Inhibition of jejunal protein synthesis and breakdown in <i>Pseudomonas aeruginosa</i>-induced sepsis pig model

Have, Gabriella A.M. Ten; Engelen, M.P.; Wolfe, Robert R.; Deutz, N.E.P.

doi:10.1152/ajpgi.00407.2018

Cited by 9 publications

(16 citation statements)

References 40 publications

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“…We compared the protein FSR in the tissues with those described in the literature and observed that the jejunum had the highest protein FSR followed by the liver, ileum, heart, and skeletal muscle in accordance with the reported protein FSR in multi-organ analyses [ 4 , 7 ]. Our 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: Discussionsupporting

confidence: 75%

Section: Comparison Of Obtained Data To Literaturesupporting

confidence: 80%

“…Each tissue was quickly freeze clamped, snap-frozen in liquid nitrogen, and stored in -80˚C. Before analysis, the tissue homogenizing and processing was done as described [4]. In brief, the homogenized tissue powder (30-80 mg) was centrifuged to separate the supernatant, which was used for intracellular amino acid concentration measurements, and the protein https://doi.org/10.1371/journal.pone.0242926.g001…”

Section: Plos Onementioning

confidence: 99%

“…Protein FSR gives insight into metabolic regulation because the ability to create proteins faster represents the capability to adapt quicker by upregulation or downregulation of processes controlled by protein concentrations. For instance, the intestines have a high protein FSR [ 4 ] which allows for the intestinal system to quickly react to stimuli or environmental changes.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 75%

Section: Comparison Of Obtained Data To Literaturesupporting

confidence: 80%

Section: Plos Onementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…Alterations in protein synthesis can be considered among the earliest molecular events of disease progression [ 21 , 22 ]. Bacterial pathogenesis has recently been associated with alterations in protein synthesis in platelets and gut epithelial cells [ 23 , 24 ], although little is still known about how the cell renewal mechanism becomes impaired in the whole organism vascular bed layers. Novel systems biology methods coupled to the study of whole organism vascular beds hold promise for advancing the understanding of the effects of sepsis on protein synthesis in vascular and capillary beds.…”

Section: Introductionmentioning

confidence: 99%

System-wide molecular dynamics of endothelial dysfunction in Gram-negative sepsis

2020

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Background Inflammation affecting whole organism vascular networks plays a central role in the progression and establishment of several human diseases, including Gram-negative sepsis. Although the molecular mechanisms that control inflammation of specific vascular beds have been partially defined, knowledge lacks on the impact of these on the molecular dynamics of whole organism vascular beds. In this study, we have generated an in vivo model by coupling administration of lipopolysaccharide with stable isotope labeling in mammals to mimic vascular beds inflammation in Gram-negative sepsis and to evaluate its effects on the proteome molecular dynamics. Proteome molecular dynamics of individual vascular layers (glycocalyx (GC), endothelial cells (EC), and smooth muscle cells (SMC)) were then evaluated by coupling differential systemic decellularization in vivo with unbiased systems biology proteomics. Results Our data confirmed the presence of sepsis-induced disruption of the glycocalyx, and we show for the first time the downregulation of essential molecular maintenance processes in endothelial cells affecting this apical vascular coating. Similarly, a novel catabolic phenotype was identified in the newly synthesized EC proteomes that involved the impairment of protein synthesis, which affected multiple cellular mechanisms, including oxidative stress, the immune system, and exacerbated EC-specific protein turnover. In addition, several endogenous molecular protective mechanisms involving the synthesis of novel antithrombotic and anti-inflammatory proteins were also identified as active in EC. The molecular dynamics of smooth muscle cells in whole organism vascular beds revealed similar patterns of impairment as those identified in EC, although this was observed to a lesser extent. Furthermore, the dynamics of protein posttranslational modifications showed disease-specific phosphorylation sites in the EC proteomes. Conclusions Together, the novel findings reported here provide a broader picture of the molecular dynamics that take place in whole organism vascular beds in Gram-negative sepsis inflammation. Similarly, the obtained data can pave the way for future therapeutic strategies aimed at intervening in specific protein synthesis mechanisms of the vascular unit during acute inflammatory processes.

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