Biphasic effect of metformin on human cardiac energetics

Authors

Larisa Emelyanova, Advocate Aurora HealthFollow
Xiaowen Bai
Yasheng Yan
Zeljko J BosnjakFollow
David C. Kress, Advocate Aurora HealthFollow
Catherine Warner, Advocate Aurora HealthFollow
Stacie L. Kroboth, Advocate Aurora HealthFollow
Teodore Rudic, Advocate Aurora Health
Sirisha Kaushik, Advocate Aurora Health
Elizabeth Stoeckl, Advocate Aurora HealthFollow
Gracious Ross, Advocate Aurora HealthFollow
Farhan Rizvi, Advocate Aurora HealthFollow
A. Jamil Tajik, Advocate Aurora HealthFollow
Arshad Jahangir, Advocate Aurora HealthFollow

Recommended Citation

Emelyanova L, Bai X, Yan Y, et al. Biphasic effect of metformin on human cardiac energetics. Transl Res. 2021;229:5-23. doi:10.1016/j.trsl.2020.10.002

Affiliations

Center for Integrative Research on Cardiovascular Aging, Advocate Aurora Research Institute, Aurora Cardiovascular and Thoracic Services, St. Luke's Medical Center

Abstract

Metformin is the first-line medication for treatment of type 2 diabetes and has been shown to reduce heart damage and death. However, mechanisms by which metformin protects human heart remain debated. The aim of the study was to evaluate the cardioprotective effect of metformin on cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) and mitochondria isolated from human cardiac tissue. At concentrations ≤2.5 mM, metformin significantly increased oxygen consumption rate (OCR) in the hiPSC-CMs by activating adenosine monophosphate activated protein kinase (AMPK)-dependent signaling and enhancing mitochondrial biogenesis. This effect was abrogated by compound C, an inhibitor of AMPK. At concentrations >5 mM, metformin inhibited the cellular OCR and triggered metabolic reprogramming by enhancing glycolysis and glutaminolysis in the cardiomyocytes. In isolated cardiac mitochondria, metformin did not increase the OCR at any concentrations but inhibited the OCR starting at 1 mM through direct inhibition of electron-transport chain complex I. This was associated with reduction of superoxide production and attenuation of Ca2+-induced mitochondrial permeability transition pore (mPTP) opening in the mitochondria. Thus, in human heart, metformin might improve cardioprotection due to its biphasic effect on mitochondria: at low concentrations, it activates mitochondrial biogenesis via AMPK signaling and increases the OCR; at high concentrations, it inhibits the respiration by directly affecting the activity of complex I, reduces oxidative stress and delays mPTP formation. Moreover, metformin at high concentrations causes metabolic reprogramming by enhancing glycolysis and glutaminolysis. These effects can be a beneficial adjunct to patients with impaired endogenous cardioprotective responses.

Document Type

Article

PubMed ID

33045408