Summary of Study ST002178

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001386. The data can be accessed directly via it's Project DOI: 10.21228/M8K11W This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

Study ID	ST002178
Study Title	Age-independent Cardiac Protection by Pharmacological Activation of Beclin-1 During Endotoxemia and Its Association with Energy Metabolic Reprograming in Myocardium — A Targeted Metabolomics Study
Study Summary	Background: We previously showed that Beclin-1-dependent autophagy is cardiac protective in a rodent model of endotoxemia using young adult mice. In this report, we compared the potential therapeutic effects of pharmacological Beclin-1 activating peptide, TB-peptide, on the cardiac outcomes of young adult and aged mice during endotoxemia. We further examined alterations in myocardial metabolism induced by lipopolysaccharide (LPS) challenge with and without the TB-peptide treatment. Methods and Results: C57BL/6J mice of 10-week and 24-month-old were challenged by LPS at doses at which cardiac dysfunction occurred. Following the treatment of TB-peptide or control vehicle, heart contractility, circulating cytokines, and myocardial autophagy were evaluated. A targeted metabolomics assay was applied to analyze cardiac metabolism. TB-peptide boosted autophagic response, attenuated cytokine production, and improved cardiac performance in both young and aged mice during endotoxemia. A targeted metabolomics assay was designed to detect a pool of 361 known metabolites, of which 156 were detected in at least one of the heart tissue samples. LPS-induced impairments were found in glucose and amino acid (AA) metabolisms in mice of all ages, and TB-peptide provided ameliorative effects to rescue these alterations. However, lipid metabolites were upregulated in the young group but moderately downregulated in the aged by LPS, suggesting an age-dependent response. TB-peptide mitigated LPS-mediated trend of lipids in the young mice but provided little effect on the aged ones. Conclusion: Pharmacological activation of Beclin-1 by TB-peptide protects the heart in both young and aged population during endotoxemia, suggest a therapeutic potential for sepsis-induced cardiomyopathy. Metabolomics analysis suggests that this age-independent protection by TB-peptide is associated with reprograming of energy production via glucose and AA metabolisms.
Institute	Loyola University Chicago Stritch School of Medicine
Department	Surgery
Last Name	Zang
First Name	Qun
Address	2160 S. 1st Ave, Maywood, IL 60153
Email	qzang@luc.edu
Phone	708-327-2472
Submit Date	2022-05-23
Raw Data Available	Yes
Raw Data File Type(s)	wiff
Analysis Type Detail	LC-MS
Release Date	2022-06-08
Release Version	1

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Treatment:

Treatment ID:	TR002276
Treatment Summary:	Endotoxemia was induced in young (10-week) and aged (24-week) male mice by lipopolysaccharide (LPS). Based on published results as well as observations in our laboratory, male and female mice showed significantly different susceptibility to systemic symptoms in sepsis models. Thus, male but not female mice were chosen for the experiments presented in this report. LPS was administered intraperitoneally (i.p.), and mice were weighed individually to determine the exact amount of LPS (MilliporeSigma, Burlington, MA; catalog number L3012) required to achieve the required doses. Sterile endotoxin-free PBS was used as a vehicle control in sham groups. Consistent with literature and as expected, we observed that older mice were more susceptible to the toxic effects induced by LPS. 24-month-old (aged) mice showed impaired cardiac function but were able to survive when receiving LPS challenged at 1mg/kg. However, greater fatality was observed when LPS dose was increased to 3 mg/kg. In 10-week-old (young adult) mice, 3 mg/kg LPS triggered heart dysfunction without impact on survival, whereases at 10 mg/kg, we observed significant LPS-induced fatality in the group. Due to the different sensitivities to LPS between the aged and young adult mice, we were not able to choose a universal dose of LPS to induce cardiac dysfunction and to perform follow up analysis in both groups. Therefore, we used the physiological function of the heart as a base for comparison in the studies performed in this report. Our previous research provided evidence that stimulating beclin-1 dependent autophagy improves cardiac performance during endotoxemia in young adult mice, and thus Beclin-1-activating peptide (TB peptide) holds a promising therapeutic potential for sepsis. In this report, we examined whether TB-peptide exerts a similar protective effect on aged animals under the same condition. In our experimental setting, sham or LPS challenge was administered to groups of 24-month-old and 10-week-old mice followed by treatment with TB-peptide, administered i.p. at a dose of 16 mg/kg in 100μl of PBS 30 minutes post LPS-challenge. Heart tissue was collected 18 hours post LPS challenge.

Treatment ID:

TR002276

Treatment Summary:

Endotoxemia was induced in young (10-week) and aged (24-week) male mice by lipopolysaccharide (LPS). Based on published results as well as observations in our laboratory, male and female mice showed significantly different susceptibility to systemic symptoms in sepsis models. Thus, male but not female mice were chosen for the experiments presented in this report. LPS was administered intraperitoneally (i.p.), and mice were weighed individually to determine the exact amount of LPS (MilliporeSigma, Burlington, MA; catalog number L3012) required to achieve the required doses. Sterile endotoxin-free PBS was used as a vehicle control in sham groups. Consistent with literature and as expected, we observed that older mice were more susceptible to the toxic effects induced by LPS. 24-month-old (aged) mice showed impaired cardiac function but were able to survive when receiving LPS challenged at 1mg/kg. However, greater fatality was observed when LPS dose was increased to 3 mg/kg. In 10-week-old (young adult) mice, 3 mg/kg LPS triggered heart dysfunction without impact on survival, whereases at 10 mg/kg, we observed significant LPS-induced fatality in the group. Due to the different sensitivities to LPS between the aged and young adult mice, we were not able to choose a universal dose of LPS to induce cardiac dysfunction and to perform follow up analysis in both groups. Therefore, we used the physiological function of the heart as a base for comparison in the studies performed in this report. Our previous research provided evidence that stimulating beclin-1 dependent autophagy improves cardiac performance during endotoxemia in young adult mice, and thus Beclin-1-activating peptide (TB peptide) holds a promising therapeutic potential for sepsis. In this report, we examined whether TB-peptide exerts a similar protective effect on aged animals under the same condition. In our experimental setting, sham or LPS challenge was administered to groups of 24-month-old and 10-week-old mice followed by treatment with TB-peptide, administered i.p. at a dose of 16 mg/kg in 100μl of PBS 30 minutes post LPS-challenge. Heart tissue was collected 18 hours post LPS challenge.