METTL3 in Cardiac Benefits of Exercise in Diabetes

Summary / Abstract Diabetic cardiomyopathy is a major complication and the leading cause of death and disability in patients with diabetes. Effective treatment to improve outcomes is lacking, and prognosis remains poor for patients with diabetic cardiomyopathy. Thus, there is a growing unmet clinical need for novel therapeutic approaches in diabetic cardiomyopathy. Exercise is an effective strategy for the prevention and treatment of diabetic cardiomyopathy, however, the underlying molecular mechanisms remain poorly understood. N6-methyladenosine (m6A) methylation is the most common form of RNA modification in eukaryotes. METTL3, a m6A methyltransferase, has been implicated in cardiac development and cardiac injury, however, little is known about the role of METTL3 in diabetic cardiomyopathy and cardiac benefit of exercise in diabetes. Our preliminary studies found that (1) Cardiac METTL3 is downregulated in diabetes and is upregulated by exercise. (2) Cardiomyocyte-specific knockout of METT3 cancels beneficial effects of exercise on hearts from diabetes. (3) In vitro in primary cardiomyocytes, overexpression of METTL3 protects cardiomyocytes from high glucose and palmitate-induced oxidative stress and cell death. (4) METTL3 regulates YBX-1 in diabetic hearts. We hypothesize that METTL3 is sufficient/necessary in cardiac benefits of exercise in diabetes and its does so through YBX-1. We will test this hypothesis in three specific aims: (1) to determine the role of METTL3 in cardiac response to exercise in diabetes, (2) to examine the effects of METTL3 in diabetic cardiomyopathy, and (3) to examine the mechanisms by which METTL3 regulates diabetic cardiomyopathy. We anticipate that these studies will shed new lights into the role of m6A (e.g., METTL3) in the pathophysiology of diabetic cardiomyopathy. Moreover, these studies will establish clinically relevant approaches targeting METTL3 to combat cardiomyopathy in patients with diabetes. 1