MicroRNA Regulation in the Type 2 Diabetic Human Heart
Diabetic cardiomyopathy is an impairment of heart muscle, characterized by metabolic disturbance and contractile dysfunction. The mitochondrion is central in the development of diabetic cardiomyopathy however, examination of mitochondria is complicated by the fact that two subpopulations are present in the cardiac myocyte, interfibrillar mitochondria (IFM) which situate between the contractile apparatus, and subsarcolemmal mitochondria (SSM), which exist beneath the plasma membrane. Research from our laboratory using a mouse model of type 2 diabetes mellitus (db/db) have revealed a robust dysfunctional profile particularly to cardiac SSM, as indicated by disruption of energetics and proteomic make-up. MicroRNAs (miRNA) are non-coding RNAs that have been shown to regulate protein expression of target mRNAs. Data from our laboratory indicates that miRNA profiles in the heart are dynamic following diabetic insult. Further, our results indicate that the mitochondrion possesses a pool of miRNAs that translocate into and out of the organelle in a dynamic fashion. Currently, it is unclear whether similar phenomena exist in type 2 diabetic human heart or whether miRNAs outside or within the mitochondrion are associated. The objectives of this application are: (1) to assess the impact of type 2 diabetes mellitus on cardiac transcriptome profiles in atrial appendage tissue from diagnosed type 2 diabetic patients and non-diabetic patients; and (2) to assess the impact of type 2 diabetes mellitus on cardiac mitochondrial subpopulation proteomes in atrial appendage tissue from diagnosed type 2 diabetic patients and non-diabetic patients. With respect to expected outcomes, the combination of work proposed in our discovery-based experiments will provide identification of transcriptomic and proteomic targets for therapeutic intervention in the type 2 diabetic human heart while validating the biological relevance of the db/db mouse model. The results will enable progression in this field by establishing the clinical applicability of mitochondrial subpopulation-based therapeutic examinations in the diabetic heart. The data from these experiments will be critical for our future NIH R01 grant application examining energetic abnormalities in the type 2 diabetic heart.

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