Myocardial glycophagy flux dysregulation and glycogen accumulation characterize diabetic cardiomyopathy

Diabetic heart disease morbidity and mortality is escalating. No specific therapeutics exist and mechanistic understanding of diabetic cardiomyopathy etiology is lacking. While lipid accumulation is a recognized cardiomyocyte phenotype of diabetes, less is known about glycolytic fuel handling and storage. Based on in vitro studies, we postulated the operation of an autophagy pathway in the myocardium specific for glycogen homeostasis – glycophagy. Here we visualize occurrence of cardiac glycophagy and show that the diabetic myocardium is characterized by marked glycogen elevation and altered cardiomyocyte glycogen localization. We establish that cardiac glycophagy flux is disturbed in diabetes. Glycophagy may represent a potential therapeutic target for alleviating the myocardial impacts of metabolic disruption in diabetic heart disease. [Display omitted] •myocardial glycogen accumulation is a consistent feature of type 1 and type 2 diabetes•marked glycogen infiltration is visualized in diabetic myocardium, clustered near mitochondria and dispersed throughout the myofilament architecture•glycogen is captured as phago-lysosome cargo, and in process of capture or release can be visualized•disturbances in glycogen-autophagy (‘glycophagy’)-mediated glycogen degradation are linked with myocardial glycogen accumulation in the diabetic heart•cardiac glycophagy may be a potential therapeutic target for development of treatments for diabetic heart disease