Activation Of Myocardial Mitochondria Aktl Improved Diabetic Cardiomyopathy And Body Composition-The Heart As A Metabolic Organ

Insulin acutely stimulates Akt1 translocation into cardiac mitochondria, which is blunted in T2DM due to insulin resistance. To study the role of mitochondrial Akt (mito-Akt) in diabetic cardiomyopathy and its implication on whole body metabolism, we generated two transgenic mice lines with heart-specific Cre-lox, using inducible mitochondria-targeting dominant negative Akt (CAMDAKT) or constitutively active Akt (CAMCAKT). CAMDAKT mice developed cardiomyopathy and heart failure after Tamoxifen (T) induction when compared to corn oil (CO) injected CAMDAKT mice. To study whether activation of myocardial mito-Akt can reverse diabetic cardiomyopathy, two models of diabetic cardiomyopathy resembling different phases of T2DM were used in this study. First, after 5-months high fat/fructose diet (HFF), mice developed LV dysfunction, obesity, glucose intolerance, and hyperinsulinemia. In this model, T-CAMCAKT mice restored LV function and averted cardiomyopathy. A second metabolic model was induced with a 12-weeks HFF diet and low-dose streptozotocin injections, which led to overweight, hyperglycemia, and reduced insulin secretion. CO mice showed higher heart failure markers (ANF, BNP, MYH7) and increased expression of cardiac PDK4, CPT1, CPT2 and CD36. In the T-CAMCAKT mice, cardiomyopathy was reversed. Thus, activation of mito-Akt reversed diabetic cardiomyopathy. While T-CAMCAKT showed similar improvement of cardiomyopathy in these two metabolic models, body composition was different. In the first HFF model, mito-Akt activation did not alter body composition or glucose homeostasis, but fatty liver was improved. In the second metabolic model with reduced insulin secretion, T-CAMCAKT mice had better OGTT, lower fat mass (16.6% vs. 26.5%, p<0.001) and higher lean mass (77.1% vs. 68.1%, p<0.001). Summary: myocardial mito-Akt locally modulated cardiac metabolism and LV function, and remotely modulated whole body metabolism. Disclosure Y. Chen: None. A. Ta: None. H. Lee: None. H.Y. Lin: None. Y. Chen: None. P.H. Wang: None.