Myocardial glycogen metabolism and its regulation

Introduction: Although glycogen metabolism has received much research attention, many unanswered questions regarding the contribution of glycogen to myocardial energy production and the regulation of cardiac glycogen metabolism remain. Glycogen use plays an important role in heart function, especially during periods of stress such as increased work and ischemia. Understanding the contribution of glycogen to myocardial energy metabolism and its regulation are essential in order to alter its metabolism to improve heart function. Purpose: The studies in this thesis are designed to test the hypotheses that glycogen contributes significantly to myocardial energy production under non-stressful conditions, that alterations in myocardial glycogen turnover (i.e. simultaneous synthesis and degradation) occur in association with changes in the activity of 5'AMP-activated protein kinase (AMPK), and that activation of AMPK by 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) stimulates long-chain but not medium chain fatty acid oxidation by inhibiting acetyl CoA carboxylase, and stimulates cardiac glycogenolysis by stimulating glycogen phosphorylase (GP) and inhibiting glycogen synthase (GS). Methods: All studies were performed using the isolated working rat heart preparation. A new protocol was developed which allowed the direct measurement of glycolysis and glucose oxidation, both of glucose and glycogen. Results: Myocardial glycogen contributes significantly to myocardial energy production, is oxidized preferentially relative to exogenous glucose, undergoes substantial turnover (i.e. simultaneous synthesis and degradation) and is degraded in a random, rather than ordered, fashion. Further, the depletion of glycogen stores inhibits both glycogen degradation and glycogen turnover, while alterations in workload affect primarily glycogen degradation and not synthesis. Long-chain (palmitate), but not medium-chain (octanoate) fatty acid oxidation is significantly increased in the presence of AICAR. AMPK activation by AICAR did not alter glycogen content, GP or GS activity under the conditions examined. Conclusions: Glycogen contributes significantly to energy production under non-stressful conditions. Glucose from glycogen is preferentially oxidized compared to exogenous glucose Glycogen turnover occurs during periods of net glycogen degradation, but not during periods of net glycogen synthesis. AICAR activation of AMPK stimulates myocardial long-chain, but not medium-chain, fatty acid oxidation and does not alter glycogen content, or the activities of GP and GS under the conditions examined.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat