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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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Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure.
Vanninen, SUM, Leivo, K, Seppälä, EH, Aalto-Setälä, K, Pitkänen, O, Suursalmi, P, Annala, AP, Anttila, I, Alastalo, TP, Myllykangas, S, et al
PloS one. 2018;(9):e0203422
Abstract
During the last two decades, mutations in sarcomere genes have found to comprise the most common cause for hypertrophic cardiomyopathy (HCM), but still significant number of patients with dominant HCM in the family are left without molecular genetic diagnosis. Next generation sequencing (NGS) does not only enable evaluation of established HCM genes but also candidate genes for cardiomyopathy are frequently tested which may lead to a situation where conclusive interpretation of the variant requires extensive family studies. We aimed to characterize the phenotype related to a variant in the junctophilin-2 (JPH2) gene, which is less known non-sarcomeric candidate gene. In addition, we did extensive review of the literature and databases about JPH2 variation in association with cardiac disease. We characterize nine Finnish index patients with HCM and heterozygous for JPH2 c.482C>A, p.(Thr161Lys) variant were included and segregation studies were performed. We identified 20 individuals affected with HCM with or without systolic heart failure and conduction abnormalities in the nine Finnish families with JPH2 p.(Thr161Lys) variant. We found 26 heterozygotes with the variant and penetrance was 71% by age 60 and 100% by age 80. Co-segregation of the variant with HCM phenotype was observed in six families. Main clinical features were left ventricular hypertrophy, arrhythmia vulnerability and conduction abnormalities including third degree AV-block. In some patients end-stage severe left ventricular heart failure with normal or mildly enlarged diastolic dimensions was detected. In conclusion, we propose that the heterozygous JPH2 p.(Thr161Lys) variant is a new Finnish mutation causing atypical HCM.
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Identification of a missense mutation in the melusin-encoding ITGB1BP2 gene in a patient with dilated cardiomyopathy.
Ruppert, V, Meyer, T, Richter, A, Maisch, B, Pankuweit, S, ,
Gene. 2013;(2):206-10
Abstract
In a heterogeneous cohort of patients (n=255) with sporadic and familial dilated cardiomyopathy (DCM), we searched for novel disease-associated mutations in the human melusin-encoding ITGB1BP2 gene and found only one missense mutation, which was a substitution of alanine for glycine at position 313 located in the carboxy-terminal spacer region of the molecule. This point mutation (c.938C>G) was identified in a 45-year-old male with familial DCM and severe impairment of left-ventricular function, but was absent in 300 healthy control subjects. However, its functional significance in the context of heart failure is unclear, as this amino acid substitution was predicted to be without disease-causing effects. In this report, we confirm the low prevalence of mutations and single nucleotide polymorphisms in the coding sequence of the human melusin gene in patients with DCM, ruling out the possibility that genetic variations in this myocardially transcribed gene may have a significant impact on the epidemiology of DCM-induced heart failure.
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Whole-body and muscle protein metabolism are not affected by acute deviations from habitual protein intake in older men: the Hormonal Regulators of Muscle and Metabolism in Aging (HORMA) Study.
Yarasheski, KE, Castaneda-Sceppa, C, He, J, Kawakubo, M, Bhasin, S, Binder, EF, Schroeder, ET, Roubenoff, R, Azen, SP, Sattler, FR
The American journal of clinical nutrition. 2011;(1):172-81
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Abstract
BACKGROUND Acute deviations in protein intake before the quantification of protein kinetics in older humans may explain the controversy over the effects of older age on muscle protein synthesis and proteolysis rates. OBJECTIVE We hypothesized that an acute decrease in protein intake from the habitual intake is associated with lower muscle protein synthesis and higher proteolysis rates, whereas an acute increase in protein intake from the habitual intake is associated with higher muscle protein synthesis and lower proteolysis rates. DESIGN In 112 community-dwelling healthy men aged 65-90 y, we quantified resting whole-body [1,2-(13)C(2)]leucine kinetics, muscle mixed protein fractional synthesis rates (FSRs), and muscle proteasome proteolytic enzyme activities after participants consumed for 3 d controlled research meals (0.9-1.1 g protein · kg(-1) · d(-1)) that contained more or less protein than that habitually consumed and that induced alterations in nitrogen balance. RESULTS Protein kinetic parameters were not significantly different between the groups, despite controlled research protein intakes that were lower (-0.2 to -0.3 g · kg(-1) · d(-1)) or higher (+0.2 g · kg(-1) · d(-1)) than habitual intakes and that induced negative (-22 to -25 mg · kg(-1) · d(-1)) or positive (22-25 mg · kg(-1) · d(-1)) nitrogen balance. Within these acutely altered protein intake and nitrogen balance boundaries, a reduction in protein intake from habitual intake and induction of negative nitrogen balance were not associated with higher proteolysis or lower muscle FSR, and an acute increase in protein intake from habitual intake and induction of positive nitrogen balance were not associated with lower proteolysis or higher muscle FSR. A higher quantitative insulin sensitivity check index was associated with lower whole-body proteolysis rates. CONCLUSIONS The practice of acutely controlling protein intake, even at intakes lower than habitual intakes that induce negative nitrogen balance, before quantifying human protein kinetics does not significantly reduce muscle protein synthesis or increase proteolysis. Factors other than protein intake explain lower muscle protein synthesis rates with advanced age. This trial is registered at clinicaltrials.gov as NCT00183040.
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Total parenteral nutrition enriched with arginine and glutamate generates glutamine and limits protein catabolism in surgical patients hospitalized in intensive care units.
Bérard, MP, Zazzo, JF, Condat, P, Vasson, MP, Cynober, L
Critical care medicine. 2000;(11):3637-44
Abstract
OBJECTIVES To study the effect of a parenteral nutrition solution enriched with potential precursors of glutamine, i.e., arginine and glutamate, on plasma glutamine concentrations and protein metabolism. DESIGN Prospective, randomized, single-blind, comparative study. SETTING Two intensive care units in two different hospitals. PATIENTS Fifteen surgical patients. INTERVENTIONS Patients were randomized to receive total parenteral nutrition for 5 days with the enriched glutamine precursor solution (GlnP+ group) or a conventional solution (control group), both total parenteral nutrition providing 0.25 gN/kg per day and 35 kcal/kg per day (glucose/lipids, 70%:30%). MEASUREMENTS AND MAIN RESULTS Plasma amino acid concentrations before (T0) and after 3 hrs (T3) of perfusion, nitrogen balance (daily and cumulated), and urinary excretion of 3-methylhistidine were measured daily from day 1 to day 5. The two groups were identical for age, weight, severity score, and nitrogen and energy intakes. After a 3-hr perfusion, plasma concentrations of arginine, ornithine, and glutamine increased, and the differences (T3 - T0) were significantly higher in the GlnP+ group: arginine, 107.6+/-7.0 vs. 51.9+/-3.3 (mean over 5 days; p < .001); ornithine, 78.9+/-7.1 vs. 43.6+/-3.1 (p < .001); and glutamine, 32.4+/-8.6 vs. 6.7+/-5.0 micromol/L (p < .05), respectively. A positive correlation was found between arginine and glutamine plasma increases only in the GlnP+ group: r = .45; p < .01 (Spearman's rank-correlation test). Daily and cumulated nitrogen balances were not significantly different between the two groups but were positive (difference from 0) only in the GlnP+ group. The urinary 3-methylhistidine/creatinine ratio decreased significantly from day 1 to day 5 only in the GlnP+ group: 24.5+/-2.7 vs. 18.8+/-2.7 micromol/mmol (p < .05). CONCLUSIONS Total parenteral nutrition enriched with arginine and glutamate promotes a better nitrogen balance, limits protein myofibrillar catabolism, and generates glutamine, with arginine (not glutamate) probably being the main contributor to the glutamine-generating effect of the solution through the formation of ornithine.