NUTRIENT REGULATION OF AUTOPHAGY IN THE HEART

Abstract

Impaired cardiac metabolism in the obese-diabetic heart leads to glucolipotoxicity and ensuing cardiomyopathy. Glucolipotoxicity causes cardiomyocyte injury by increasing energy insufficiency and by dysregulating proteolysis. Lysosomal signaling and function is governed by transcription factor EB (TFEB). However, limited studies have examined the impact of glucolipotoxicity on intra-lysosomal signaling proteins governing autophagy. Employing mouse models of diet-induced obesity, type-1 diabetes and ex-vivo model of glucolipotoxicity, we examined whether glucolipotoxicity negatively targets lysosomal proteins and TFEB to dysregulate autophagy and cause cardiac injury. Across in-vivo and ex-vivo glucolipotoxicity models, lysosomal autophagy was suppressed, which paralleled decreased cathepsin-B activity. Lysosome-associated membrane protein-2A (LAMP-2A), which is involved in chaperone-mediated autophagy (CMA), was reduced in obese-diabetic hearts and in glucolipotoxic ex-vivo models. Notably, diminished autophagy, induced by glucolipotoxicity, was highly associated with decreased CMA proteins content and cellular TFEB. Collectively, glucolipotoxicity renders cardiomyocytes susceptible to injury by depleting TFEB and impairing lysosomal proteolysis.