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An O-GlcNAcylomic Approach Reveals ACLY as a Potential Target in Sepsis in the Young Rat
Manon Denis1,2, Thomas Dupas1, Antoine Persello1,3
1Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, F-44000 Nantes, France.
Insights
Sepsis in young rats is understudied. Stimulating O-GlcNAcylation, a key metabolic regulator, improved outcomes in young septic rats, showing therapeutic potential.
Area of Science:
- Biochemistry
- Physiology
- Immunology
Background:
- Sepsis in young populations is understudied and poses significant risks.
- O-GlcNAcylation, a crucial post-translational modification, regulates cell survival and stress responses.
- While beneficial in adult sepsis, O-GlcNAcylation's role in young sepsis is less understood due to higher physiological levels.
Purpose of the Study:
- To investigate the therapeutic potential of O-GlcNAc stimulation in young rats experiencing sepsis.
- To determine if enhancing O-GlcNAcylation can improve sepsis outcomes in a pediatric rodent model.
Main Methods:
- Induction of endotoxemic shock in 28-day-old rats using lipopolysaccharide (LPS).
- Administration of fluidotherapy and/or NButGT (O-GlcNAc stimulator) post-LPS challenge.
- Assessment of physiological parameters, plasmatic markers, and cardiac O-GlcNAcylated proteins via mass spectrometry.
Main Results:
- LPS injection successfully induced septic shock, characterized by decreased mean arterial pressure and altered biological markers.
- NButGT administration, unlike fluidotherapy alone, significantly improved mean arterial pressure in young septic rats.
- Mass spectrometry identified ATP citrate lyase among cardiac O-GlcNAcylated proteins, highlighting metabolic involvement.
Conclusions:
- O-GlcNAc stimulation demonstrates therapeutic efficacy in improving outcomes for young septic rats.
- Enhanced O-GlcNAcylation positively impacts physiological parameters during sepsis in young animals.
- The identified O-GlcNAcylated proteins are primarily linked to cellular metabolic pathways.
Abstract:
Sepsis in the young population, which is particularly at risk, is rarely studied. O-GlcNAcylation is a post-translational modification involved in cell survival, stress response and metabolic regulation. O-GlcNAc stimulation is beneficial in adult septic rats. This modification is physiologically higher in the young rat, potentially limiting the therapeutic potential of O-GlcNAc stimulation in young septic rats. The aim is to evaluate whether O-GlcNAc stimulation can improve sepsis outcome in young rats. Endotoxemic challenge was induced in 28-day-old rats by lipopolysaccharide injection (E. Coli O111:B4, 20 mg·kg-1) and compared to control rats (NaCl 0.9%). One hour after lipopolysaccharide injection, rats were randomly assigned to no therapy, fluidotherapy (NaCl 0.9%, 10 mL·kg-1) ± NButGT (10 mg·kg-1) to increase O-GlcNAcylation levels. Physiological parameters and plasmatic markers were evaluated 2h later. Finally, untargeted mass spectrometry was performed to map cardiac O-GlcNAcylated proteins. Lipopolysaccharide injection induced shock with a decrease in mean arterial pressure and alteration of biological parameters (p < 0.05). NButGT, contrary to fluidotherapy, was associated with an improvement of arterial pressure (p < 0.05). ATP citrate lyase was identified among the O-GlcNAcylated proteins. In conclusion, O-GlcNAc stimulation improves outcomes in young septic rats. Interestingly, identified O-GlcNAcylated proteins are mainly involved in cellular metabolism.
