AMPK-mTOR pathway modulates glycolysis reprogramming in unexplained recurrent spontaneous abortion

Area of Science:

• Immunology
• Reproductive Biology
• Metabolic Regulation

Background:

• Unexplained recurrent spontaneous abortion (URSA) remains a significant clinical challenge with unclear etiology.
• CD4+ T cell differentiation, particularly into regulatory T cells (Tregs), is implicated in preventing URSA.
• The mechanistic role of mTOR in regulating CD4+ T cell differentiation requires further elucidation.

Purpose of the Study:

• To investigate the regulatory role of mTOR in CD4+ T cell differentiation.
• To evaluate the therapeutic potential of metformin (Met) and 2-deoxy-D-glucose (2-DG) for URSA.

Main Methods:

• Transcriptome sequencing of clinical decidua tissue to identify gene expression differences.
• Assessment of AMPK, mTOR, and glycolytic activity in URSA mouse models using RT-qPCR and Western Blot.
• Flow cytometry (FCM) and ELISA to quantify CD4+ T cell differentiation into Th17 and Treg subsets.

Main Results:

• URSA group exhibited distinct gene expression patterns related to female reproduction and Th17 cell differentiation compared to controls.
• AMPK activation and glycolysis inhibition significantly reduced abortion rates in URSA mice (p=0.0013).
• These interventions suppressed CD4+ T cell differentiation into Th17 cells, increasing the Treg/Th17 ratio (p<0.001) and improving pregnancy outcomes.

Conclusions:

• The AMPK-mTOR pathway plays a crucial role in regulating glycolysis and enhancing pregnancy outcomes in URSA.
• Metformin and 2-deoxy-D-glucose facilitate CD4+ T cell differentiation into Treg cells, offering a potential strategy for URSA prevention.