UC Irvine

Diabetic cardiomyopathy, the changes to myocardial structure and function directly attributed to diabetes, is increasing in prevalence, correlating with this rise of the diabetes and obesity epidemics. Despite this, the exact mechanisms are unclear and no specific treatments for diabetic cardiomyopathy (DCM) yet exists, thus the need for further research. Mitochondrial dysfunction is characteristic of DCM and we have demonstrated that impaired translocation of AKT1 to mitochondria due to insulin resistance in animal models of diet-induced diabetes, accompanied by changes of mitochondrial structure and function. Here we showed that maintaining mito-Akt1 signaling in the context of diet-induced diabetes protected against the development of DCM. I investigated the underlying mechanisms, using a novel cardiomyocyte-specific transgenic mice harboring an inducible mitochondria-targeting constitutively active AKT (CAMCAKT) with a Cre-lox strategy. Under a high fat, high fructose diet, diabetic CAMCAKT mice exhibited improved heart function, whereby ejection fraction was 17 % higher than in diabetic controls (p < 0.05) and fractional shortening was 22% greater (p < 0.05). Left ventricular hypertrophy and perivascular fibrosis was also significantly reduced (p < 0.05). Gene expression analysis suggested that fatty acid. metabolism was upregulated by mito-Akt1 while simultaneously, extracellular flux assays measured improved respiratory efficiency coupled with increased myocardial ATP concentration (p < 0.05). Interestingly, improvements in heart function was associated with improvements in whole body metabolism, in vivo studies indicated increased energy expenditure (p < 0.05) and improved whole body leanness (p < 0.05). Liver steatosis was reduced (p < 0.05) in the CAMCAKT mice, furthermore, inter organ endocrine peptide analysis predicted remote modulation of liver metabolism by the heart. In summary, we showed a substantial role of cardiac mitochondrial AKT signaling during the development of DCM and demonstrated its metabolic and regulatory benefits in both the myocardium and also in whole body metabolism.