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.