Metformin protects diabetes-induced atrial mitochondrial from oxidative stress and improves mitochondrial biogenesis via the AMPK signaling pathway

Abstract Background Oxidative stress leads to adverse atrial remodeling in diabetes mellitus. AMP-activated protein kinase (AMPK) agonists have been shown to prevent cardiomyocytes from oxidative stress by improving mitochondrial function, but their underlying mechanisms are not completely understood. This study investigated the molecular changes and their underlying regulatory mechanisms by the AMPK agonists, metformin and AICA ribonucleotide (AICAR). Methods Mouse atrial cardiomyocytes (HL-1 cells) and rats with type 2 diabetes mellitus (DM) were used as study models. A total of 40 rats were randomly divided into control, DM alone, DM treated with metformin, AICAR, or metformin with the AMPK inhibitor Compound C. Echocardiographic, hemodynamic, and electrophysiological measurements were made in vivo . Reactive oxygen species (ROS) production rate and mitochondrial membrane potential (MMP) levels were performed in vitro . Protein expression of SOD, COX43 and mitochondrial biogenesis related proteins were measured using Western blotting. Results Compared with controls, the diabetes group demonstrated larger left atrial diameter and fibrosis area associated with a higher incidence of inducible atrial fibrillation (AF). Lower Mn-SOD, COX42, and mitochondrial biogenesis (PGC-1α, NRF1 and TFAM)-related proteins were observed, accompanied by mitochondrial swelling. Metformin treatment led to reversal of structural remodeling and lower inducible AF incidence, which were associated with higher Mn-SOD, COX42, and biogenesis-related proteins as well as improvement in the structure and function of mitochondria. Similar protective changes were observed following AICAR or metformin with Compound C treatment. In HL-1 cell line, compared with controls, the DM group demonstrated higher mitochondrial ROS production rat and lower MMP levels. Mn-SOD, COX42, and mitochondrial biogenesis (PGC-1α, NRF1 and TFAM)-related proteins expression were consistent with animal levels. Conclusions Diabetes mellitus induces adverse atrial structural, electrophysiological remodeling, and mitochondrial damage and dysfunction. Metformin prevented these abnormalities through activation of the AMPK signaling pathway.