Liver-like glycogen metabolism supports glycolysis in naked mole-rat heart during ischaemia

Abstract

As a subterranean eusocial mammal, the naked mole-rat faces a particularly challenging environment characterised by patchily available food, low O2 and high CO2 levels. In response, naked mole-rats have evolved a suite of molecular and physiological adaptations to survive extreme hypoxia. Yet, how naked mole-rats rewire their metabolism to protect the heart has not been comprehensively addressed. Here, we performed comparative analyses of naked mole-rat and mouse organs exposed to ischaemic conditions. We show that naked mole-rats have retained features of foetal cardiac metabolism replacing fatty acid utilisation for a unique type of carbohydrate metabolism largely dependent on glycogen. We found that naked mole-rats have co-opted specialised liver-like glycogen handling mechanisms in the heart. Amongst these is the expression of liver-specific enzyme isoforms and amylase, a digestive enzyme known for starch breakdown in saliva and intestine but whose biological role in glycogen processing has not been fully recognised. We show that amylase is rapidly activated in ischaemia and hydrolyses internal glycosidic bonds for more efficient downstream processing. This biochemical adaptation occurred in both mouse and naked mole-rat livers but exclusively in the naked mole-rat heart, which retained higher ATP levels by maintaining an increased glycolytic flux in an amylase-dependent mechanism. Overall, we discovered a previously unknown type of glycogen metabolism in the naked mole-rat that holds relevance to pathologies where glycogen plays a role. Furthermore, we describe a novel type of metabolic plasticity in the heart which may be harnessed for cardiac disease.