Cardiac amylase sustains glycolysis and protects the naked mole-rat heart in ischemia

Abstract The high ATP demands of the adult heart are normally met by aerobic fatty acid oxidation, making it vulnerable to oxygen limitation. Here, we identify a previously unrecognized glycogen mobilization pathway that relies on the digestive enzyme amylase and supports cardiac energy metabolism under ischemia. We find that amylase is part of a liver glycogen-handling program conserved across mammals, but that naked mole-rats deploy this mechanism in the heart. Naked mole-rats thrive in low-oxygen environments and endure extreme hypoxia without cardiac injury. We show that their hearts rely on carbohydrate-centered energy metabolism, marked by reduced 49lipid utilization and enhanced liver-like glycogen storage. During ischemia, cardiac amylase promotes glycogen breakdown into polysaccharides, sustaining glycolytic flux and preserving energetic balance. Inhibition of amylase increases ischemia–reperfusion injury, indicating that this non-canonical glycogen mobilization pathway contributes to cardiac protection. These findings reveal a distinct cardiac metabolic program that supports energy production and resistance to hypoxic stress.