Arginine Depletion by Arginine Deiminase Does Not Affect Whole Protein Metabolism or Muscle Fractional Protein Synthesis Rate in Mice

Marini, Juan C.; Didelija, Inka Cajo

doi:10.1371/journal.pone.0119801

Cited by 18 publications

(10 citation statements)

References 36 publications

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“…observed tissue-specific protein FSR values were comparable to those reported using D 2 O [7,20,32] and [ 2 H 5 ]phenylalanine flood dose methods [33,34] in mice [33], rat [7], and humans [20].…”

Section: Plos Onesupporting

confidence: 82%

Protein fractional synthesis rates within tissues of high- and low-active mice

et al. 2020

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With the rise in physical inactivity and its related diseases, it is necessary to understand the mechanisms involved in physical activity regulation. Biological factors regulating physical activity are studied to establish a possible target for improving the physical activity level. However, little is known about the role metabolism plays in physical activity regulation. Therefore, we studied protein fractional synthesis rate (FSR) of multiple organ tissues of 12-week-old male mice that were previously established as inherently low-active (n = 15, C3H/HeJ strain) and high-active (n = 15, C57L/J strain). Total body water of each mouse was enriched to 5% deuterium oxide (D2O) via intraperitoneal injection and maintained with D2O enriched drinking water for about 24 h. Blood samples from the jugular vein and tissues (kidney, heart, lung, muscle, fat, jejunum, ileum, liver, brain, skin, and bone) were collected for enrichment analysis of alanine by LC-MS/MS. Protein FSR was calculated as -ln(1-enrichment). Data are mean±SE as fraction/day (unpaired t-test). Kidney protein FSR in the low-active mice was 7.82% higher than in high-active mice (low-active: 0.1863±0.0018, high-active: 0.1754±0.0028, p = 0.0030). No differences were found in any of the other measured organ tissues. However, all tissues resulted in a generally higher protein FSR in the low-activity mice compared to the high-activity mice (e.g. lung LA: 0.0711±0.0015, HA: 0.0643±0.0020, heart LA: 0.0649± 0.0013 HA: 0.0712±0.0073). Our observations suggest that high-active mice in most organ tissues are no more inherently equipped for metabolic adaptation than low-active mice, but there may be a connection between protein metabolism of kidney tissue and physical activity level. In addition, low-active mice have higher organ-specific baseline protein FSR possibly contributing to the inability to achieve higher physical activity levels.

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Section: Plos Onesupporting

confidence: 82%

Protein fractional synthesis rates within tissues of high- and low-active mice

et al. 2020

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“…In this study, ADI-PEG20 resulted in the depletion of circulating arginine as previously reported (9,17). As a consequence, plasma citrulline concentrations and fluxes were greater in these mice.…”

Section: Discussionsupporting

confidence: 81%

“…The administration of ADI-PEG20 disrupts the interorgan metabolism of arginine, because all circulating arginine is converted into citrulline and any arginine synthesized and exported by the kidney is then converted back to citrulline upon entering the circulation. Although circulating arginine is considered essential for blood pressure maintenance (33), the depletion of arginine per se has little consequence on the metabolism of animals and humans when citrulline is available for local arginine synthesis (9,16,17). This is best exemplified by arginine depletion by arginase, which results in weight loss and death, but that can be prevented by citrulline supplementation (34).…”

Section: Discussionmentioning

confidence: 99%

“…Citrulline has the potential to be recycled intracellularly through the action of argininosuccinate synthase 1 (ASS1) and argininosuccinate lyase (ASL) to regenerate a new arginine molecule and thus sustain NO production (7,8). Furthermore, extracellular citrulline can also be transported into the cell and utilized to produce arginine locally (9,10).…”

Section: Introductionmentioning

confidence: 99%

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The Citrulline Recycling Pathway Sustains Cardiovascular Function in Arginine-Depleted Healthy Mice, but Cannot Sustain Nitric Oxide Production during Endotoxin Challenge

Yuan

Mohammad

Betancourt³

et al. 2018

The Journal of Nutrition

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Background The recycling of citrulline by argininosuccinate synthase 1 (ASS1) and argininosuccinate lyase (ASL) is crucial to maintain arginine availability and nitric oxide (NO) production. Pegylated arginine deiminase (ADI-PEG20) is a bacterial enzyme used to deplete circulating arginine. Objective The goal of this research was to test the hypothesis that citrulline is able to sustain intracellular arginine availability for NO production in ADI-PEG20 arginine–depleted mice. Methods Six- to 8-wk-old male C57BL/6J mice injected with ADI-PEG20 (5 IU) or saline (control) were used in 4 different studies. Arginine, citrulline, and NO kinetics were determined by using stable isotopes in unchallenged (study 1) and endotoxin-challenged (study 2) mice. Blood pressure was determined by telemetry for 6 d after ADI-PEG20 administration (study 3), and vasomotor activity and ASS1 and ASL gene expression were determined in mesenteric arteries collected from additional mice (study 4). Results ADI-PEG20 administration resulted in arginine depletion (<1 compared with 111 ± 37 µmol/L) but in greater plasma citrulline concentrations (900 ± 123 compared with 76 ± 8 µmol/L; P < 0.001) and fluxes (402 ± 17 compared with 126 ± 4 µmol ⋅ kg−1 ⋅ h−1; P < 0.001) compared with controls. Endotoxin-challenged ADI-PEG20–treated mice produced less NO than controls (13 ± 1 compared with 27 ± 2 µmol ⋅ kg−1 ⋅ h−1; P < 0.001). No differences (P > 0.50) were observed for cardiovascular variables (heart rate, blood pressure) between ADI-PEG20–treated and control mice. Furthermore, no ex vivo vasomotor differences were observed between the 2 treatments. ADI-PEG20 administration resulted in greater gene expression of ASS1 (∼3-fold) but lower expression of ASL (–30%). Conclusion ADI-PEG20 successfully depleted circulating arginine without any effect on cardiovascular endpoints in healthy mice but limited NO production after endotoxin challenge. Therefore, the citrulline recycling pathway can sustain local arginine availability independently from circulating arginine, satisfying the demand of arginine for endothelial NO production; however, it is unable to do so when a high demand for arginine is elicited by endotoxin.

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“…The citrulline produced by the enterocytes enters the portal circulation, bypasses the liver, enters the general circulation and is utilized by the kidney and other tissues for the synthesis of arginine [20▪,21▪]. Small amounts of circulating citrulline are produced as co-product in the synthesis of nitric oxide and in the turnover of posttranslational modified arginine (citrullinated and methylated).…”

Section: Introductionmentioning

confidence: 99%

Interrelationships between glutamine and citrulline metabolism

Marini

2016

Current Opinion in Clinical Nutrition and Metabolic Care

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Purpose of review To analyze the evidence that glutamine supplementation increases citrulline production. To determine the contribution of glutamine to the synthesis of citrulline. Recent findings Glutamine supplementation has been proposed in the treatment of critically ill patients; however, a recent large multicenter randomized controlled trial resulted in increased mortality in the glutamine supplemented group. Within this context, defining the contribution of glutamine to the production of citrulline, and thus to de novo arginine synthesis, has become a pressing issue. Summary The beneficial effects of glutamine supplementation may be partially mediated by the effects of glutamine on citrulline synthesis by the gut and the de novo synthesis of arginine by the kidney and other tissues. Although there is no strong evidence to support that glutamine is a major precursor for citrulline synthesis in humans, glutamine has the potential to increase overall gut function and in this way increase citrulline production.

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Arginine Depletion by Arginine Deiminase Does Not Affect Whole Protein Metabolism or Muscle Fractional Protein Synthesis Rate in Mice

Cited by 18 publications

References 36 publications

Protein fractional synthesis rates within tissues of high- and low-active mice

Protein fractional synthesis rates within tissues of high- and low-active mice

The Citrulline Recycling Pathway Sustains Cardiovascular Function in Arginine-Depleted Healthy Mice, but Cannot Sustain Nitric Oxide Production during Endotoxin Challenge

Interrelationships between glutamine and citrulline metabolism

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