Clinical and experimental investigations demonstrated that metformin, a widely used anti-diabetic drug, exhibits cardioprotective properties against myocardial infarction. Interestingly, metformin was previously shown to increase the expression of PGC-1α a key controller of energy metabolism in skeletal muscle, which is down-regulated in diabetic conditions. We hypothesized that chronic treatment with metformin could protect the aged, diabetic heart against ischemia-reperfusion injury (IRI) by up-regulating PGC-1α and improving the impaired functionality of diabetic mitochondria.
Following 4 weeks of metformin (300 mg/kg) administered in the drinking water, 12 month-old diabetic Goto Kakizaki and non-diabetic Wistar rat hearts were assigned for infarct measurement following 35 min ischemia and 60 min reperfusion or for electron microscopy (EM) and Western blotting (WB) investigations.
Metformin elicited a cardioprotective effect in both non-diabetic and diabetic hearts. In contrast with the diabetic non-treated hearts, the diabetic hearts treated with metformin showed more organized and elongated mitochondria and demonstrated a significant increase in phosphorylated AMPK and in PGC-1α expression.
In summary these results show for the first time that chronic metformin treatment augments myocardial resistance to ischemia-reperfusion injury, by an alternative mechanism in addition to the lowering of blood glucose. This consisted of a positive effect on mitochondrial structure possibly via a pathway involving AMPK activation and PGC-1α. Thus, metformin prescribed chronically to patients may lead to a basal state of cardioprotection thereby potentially limiting the occurrence of myocardial damage by cardiovascular events.
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The authors thank the British Heart Foundation (Program Grant RG/08/015/26411 and FS/09/058/27987) for on-going funding and support. This work was undertaken at University College London Hospital/University College London (UCLH/UCL) which received a proportion of funding from the Department of Health’s National Institute of Health Research (NIHR) Biomedical Research Centres funding scheme.
H.J.W researched data, performed experiments, wrote, reviewed and edited manuscript. A.R.H assisted in experimental work and contributed to discussion. C.P.M. researched data and assisted in experimental work. D.J.H. contributed to discussion. D.M.Y contributed to discussion and reviewed & edited the manuscript. M.M.M researched data, contributed to discussion, reviewed, and edited the manuscript.
The authors thank Louise Casson and other staff at the central unit of Biological Services Unit, UCL, London for the help in maintaining the animal colonies, administrating the drug and blood testing. We also thank Mark Turmaine for assisting with the Electron Microscopy analysis.
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Whittington, H.J., Hall, A.R., McLaughlin, C.P. et al. Chronic Metformin Associated Cardioprotection Against Infarction: Not Just a Glucose Lowering Phenomenon. Cardiovasc Drugs Ther 27, 5–16 (2013). https://doi.org/10.1007/s10557-012-6425-x
- Ischemia–reperfusion injury