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.

Glycogen-autophagy: Molecular machinery and cellular mechanisms of glycophagy.

Autophagy is an essential cellular process involving degradation of superfluous or defective macromolecules and organelles as a form of homeostatic recycling. Initially proposed to be a "bulk" degradation pathway, a more nuanced appreciation of selective autophagy pathways has developed in the literature in recent years. As a glycogen-selective autophagy process, "glycophagy" is emerging as a key metabolic route of transport and delivery of glycolytic fuel substrate. Study of glycophagy is at an early stage. Enhanced understanding of this major noncanonical pathway of glycogen flux will provide important opportunities for new insights into cellular energy metabolism. In addition, glycogen metabolic mishandling is centrally involved in the pathophysiology of several metabolic diseases in a wide range of tissues, including the liver, skeletal muscle, cardiac muscle, and brain. Thus, advances in this exciting new field are of broad multidisciplinary interest relevant to many cell types and metabolic states. Here, we review the current evidence of glycophagy involvement in homeostatic cellular metabolic processes and of molecular mediators participating in glycophagy flux. We integrate information from a variety of settings including cell lines, primary cell culture systems, ex vivo tissue preparations, genetic disease models, and clinical glycogen disease states.

Elevated myocardial fructose and sorbitol levels are associated with diastolic dysfunction in diabetic patients, and cardiomyocyte lipid inclusions in vitro.

Diabetes is associated with cardiac metabolic disturbances and increased heart failure risk. Plasma fructose levels are elevated in diabetic patients. A direct role for fructose involvement in diabetic heart pathology has not been investigated. The goals of this study were to clinically evaluate links between myocardial fructose and sorbitol (a polyol pathway fructose precursor) levels with evidence of cardiac dysfunction, and to experimentally assess the cardiomyocyte mechanisms involved in mediating the metabolic effects of elevated fructose. Fructose and sorbitol levels were increased in right atrial appendage tissues of type 2 diabetic patients (2.8- and 1.5-fold increase respectively). Elevated cardiac fructose levels were confirmed in type 2 diabetic rats. Diastolic dysfunction (increased E/e', echocardiography) was significantly correlated with cardiac sorbitol levels. Elevated myocardial mRNA expression of the fructose-specific transporter, Glut5 (43% increase), and the key fructose-metabolizing enzyme, Fructokinase-A (50% increase) was observed in type 2 diabetic rats (Zucker diabetic fatty rat). In neonatal rat ventricular myocytes, fructose increased glycolytic capacity and cytosolic lipid inclusions (28% increase in lipid droplets/cell). This study provides the first evidence that elevated myocardial fructose and sorbitol are associated with diastolic dysfunction in diabetic patients. Experimental evidence suggests that fructose promotes the formation of cardiomyocyte cytosolic lipid inclusions, and may contribute to lipotoxicity in the diabetic heart.

Myocardial Energy Stress, Autophagy Induction, and Cardiomyocyte Functional Responses.

Significance: Energy stress in the myocardium occurs in a variety of acute and chronic pathophysiological contexts, including ischemia, nutrient deprivation, and diabetic disease settings of substrate disturbance. Although the heart is highly adaptive and flexible in relation to fuel utilization and routes of adenosine-5'-triphosphate (ATP) generation, maladaptations in energy stress situations confer functional deficit. An understanding of the mechanisms that link energy stress to impaired myocardial performance is crucial. Recent Advances: Emerging evidence suggests that, in parallel with regulated enzymatic pathways that control intracellular substrate supply, other processes of "bulk" autophagic macromolecular breakdown may be important in energy stress conditions. Recent findings indicate that cargo-specific autophagic activity may be important in different stress states. In particular, induction of glycophagy, a glycogen-specific autophagy, has been described in acute and chronic energy stress situations. The impact of elevated cardiomyocyte glucose flux relating to glycophagy dysregulation on contractile function is unknown. Critical Issues: Ischemia- and diabetes-related cardiac adverse events comprise the majority of cardiovascular disease morbidity and mortality. Current therapies involve management of systemic comorbidities. Cardiac-specific adjunct treatments targeted to manage myocardial energy stress responses are lacking. Future Directions: New knowledge is required to understand the mechanisms involved in selective recruitment of autophagic responses in the cardiomyocyte energy stress response. In particular, exploration of the links between cell substrate flux, calcium ion (Ca2+) flux, and phagosomal cargo flux is required. Strategies to target specific fuel "bulk" management defects in cardiac energy stress states may be of therapeutic value.