supplementation increased LM and ASMM, and decreased FM.
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A randomized controlled trial of the impact of protein supplementation on leg lean mass and integrated muscle protein synthesis during inactivity and energy restriction in older persons.
Oikawa, SY, McGlory, C, D'Souza, LK, Morgan, AK, Saddler, NI, Baker, SK, Parise, G, Phillips, SM
The American journal of clinical nutrition. 2018;(5):1060-1068
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Abstract
BACKGROUND In older persons, muscle loss is accelerated during physical inactivity and hypoenergetic states, both of which are features of hospitalization. Protein supplementation may represent a strategy to offset the loss of muscle during inactivity, and enhance recovery on resumption of activity. OBJECTIVE We aimed to determine if protein supplementation, with proteins of substantially different quality, would alleviate the loss of lean mass by augmenting muscle protein synthesis (MPS) while inactive during a hypoenergetic state. DESIGN Participants (16 men, mean ± SD age: 69 ± 3 y; 15 women, mean ± SD age: 68 ± 4 y) consumed a diet containing 1.6 g protein · kg-1 · d-1, with 55% ± 9% of protein from foods and 45% ± 9% from supplements, namely, whey protein (WP) or collagen peptides (CP): 30 g each, consumed 2 times/d. Participants were in energy balance (EB) for 1 wk, then began a period of energy restriction (ER; -500 kcal/d) for 1 wk, followed by ER with step reduction (ER + SR; <750 steps/d) for 2 wk, before a return to habitual activity in recovery (RC) for 1 wk. RESULTS There were significant reductions in leg lean mass (LLM) from EB to ER, and from ER to ER + SR in both groups (P < 0.001) with no differences between WP and CP or when comparing the change from phase to phase. During RC, LLM increased from ER + SR, but in the WP group only. Rates of integrated muscle protein synthesis decreased during ER and ER + SR in both groups (P < 0.01), but increased during RC only in the WP group (P = 0.05). CONCLUSIONS Protein supplementation did not confer a benefit in protecting LLM, but only supplemental WP augmented LLM and muscle protein synthesis during recovery from inactivity and a hypoenergetic state. This trial was registered at http://www.clinicaltrials.gov as NCT03285737.
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Protein intake distribution pattern does not affect anabolic response, lean body mass, muscle strength or function over 8 weeks in older adults: A randomized-controlled trial.
Kim, IY, Schutzler, S, Schrader, AM, Spencer, HJ, Azhar, G, Wolfe, RR, Ferrando, AA
Clinical nutrition (Edinburgh, Scotland). 2018;(2):488-493
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Abstract
BACKGROUND & AIMS In our recent acute metabolic study, we found no differences in the anabolic response to differing patterns of dietary protein intake. To confirm this in a chronic study, we investigated the effects of protein distribution pattern on functional outcomes and protein kinetics in older adults over 8 weeks. METHODS To determine chronic effects of protein intake pattern at 1.1 g protein/kg/day in mixed meals on lean body mass (LBM), functional outcomes, whole body protein kinetics and muscle protein fractional synthesis rate (MPS) over 8-week respective dietary intervention, fourteen older subjects were randomly divided into either EVEN or UNVEN group. The UNEVEN group (n = 7) consumed the majority of dietary protein with dinner (UNEVEN, 15/20/65%; breakfast, lunch, dinner), while the EVEN group (n = 7) consumed dietary protein evenly throughout the day (EVEN: 33/33/33%). RESULTS We found no significant differences in LBM, muscle strength, and other functional outcomes between EVEN and UNEVEN before and after 8-week intervention. Consistent with these functional outcomes, we did not find significant differences in the 20-h integrated whole body protein kinetics [net protein balance (NB), protein synthesis (PS), and breakdown (PB)] above basal states and MPS between EVEN and UNEVEN intake patterns. CONCLUSIONS We conclude that over an 8-week intervention period, the protein intake distribution pattern in mixed meals does not play an important role in determining anabolic response, muscle strength, or functional outcomes. This trial is registered at https://ClinicalTrials.gov as NCT02787889.
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Rates of cerebral protein synthesis in primary visual cortex during sleep-dependent memory consolidation, a study in human subjects.
Picchioni, D, Schmidt, KC, McWhirter, KK, Loutaev, I, Pavletic, AJ, Speer, AM, Zametkin, AJ, Miao, N, Bishu, S, Turetsky, KM, et al
Sleep. 2018;(7)
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Abstract
If protein synthesis during sleep is required for sleep-dependent memory consolidation, we might expect rates of cerebral protein synthesis (rCPS) to increase during sleep in the local brain circuits that support performance on a particular task following training on that task. To measure circuit-specific brain protein synthesis during a daytime nap opportunity, we used the L-[1-(11)C]leucine positron emission tomography (PET) method with simultaneous polysomnography. We trained subjects on the visual texture discrimination task (TDT). This was followed by a nap opportunity during the PET scan, and we retested them later in the day after the scan. The TDT is considered retinotopically specific, so we hypothesized that higher rCPS in primary visual cortex would be observed in the trained hemisphere compared to the untrained hemisphere in subjects who were randomized to a sleep condition. Our results indicate that the changes in rCPS in primary visual cortex depended on whether subjects were in the wakefulness or sleep condition but were independent of the side of the visual field trained. That is, only in the subjects randomized to sleep, rCPS in the right primary visual cortex was higher than the left regardless of side trained. Other brain regions examined were not so affected. In the subjects who slept, performance on the TDT improved similarly regardless of the side trained. Results indicate a regionally selective and sleep-dependent effect that occurs with improved performance on the TDT.
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Effectiveness of essential amino acid supplementation in stimulating whole body net protein anabolism is comparable between COPD patients and healthy older adults.
Jonker, R, Deutz, NE, Erbland, ML, Anderson, PJ, Engelen, MP
Metabolism: clinical and experimental. 2017;:120-129
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Abstract
BACKGROUND The development of effective nutritional strategies in support of muscle growth for patients with chronic obstructive pulmonary disease (COPD) remains challenging. Dietary essential amino acids (EAAs) are the main driver of postprandial net protein anabolism. In agreement, EAA supplements in healthy older adults are more effective than supplements with the composition of complete proteins. In patients with COPD it is still unknown whether complete protein supplements can be substituted with only EAAs, and whether they are as effective as in healthy older adults. METHODS According to a double-blind randomized crossover design, we examined in 23 patients with moderate to very severe COPD (age: 65±2 years, FEV1: 40±2% of predicted) and 19 healthy age-matched subjects (age: 64±2 years), whether a free EAA mixture with a high proportion (40%) of leucine (EAA mixture) stimulated whole body net protein gain more than a similar mixture of balanced free EAAs and non-EAAs as present in whey protein (TAA mixture). Whole body net protein gain and splanchnic extraction of phenylalanine (PHE) were assessed by continuous IV infusion of L-[ring-2H5]-PHE and L-[ring-2H2]-tyrosine, and enteral intake of L-[15N]-PHE (added to the mixtures). RESULTS Besides an excellent positive linear relationship between PHE intake and net protein gain in both groups (r=0.84-0.91, P<0.001), net protein gain was 42% higher in healthy controls and 49% higher in COPD patients after intake of the EAA mixture compared to the TAA mixture (P<0.0001). These findings could not be attributed to the high LEU content, as in both groups net protein gain per gram EAA intake was lower for the EAA mixture (P<0.0001). Net protein gain was higher in COPD patients for both mixtures due to a 40% lower splanchnic extraction (P<0.0001), but was similarly related to dietary PHE (i.e. EAA) plasma appearance. CONCLUSIONS In COPD patients, similarly to healthy older adults, free EAA supplements stimulate whole body protein anabolism more than free amino acid supplements with the composition of complete proteins. Therefore, free EAA supplements may aid in the prevention and treatment of muscle wasting in this patient population.
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Sodium nitrate co-ingestion with protein does not augment postprandial muscle protein synthesis rates in older, type 2 diabetes patients.
Kouw, IW, Cermak, NM, Burd, NA, Churchward-Venne, TA, Senden, JM, Gijsen, AP, van Loon, LJ
American journal of physiology. Endocrinology and metabolism. 2016;(2):E325-34
Abstract
The age-related anabolic resistance to protein ingestion is suggested to be associated with impairments in insulin-mediated capillary recruitment and postprandial muscle tissue perfusion. The present study investigated whether dietary nitrate co-ingestion with protein improves muscle protein synthesis in older, type 2 diabetes patients. Twenty-four men with type 2 diabetes (72 ± 1 yr, 26.7 ± 1.4 m/kg(2) body mass index, 7.3 ± 0.4% HbA1C) received a primed continuous infusion of l-[ring-(2)H5]phenylalanine and l-[1-(13)C]leucine and ingested 20 g of intrinsically l-[1-(13)C]phenylalanine- and l-[1-(13)C]leucine-labeled protein with (PRONO3) or without (PRO) sodium nitrate (0.15 mmol/kg). Blood and muscle samples were collected to assess protein digestion and absorption kinetics and postprandial muscle protein synthesis rates. Upon protein ingestion, exogenous phenylalanine appearance rates increased in both groups (P < 0.001), resulting in 55 ± 2% and 53 ± 2% of dietary protein-derived amino acids becoming available in the circulation over the 5h postprandial period in the PRO and PRONO3 groups, respectively. Postprandial myofibrillar protein synthesis rates based on l-[ring-(2)H5]phenylalanine did not differ between groups (0.025 ± 0.004 and 0.021 ± 0.007%/h over 0-2 h and 0.032 ± 0.004 and 0.030 ± 0.003%/h over 2-5 h in PRO and PRONO3, respectively, P = 0.7). No differences in incorporation of dietary protein-derived l-[1-(13)C]phenylalanine into de novo myofibrillar protein were observed at 5 h (0.016 ± 0.002 and 0.014 ± 0.002 mole percent excess in PRO and PRONO3, respectively, P = 0.8). Dietary nitrate co-ingestion with protein does not modulate protein digestion and absorption kinetics, nor does it further increase postprandial muscle protein synthesis rates or the incorporation of dietary protein-derived amino acids into de novo myofibrillar protein in older, type 2 diabetes patients.
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Leucine supplementation enhances integrative myofibrillar protein synthesis in free-living older men consuming lower- and higher-protein diets: a parallel-group crossover study.
Murphy, CH, Saddler, NI, Devries, MC, McGlory, C, Baker, SK, Phillips, SM
The American journal of clinical nutrition. 2016;(6):1594-1606
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Abstract
BACKGROUND Leucine co-ingestion with lower-protein (LP)-containing meals may overcome the blunted muscle protein synthetic response to food intake in the elderly but may be effective only in individuals who consume LP diets. OBJECTIVE We examined the impact of leucine co-ingestion with mixed macronutrient meals on integrated 3-d rates of myofibrillar protein synthesis (MyoPS) in free-living older men who consumed higher protein (HP) (1.2 g · kg-1 · d-1) or LP (0.8 g · kg-1 · d-1) in rested and resistance exercise (REX) conditions. DESIGN In a crossover design, 20 healthy older men [aged 65-85 y] were randomly assigned to receive LP or HP diets while ingesting a placebo (days 0-2) and Leu supplement (5 g leucine/meal; days 3-5) with their 3 main daily meals. A bout of unilateral REX was performed during the placebo and Leu treatments. Ingested 2H2O and skeletal muscle biopsies were used to measure the 3-d integrated rate of MyoPS during the placebo and Leu treatments in the rested and REX legs. RESULTS Leucinemia was higher with Leu treatment than with placebo treatment (P < 0.001). MyoPS was similar in LP and HP during both treatments (P = 0.39) but was higher with Leu treatment than with placebo treatment in the rested (pooled mean ± SD: Leu, 1.57% ± 0.11%/d; placebo, 1.48% ± 0.08%/d; main effect of treatment: P < 0.001) and REX (pooled mean: Leu, 1.87% ± 0.09%/d; placebo, 1.71 ± 0.10%/d; main effect of treatment: P < 0.001) legs. CONCLUSIONS Leu co-ingestion with daily meals enhances integrated MyoPS in free-living older men in rested and REX conditions and is equally effective in older men who consume daily protein intakes greater than or equal to the RDA. This trial was registered at clinicaltrials.gov as NCT02371278.
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Preoperative overnight parenteral nutrition (TPN) improves skeletal muscle protein metabolism indicated by microarray algorithm analyses in a randomized trial.
Iresjö, BM, Engström, C, Lundholm, K
Physiological reports. 2016;(11)
Abstract
Loss of muscle mass is associated with increased risk of morbidity and mortality in hospitalized patients. Uncertainties of treatment efficiency by short-term artificial nutrition remain, specifically improvement of protein balance in skeletal muscles. In this study, algorithmic microarray analysis was applied to map cellular changes related to muscle protein metabolism in human skeletal muscle tissue during provision of overnight preoperative total parenteral nutrition (TPN). Twenty-two patients (11/group) scheduled for upper GI surgery due to malignant or benign disease received a continuous peripheral all-in-one TPN infusion (30 kcal/kg/day, 0.16 gN/kg/day) or saline infusion for 12 h prior operation. Biopsies from the rectus abdominis muscle were taken at the start of operation for isolation of muscle RNA RNA expression microarray analyses were performed with Agilent Sureprint G3, 8 × 60K arrays using one-color labeling. 447 mRNAs were differently expressed between study and control patients (P < 0.1). mRNAs related to ribosomal biogenesis, mRNA processing, and translation were upregulated during overnight nutrition; particularly anabolic signaling S6K1 (P < 0.01-0.1). Transcripts of genes associated with lysosomal degradation showed consistently lower expression during TPN while mRNAs for ubiquitin-mediated degradation of proteins as well as transcripts related to intracellular signaling pathways, PI3 kinase/MAPkinase, were either increased or decreased. In conclusion, muscle mRNA alterations during overnight standard TPN infusions at constant rate altered mRNAs associated with mTOR signaling; increased initiation of protein translation; and suppressed autophagy/lysosomal degradation of proteins. This indicates that overnight preoperative parenteral nutrition is effective to promote muscle protein metabolism.