Inherent Metabolic Adaptations in Adult Spiny Mouse (Acomys) Cardiomyocytes Facilitate Enhanced Cardiac Recovery Following Myocardial Infarction

Abstract

AbstractThe adult mammalian heart has limited regenerative capacity following injury, leading to progressive heart failure and mortality. Recent studies have identified the spiny mouse (Acomys) as a unique model for mammalian cardiac isch3emic resilience, exhibiting enhanced recovery after myocardial infarction (MI) compared to commonly used laboratory mouse strains. However, the underlying cellular and molecular mechanisms behind this unique response remain poorly understood. In this study, we comprehensively characterized the metabolic characteristics of cardiomyocytes inAcomyscompared to the non-regenerativeMus musculus.We utilized single-nucleus RNA sequencing (snRNA-seq) in sham-operated animals and 1, 3, and 7 days post-myocardial infarction to investigate cardiomyocytes’ transcriptomic and metabolomic profiles in response to myocardial infarction. Complementary targeted metabolomics, stable isotope-resolved metabolomics, and functional mitochondrial assays were performed on heart tissues from both species to validate the transcriptomic findings and elucidate the metabolic adaptations in cardiomyocytes following ischemic injury.Transcriptomic analysis revealed thatAcomyscardiomyocytes inherently upregulate genes associated with glycolysis, the pentose phosphate pathway, and glutathione metabolism while downregulating genes involved in oxidative phosphorylation (OXPHOS). These metabolic characteristics are linked to decreased reactive oxygen species (ROS) production and increased antioxidant capacity. Our targeted metabolomic studies in heart tissue corroborated these findings, showing a shift from fatty acid oxidation to glycolysis and ancillary biosynthetic pathways inAcomysat baseline with adaptive changes post-MI. Functional mitochondrial studies indicated a higher reliance on glycolysis inAcomyscompared toMus, underscoring the unique metabolic phenotype ofAcomyshearts. Stable isotope tracing experiments confirmed a shift in glucose utilization from oxidative phosphorylation inAcomys.In conclusion, our study identifies unique metabolic characteristics ofAcomyscardiomyocytes that contribute to their enhanced ischemic resilience following myocardial infarction. These findings provide novel insights into the role of metabolism in regulating cardiac repair in adult mammals. Our work highlights the importance of inherent and adaptive metabolic flexibility in determining cardiomyocyte ischemic responses and establishesAcomysas a valuable model for studying cardiac ischemic resilience in adult mammals.Graphical abstract