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Research Paper|Volume 13, Issue 6|pp 7828—7845

Chronic metformin treatment decreases cardiac injury during ischemia-reperfusion by attenuating endoplasmic reticulum stress with improved mitochondrial function

Qun Chen1, Jeremy Thompson1, Ying Hu1, Edward J. Lesnefsky1,2,3,4
  • 1Departments of Medicine, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, USA
  • 2Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA
  • 3Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA 23298, USA
  • 4McGuire Department of Veterans Affairs Medical Center, Richmond, VA 23249, USA
Received: August 11, 2020Accepted: February 11, 2021Published: March 22, 2021
https://doi.org/10.18632/aging.202858

Copyright: © 2021 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Aging impairs mitochondrial function that leads to greater cardiac injury during ischemia and reperfusion. Cardiac endoplasm reticulum (ER) stress increases with age and contributes to mitochondrial dysfunction. Metformin is an anti-diabetic drug that protects cardiac mitochondria during acute ER stress. We hypothesized that metformin treatment would improve preexisting mitochondrial dysfunction in aged hearts by attenuating ER stress, followed by a decrease in cardiac injury during subsequent ischemia and reperfusion.

Male young (3 mo.) and aged mice (24 mo.) received metformin (300 mg/kg/day) dissolved in drinking water with sucrose (0.2 g/100 ml) as sweetener for two weeks versus sucrose vehicle alone. Cytosol, subsarcolemmal (SSM), and interfibrillar mitochondria (IFM) were isolated. In separate groups, cardioprotection was evaluated using ex vivo isolated heart perfusion with 25 min. global ischemia and 60 min. reperfusion. Infarct size was measured.

The contents of CHOP and cleaved ATF6 were decreased in metformin-treated 24 mo. mice compared to vehicle, supporting a decrease in ER stress. Metformin treatment improved OXPHOS in IFM in 24 mo. using a complex I substrate. Metformin treatment decreased infarct size following ischemia-reperfusion. Thus, metformin feeding decreased cardiac injury in aged mice during ischemia-reperfusion by improving pre-ischemic mitochondrial function via inhibition of ER stress.