Effects of leucine and citrulline versus non-essential amino acids on muscle protein synthesis in fasted rat: a common activation pathway?

Plénier, S. Le; Walrand, Stéphane; Noirt, Richard; Cynober, Luc; Moinard, Christophe

doi:10.1007/s00726-011-1172-z

Cited by 51 publications

(52 citation statements)

References 30 publications

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“…A previous report indicated that citrulline, which is metabolized from Orn, is able to promote the phosphorylation of 4EBP1 but not that of S6 (19). In our experiment, S6 phosphorylation was promoted more predominantly than that of 4EBP1.…”

Section: Discussionsupporting

confidence: 57%

“…Its effect on promoting tissue protein synthesis has also been shown (12). Recently, citrulline, a urea cycle amino acid that is metabolized from Orn, was reported as a potent regulator of the mTORC1 pathway following protein synthesis (19). mTORC1 is a master regulator that controls protein synthesis (16,17).…”

Section: Discussionmentioning

confidence: 99%

“…Rats were starved for 18 h before the experiment began and dissected 1 and 3 h after Orn administration. In various previous reports investigating the effect of Leu, 1.35 g/kg body weight of Leu was administered (19,27,28). We calculated the Orn hydrochloride dosage for 1.74 g/kg body weight as equivalent molar to 1.35 g/kg body weight of Leu.…”

Section: Discussionmentioning

confidence: 99%

“…Of these, L-leucine (Leu) and insulin are well known to promote protein synthesis through the activation of mTORC1 signaling. In addition, recent evidence demonstrated that another amino acid, L-citrulline, is a similar potent regulator of mTORC1 signaling (19).…”

Section: Introductionmentioning

confidence: 99%

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The Effect of L-Ornithine on the Phosphorylation of mTORC1 Downstream Targets in Rat Liver

Kokubo

Maeda

Tazumi

et al. 2015

JFN

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A non-protein amino acid, L-ornithine (Orn), has been shown to stimulate the urea cycle and tissue protein synthesis in the liver. The purpose of the current study was to assess whether Orn affects the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) pathway, which is involved in protein synthesis. Primary cultured cells isolated from Wistar rat liver were incubated in an amino acid-free medium, followed by addition of Orn for 3 h. The cell lysate was subjected to immunoblotting to evaluate the phosphorylation of downstream targets of mTORC1, including p70S6K, S6, and 4EBP1. To assess the involvement of mTORC1 for the effect of Orn, the cells were pretreated with the mTOR inhibitor rapamycin before the addition of Orn and the cell lysate was subjected to immunoblotting. We next examined whether the effects of Orn were exerted in vivo. Orn was orally administered to 18 h food-deprived rats, the blood and the livers were collected at 1 and 3 h after administration for immunoblotting. Orn treatment for primary cultured cells for 3 h enhanced the phosphorylation of p70S6K, S6, and 4EBP1. In addition, rapamycin blocked the effects of Orn completely (p70S6K and S6) or partially (4EBP1). The oral administration of Orn to the rat also augmented the phosphorylation of mTORC1 downstream targets notably in S6 at 1 h. Our findings demonstrate that Orn has the potential to induce the phosphorylation of downstream targets of mTORC1 in the rat liver. This may be mediated by the augmentation of mTORC1 activity.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Effect of L-Ornithine on the Phosphorylation of mTORC1 Downstream Targets in Rat Liver

Kokubo

Maeda

Tazumi

et al. 2015

JFN

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“…Following completion of the resistance exercise, participants immediately ingested their designated nutrient treatment in a blinded manner (Table 2) and returned to bed, where they rested in a supine position for the remainder of the protocol. Heart rate, blood pressure, and blood flow through the right and left common femoral arteries were then assessed at 15,30,60,90,120,180,240, and 300 min postexercise, whereas CEUS-derived measurements of microvascular circulation were obtained at 90 min following exercise and treatment administration. Bilateral biopsy samples were obtained from the vastus lateralis muscle at 150 min and 300 min following exercise and treatment administration.…”

mentioning

confidence: 99%

Citrulline does not enhance blood flow, microvascular circulation, or myofibrillar protein synthesis in elderly men at rest or following exercise

Churchward‐Venne¹,

Cotie²,

MacDonald³

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Churchward-Venne TA, Cotie LM, MacDonald MJ, Mitchell CJ, Prior T, Baker SK, Phillips SM. Citrulline does not enhance blood flow, microvascular circulation, or myofibrillar protein synthesis in elderly men at rest or following exercise. Am J Physiol Endocrinol Metab 307: E71-E83, 2014. First published May 13, 2014; doi:10.1152/ajpendo.00096.2014.-Aging is associated with anabolic resistance, a reduced sensitivity of myofibrillar protein synthesis (MPS) to postprandial hyperaminoacidemia, particularly with low protein doses. Impairments in postprandial skeletal muscle blood flow and/or microvascular perfusion with hyperaminoacidemia and hyperinsulinemia may contribute to anabolic resistance. We examined whether providing citrulline, a precursor for arginine and nitric oxide synthesis, would increase arterial blood flow, skeletal muscle microvascular perfusion, MPS, and signaling through mTORC1. Twentyone elderly males (65-80 yr) completed acute unilateral resistance exercise prior to being assigned to ingest a high dose (45 g) of whey protein (WHEY) or a low dose (15 g) of whey protein with 10 g of citrulline (WHEY ϩ CIT) or with 10 g of nonessential amino acids (WHEY ϩ NEAA). A primed, continuous infusion of L-[ring-13 C6] phenylalanine with serial muscle biopsies was used to measure MPS and protein phosphorylation, whereas ultrasound was used to measure microvascular circulation under basal and postprandial conditions in both a rested (FED) and exercised (EX-FED) leg. Argininemia was greater in WHEY ϩ CIT vs. WHEY and WHEY ϩ NEAA from 30 to 300 min postexercise (P Ͻ 0.001), but there were no treatment differences in blood flow or microvascular perfusion (all P Ͼ 0.05). Phosphorylation of p70S6K-Thr 389 was greater in WHEY vs. WHEY ϩ NEAA (P ϭ 0.02). Postprandial MPS was greater in WHEY vs. WHEY ϩ CIT and WHEY ϩ NEAA under both FED (WHEY: ϳ128%; WHEY ϩ CIT: ϳ56%; WHEY ϩ NEAA: ϳ38%) and EX-FED (WHEY: ϳ251%; WHEY ϩ CIT: ϳ124%; WHEY ϩ NEAA: ϳ108%) conditions (P ϭ 0.003). Citrulline coingestion with a low quantity of protein was ineffective in augmenting the anabolic properties of protein compared with nonessential amino acids. citrulline; myofibrillar protein synthesis; elderly DECLINES IN MUSCLE MASS WITH AGING are due to rates of myofibrillar protein synthesis (MPS) being less than the net rate of muscle protein breakdown (37). Aminoacidemia and physical exercise are potent anabolic stimuli that elicit the synthesis of new muscle proteins; however, aging is associated with a reduced MPS response following both hyperaminoacidemia (54) and resistance exercise (28), a phenomenon termed "anabolic resistance" (for review, see Ref. 10). Although the mechanisms underlying anabolic resistance are not fully understood, age-related impairments in blood flow may be involved (31,48,50).Aminoacidemia and insulinemia increase MPS (54), arterial blood flow (54), and muscle microvascular perfusion (52) in the young; however, these responses are blunted in the elderly (48, 54). Age-related impairments in vascular function may be...

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Citrulline stimulates muscle protein synthesis, by reallocating ATP consumption to muscle protein synthesis

Goron

Lamarche

Blanchet

et al. 2019

J cachexia sarcopenia muscle

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Background Animal studies and clinical data support the interest of citrulline as a promising therapeutic for sarcopenia. Citrulline is known to stimulate muscle protein synthesis, but how it affects energy metabolism to support the highly energy‐dependent protein synthesis machinery is poorly understood. Methods Here, we used myotubes derived from primary culture of mouse myoblasts to study the effect of citrulline on both energy metabolism and protein synthesis under different limiting conditions. Results When serum/amino acid deficiency or energy stress (mild uncoupling) were applied, citrulline stimulated muscle protein synthesis by +22% and +11%, respectively. Importantly, this increase was not associated with enhanced energy status (ATP/ADP ratio) or mitochondrial respiration. We further analysed the share of mitochondrial respiration and thus of generated ATP allocated to different metabolic pathways by using specific inhibitors. Our results indicate that addition of citrulline allocated an increased share of mitochondrially generated ATP to the protein synthesis machinery under conditions of both serum/amino acid deficiency (+28%) and energy stress (+21%). This reallocation was not because of reduced ATP supply to DNA synthesis or activities of sodium and calcium cycling ion pumps. Conclusions Under certain stress conditions, citrulline increases muscle protein synthesis by specifically reallocating mitochondrial fuel to the protein synthesis machinery. Because ATP/ADP ratios and thus Gibbs free energy of ATP hydrolysis remained globally constant, this reallocation may be linked to decreased activation energies of one or several ATP (and GTP)‐consuming reactions involved in muscle protein synthesis.

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Effects of leucine and citrulline versus non-essential amino acids on muscle protein synthesis in fasted rat: a common activation pathway?

Cited by 51 publications

References 30 publications

The Effect of L-Ornithine on the Phosphorylation of mTORC1 Downstream Targets in Rat Liver

The Effect of L-Ornithine on the Phosphorylation of mTORC1 Downstream Targets in Rat Liver

Citrulline does not enhance blood flow, microvascular circulation, or myofibrillar protein synthesis in elderly men at rest or following exercise

Citrulline stimulates muscle protein synthesis, by reallocating ATP consumption to muscle protein synthesis

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