Metformin promotes autophagy in ischemia/reperfusion myocardium via cytoplasmic AMPKα1 and nuclear AMPKα2 pathways

Area of Science:

• Cardiology
• Molecular Biology
• Cellular Biology

Background:

• Myocardial ischemia-reperfusion (MI/R) injury impairs cardiomyocyte autophagy, exacerbating cell death.
• AMP-activated protein kinase (AMPK) plays a key role in cardioprotection and myocardial autophagy.
• The specific roles of AMPKα1 and AMPKα2 isoforms in regulating autophagy during MI/R are not fully understood.

Purpose of the Study:

• To investigate the isoform-specific roles of AMPKα1 and AMPKα2 in regulating autophagy during MI/R.
• To elucidate the signaling pathways involved in AMPK-mediated autophagy during MI/R.
• To determine the effects of metformin on AMPK-mediated autophagy in the context of MI/R.

Main Methods:

• Established a myocardial ischemia-reperfusion (MI/R) injury model.
• Utilized western blotting to assess protein expression of key autophagy and signaling molecules (AMPK, mTOR, TFEB, etc.).
• Employed adeno-associated virus vectors for autophagy monitoring and conducted in vivo studies using AMPKα2 knockout mice.

Main Results:

• Both AMPKα1 and AMPKα2 expression decreased during reperfusion, inhibiting AMPKα1-mTOR-TFEB and AMPKα2-Skp2-CARM1-TFEB signaling, leading to suppressed autophagy.
• Metformin treatment restored autophagy flux by activating both AMPKα1 and AMPKα2 pathways.
• AMPKα2 knockout mice showed impaired metformin-enhanced autophagy, highlighting the importance of the α2 isoform's signaling pathway.

Conclusions:

• Metformin exerts dual effects, promoting both cytoplasmic AMPKα1 and nuclear AMPKα2 signaling.
• This dual activation improves autophagic flux and restores cardiac function during MI/R.
• The study clarifies the distinct yet complementary roles of AMPK isoforms in cardiac protection during MI/R.