Autophagy maintains cardiac function in the starved adult

To examine the functional significance and detailed morphological characteristics of starvation-induced autophagy in the adult heart, we starved green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3 (LC3) transgenic mice for up to 3 days. Electron microscopy revealed that, after as little as 12 hours of starvation, round and homogenously electron-dense lipid droplet-like vacuoles appeared in cardiomyocytes. These were determined to be lysosomes based on cathepsin D immunopositivity and acid phosphatase activity. The number of these lysosomes increased with starvation time, and typical autolysosomes with intracellular organelles destined for degradation appeared and increased in number at later times during the starvation period. Myocardial expression of the autophagy-related proteins LC3-II, cathepsin D and ubiquitin increased, while myocardial ATP content decreased, as the starvation interval proceeded. Treatment with bafilomycin A(1), an autophagy inhibitor, did not affect cardiac function in normally fed mice, but it significantly depressed cardiac function and caused significant left ventricular dilatation in the mice starved for 3 days. Cardiomyocytes from starved mice treated with bafilomycin A(1) showed marked accumulation of lysosomes, and the myocardial amino acid content, which increased during starvation in normally fed mice, as well as the myocardial ATP content, were severely reduced, which likely contributed to the cardiac dysfunction. The present findings suggest autophagy plays a critical role in the maintenance of cardiac function during starvation in the adult.