Loss of cardiomyocyte AKT signaling causes deterioration of lipid metabolism and cellular atrophy

Abstract The mammalian heart critically depends on oxidative metabolism of fatty acids, glucose, ketones, and amino acids to meet its extensive ATP demands. AKT/protein kinase B plays a central role in regulating cell growth and metabolism by coordinating an anabolic metabolism in response to insulin or IGF1, particularly by elevating glucose uptake and mTOR activity. Here, we investigated the effect of simultaneous deletion of the two major cardiac isoforms AKT1 and AKT2 on the function and metabolism of the adult mouse heart. Inducible cardiomyocyte specific AKT1 AKT2 double knockout mice developed a rapidly progressing and lethal heart failure with extensive cardiomyocyte atrophy. Metabolic analyses of substrate–specific respiration of mitochondria (respirometry) and of isolated cardiac tissue (Seahorse flux analysis) demonstrated that fatty acid metabolism was severely compromised, whereas glucose metabolism was less affected. Volume-specific in vivo NMR spectroscopy and CrCEST (Creatine chemical exchange saturation transfer) imaging revealed a drop of the cardiac phosphocreatine/ATP ratios from 2 to 1.5, indicating severe energetic depletion. Transcriptomic and proteomic studies showed that genes of the TCA cycle, β-oxidation, and oxidative phosphorylation were coordinately down-regulated. Moreover, AKT1/AKT2 deficient cardiomyocytes lost the ability to store fatty acids in lipid droplets (LDs) due to an early loss of perilipins and other proteins involved in LD generation and function. In conclusion, our data show that general, isoform-independent AKT signaling in cardiac myocytes is indispensable for preservation of cardiac fatty acid metabolism and energy supply.