부산대학교 도서관

Context: Metabolic heart failure with preserved ejection fraction (HFpEF) is a frequent and disabling disease with yet no therapy and limited knowledge on the cardiac underlying molecular mechanisms. Ca transfer at mitochondria-associated reticular membranes (MAM) is crucial in the cardiomyocyte to tightly regulate mitochondrial Ca content and assure the excitation-energetics coupling. We aimed to specify the role of the MAM Ca coupling in both human and mouse hearts with metabolic HFpEF.Results: Mass spectrometry analysis of cardiac MAM showed an upregulation of cellular response to stress and lipid metabolism processes in two obesogenic T2D mouse models (16 weeks of high-fat high-sucrose diet, HFHSD vs standard diet, SD; 12-week old leptin-deficient ob/ob vs WT), while Ca transport was downregulated only in the HFHSD MAM. MAM Ca coupling assessment by adenoviral infection of a FRET-based mitochondrial Ca sensor, revealed a MAM Ca uncoupling in the HFHSD cardiomyocyte, leading to reduced mitochondrial Ca content and bioenergetics, while no change was measured in the ob/ob cell. HFHSD mice exhibited cardiac hypertrophy, diastolic dysfunction and mild strain rate reduction with preserved EF. Ob/ob mice only displayed strain rate reduction and concentric hypertrophy. Principal component analysis (PCA) demonstrated a divergence between the HFHSD group and the three others, as displayed by their scattering along the first PC (61% of variance) contributed mainly by strain rate, wall thickness, body weight and Ca peak amplitude. Proximity ligation assay revealed a decreased proximity between the reticular IP3-receptor and the mitochondrial porin VDAC in human left ventricle biopsies from T2D versus non-diabetic patients, obtained during valve replacement surgery: this suggests a reduced formation of the IP3R-driven Ca channeling complex.Conclusion: The ob/ob model does not recapitulate the main hallmarks of metabolic HFpEF and does not display any change in MAM Ca coupling. On the contrary, a MAM Ca uncoupling was detected both in the human T2D heart and in the heart of the HFHSD-induced metabolic HFpEF mouse, suggesting the reticulum-mitochondria Ca coupling as a critical therapeutic target in metabolic HFpEF.