Metformin Therapy for Ischemic Insult and Reperfusion Injury in Aging

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In aging, myocardial injury is increased during ischemia-reperfusion and accelerates the transition to post-infarction heart failure. In addition, most therapeutic strategies that effectively decrease cardiac injury in younger hearts fail in aged hearts. Thus, it is a critical unmet need to find an effective approach to decrease cardiac injury in the high risk aged heart during myocardial infarctions and their treatment. Metformin is a currently approved drug for the treatment of type II diabetes. We found that metformin is a reversible inhibitor of electron transport chain complex I. Metformin (2 mM) decreased complex I activity in ischemia-damaged heart mitochondria. Administration of metformin (2 mM) acutely during early reperfusion decreased infarct size in both in vitro and in vivo murine models. The protection of metformin was independent of AMPK activation, since cardiac injury was also decreased in the metformin- treated AMPK kinase dead mouse. Thus, we propose to repurpose metformin as a complex I inhibitor to decrease cardiac injury in aged hearts during the acute phase of reperfusion. AMPK is also a critical stress-activated kinase that exerts longer-term cardiac protection during prolonged recovery periods of reperfusion following myocardial infarction. Aging attenuates AMPK activation and subsequently enhances cardiac injury during ischemia and reperfusion. Sestrin2 is a scaffold protein critical to the activation of AMPK. Sestrin2 deficiency in the aging heart leads to decreased AMPK activation and impairs protective autophagy and mitochondrial biogenesis. We hypothesize that metformin treatment will activate AMPK in aged hearts through modulation of sestrin 2 during prolonged reperfusion. Thus, we propose that high dose metformin treatment provides acute protection in aged hearts during early reperfusion by transiently inhibiting complex I and decreasing mitochondrial-driven injury. Modulation of sestrin2-dependent AMPK activation in aged hearts by continued metformin treatment during longer term reperfusion should provide prolonged protection and consolidate the benefit during longer term recovery and decrease the transition to heart failure. Taken together, metformin presents an attractive opportunity to repurpose a currently approved drug for a new use to potentially attenuate both phases of the enhanced injury following a heart attack in the aged heart in order to improve outcomes in the high risk elderly patient.