Molecular mechanisms of the cardiac glycogen response to physiological metabolic stress

Abstract

Background: The heart relies mainly on the oxidation of fatty acids and glucose for energy production, stored in the heart as triglycerides and glycogen respectively. Cardiac glycogen accumulation occurs in the heart in pathological settings, such as in diabetes and glycogen storage diseases, and in physiological settings, such as with exercise. The Mellor-Delbridge labs have recently described a novel pathway of autophagy-mediated glycogen handling (‘glycophagy’) in the heart, which may play an important role in regulating glycogen in response to metabolic stress. Understanding the regulatory mechanisms underlying the glycogen response to exercise will help advance fundamental understanding of cardiac glycogen dynamics and may provide important contrast for insight into pathological mechanisms in disease states. Aim: To characterise the cardiac glycogen response to exercise and investigate a role for glycophagy in cardiac glycogen recovery post-exercise. Methods: Cardiac tissues were collected from mice following either 8 weeks voluntary running-wheel, 1 hr high intensity interval exercise (treadmill; 0, 2, 4, and 16 hrs post-exercise) or exhaustive exercise (treadmill; 0, 2, 4, and 16 hrs post-exercise). Glycogen and triglycerides were measured by amyloglucosidase and lipase assay respectively, and protein expression evaluated by western blot. Results: Cardiac glycogen was positively correlated with distance travelled on a voluntary running wheel over 8 weeks. Following acute high intensity interval treadmill exercise, delayed cardiac glycogen accumulation was evident at 16 hrs (1.8-fold). Following acute exhaustive treadmill exercise, cardiac glycogen elevation peaked at 2 hrs (3.7-fold) and recovered to 1.6-fold elevation at 16 hrs. In this model, initial glycogen synthase activation was evident, followed by inactivation at 2 and 4 hrs post-exercise. Glycogen degradation during recovery was not associated with upregulation of the cytosolic glycogen degradation enzyme, phosphorylase, and may be mediated by glycophagy breakdown. A 54% depletion of the glycogen-autophagy tagging protein, starch binding domain-containing protein 1 (STBD1), was observed at 4 hrs post-exercise, returning to baseline by 16 hrs. Upregulation of total expression of the glycophagosome protein, gamma-aminobutyric acid type A receptor-associated protein like 1 (GABARAPL1), was observed at 4 and 16 hrs post-exercise relative to 0 hrs, with membrane-bound GABARAPL1 (active) upregulated at 4 hrs post-exercise. Triglycerides were depleted at 0 hrs post-exercise before returning to baseline. Conclusion: This study demonstrates that glycogen supercompensation in the exercise to exhaustion model is driven by increased glycogen synthase activity, with glycophagy playing a role in returning glycogen towards basal levels. This contrasts to a pathological setting, where recent evidence suggests that inhibition of glycophagy induces glycogen accumulation. Surprisingly, the heart accumulates glycogen but not lipids in response to exercise. These findings provide the first evidence that glycophagy is involved in cardiac glycogen recovery post-exercise and further investigation is now warranted to fully elucidate the mechanisms involved.