Activation of Cardiac Mitochondrial Akt Signaling Improved Diabetic Cardiomyopathy and Induced Liver Metabolic Remodeling

Insulin stimulates Akt translocation to cardiac mitochondria, and we have recently shown that inhibition of cardiac mitochondrial Akt led to mitochondria dysfunction and cardiomyopathy. However, it is unknown whether activation of mitochondrial Akt in cardiac muscle can protect against the development of diabetic cardiomyopathy. To this end, we have generated an inducible, heart-specific, transgenic mice harboring a mitochondria-targeting constitutively active Akt (CAMAAKT). After 5 months of high fat-high fructose diet (HFF), the control mice developed myocardial fibrosis and cardiomegaly. In contrast, myocardial fibrosis and cardiomegaly were attenuated in the CAMAAKT mice on HFF. Compared to the control mice, the expression of myocardial BNPa, BNPb, and Myh7 (heart failure genes) were significantly suppressed in the CAMAAKT mice by 80%, 90%, and 80%, respectively (all p<0.01). Col1a1 and Col3a1 expression were reduced in the HFF-CAMAAKT mice, corroborating the reduction of myocardial fibrosis. These data indicated that activation of mitochondrial Akt protected against cardiomyopathy in diet-induced diabetes. In OGTT, fasting glucose level was unchanged but postprandial glucose levels were lower in the CAMAAKT mice. In another heart-specific transgenic mice harboring a mitochondria-targeting dominant negative Akt (CAMDAKT), the glucose curve in OGTT was significantly higher than the control mice. Therefore, mitochondrial Akt signaling in the heart could modulate whole body glucose homeostasis. Interestingly, the diet-induced fatty liver in the CAMAAKT mice was significantly less than the controls, suggesting that cardiac mitochondrial Akt signaling may remotely modulate fat metabolism in the liver. In summary, activating cardiac mitochondrial Akt protected against diabetic cardiomyopathy, improved glucose tolerance, and attenuated fatty liver in HFF-induced diabetes. Disclosure A. Ta: None. Y. Chen: None. Y. Chen: None. H. Lee: None. H. Lin: None. P.H. Wang: None.