Abstract
Diabetic mellitus (DM) cardiomyopathy is a DM-induced metabolic disorder where energy dependence on fatty acid (FA) metabolism causes FA influx overload. While we reported that miR-133a overexpression prevented deleterious lipid accumulation in the diabetic Akita heart, it is unclear whether miR-133a regulates diabetes-induced metabolic remodeling in the DM heart. Thus, we performed deep sequencing on the heart from DM Akita (Ak), cardiac-specific miR-133aTg (Tg), Ak/Tg mice, and sibling wild-type (WT) mice. Ingenuity pathway analysis showed that FAO was the highest activated pathway in the DM heart (p-value=4.59E-11). Therefore, we hypothesized that miR-133a overexpression in the DM heart improves cardiac metabolism by increasing FA clearance via enhancing FA oxidation (FAO). Notably, mitochondrial FA transport protein carnitine palmitoyltransferase I (CPT1) was upregulated (WT: 0.02±0.01, Ak: 0.06±0.02, Ak/Tg: 0.17±0.02, Tg: 0.06±0.01) while changes in the intracellular FA transport protein CD36 were not significant. Interestingly, the rate-limiting enzyme of ketogenesis, the FAO spillover pathway, 3-Hydroxy-3-Methylglutaryl-CoA Synthase 2 (HMGCS2) was downregulated (WT: 0.13±0.02, Ak: 0.74±0.13, Ak/Tg: 0.39±0.07, Tg: 0.05±0.01) in Ak/Tg mice. These results support that increased miR-133a in the diabetic heart contributes to improved FAO and FA metabolism in addition to downregulating FA deposition and ketogenesis in the diabetic heart.
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