Exogenous MG53 Protects Adult Mouse Cardiomyocytes by Preventing Mitochondrial Damage in Response to Oxidative Stress

Ischemic heart disease is a major cause of mortality and morbidity world-wide and its incidence is continually increasing as other health factors, such as diabetes type II and obesity, climb. Ischemic injury of any tissue causes a loss of healthy mitochondria, due to an increase in reactive oxygen species leading to oxidative stress. MG53, also known as TRIM72, is highly expressed in skeletal muscle and modestly in other tissues and is essential to repair damage to plasma membrane by acting as a myokine. We have previously shown that MG53’s membrane repair function is associated with changes in oxidative state inside the cell. Moreover, we have shown that mg53−/− mice are more susceptible to ischemia-reperfusion injury, whereas treatment with exogenous recombinant human MG53 (rhMG53) reduces both infarct damage and fibrosis and restores cardiac function. We hypothesize that in addition to cell membrane repair, exogenous MG53 enters cardiomyocytes and can act as a myokine to protect cardiomyocytes by maintaining mitochondrial function through control of oxidative-stress induced mitophagy. In this study, MG53 protection of cardiomyocyte mitochondria was assessed by subjecting HL-1 cells (an immortalized mouse atrial cardiomyocyte cell line) to oxidative stress followed by analysis for mitochondrial structure and function. Overall, we show that treatment with rhMG53 allowed cells to maintain a healthy mitochondrial membrane potential to protect mitochondrial function. We are currently dissecting the mechanism that facilitates the endocytic uptake of MG53 from the circulation into the cardiomyocytes as well as downstream signaling pathways that mediate the protection of the mitochondria function. The novelty of this study is that it shows exogenous MG53 can protect mitochondria in cardiomyocytes upon oxidative stress. This provides a mechanism behind how rhMG53 treatment may be a clinically relevant strategy to reduce cardiomyocyte injury and maintain cardiac function in patients after ischemic injuries.