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

Publication date: Available online 3 April 2019Source: Life SciencesAuthor(s): Yishi Wang, Zheng Yang, Guoxu Zheng, Lu Yu, Yue Yin, Nan Mu, Heng MaAbstractAimsIn myocardial ischemia-reperfusion (MI/R) injury, impaired autophagy function worsens cardiomyocyte death. AMP-activated protein kinase (AMPK) is a heterotrimeric protein that plays an important role in cardioprotection and myocardial autophagic function. AMPKα1 and α2 are localized primarily in the cytoplasm and nucleus, respectively, in cardiomyocytes, but the isoform-specific autophagy regulation of AMPK during MI/R remains unclear.Materials and methodsAn MI/R model was built, and the protein expression of AMPKα1/α2, p-AMPK, mTOR, p-mTOR, TFEB, p-FoxO3a, SKP2, CARM1, TBP, Atg5, LAMP2, LC3B, and p62 during ischemia and reperfusion was determined by western blotting. Recombinant adeno-associated virus (serotype 9) vectors carrying tandem fluorescent-tagged LC3 or mRFP-GFP-LC3/GFP-LC3 were used to evaluate the autophagy status. AMPKα2 knockout mice were used for in vivo studies.Key findingsBoth cytoplasmic AMPKα1 and nuclear α2 subunit expression decreased during the reperfusion period, which led to AMPKα1-mTOR-TFEB and AMPKα2-Skp2-CARM1-TFEB signaling inhibition, respectively. The decreased TFEB level during reperfusion suppressed autophagy. Metformin could activate both the AMPKα1- and α2- mediated pathways, thus restoring autophagy flux during reperfusion. Nevertheless, in AMPKα2 knockout mice, nuclear α...
Source: Life Sciences - Category: Biology Source Type: research