Abstract 12618: Human And Mouse Demonstration Of The Reticulum-Mitochondria Ca2+ Coupling As A New Therapeutic Target In Metabolic HFpEF

ContextMetabolic 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. Ca2+ transfer at mitochondria-associated reticular membranes (MAM) is crucial in the cardiomyocyte to tightly regulate mitochondrial Ca2+ content and assure the excitation-energetics coupling. We aimed to specify the role of the MAM Ca2+ coupling in both human and mouse hearts with metabolic HFpEF. ResultsMass 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 Ca2+ transport was downregulated only in the HFHSD MAM. MAM Ca2+ coupling assessment by adenoviral infection of a FRET-based mitochondrial Ca2+ sensor, revealed a MAM Ca2+ uncoupling in the HFHSD cardiomyocyte, leading to reduced mitochondrial Ca2+ 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 Ca2+ 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 surgerythis suggests a reduced formation of the IP3R-driven Ca2+ channeling complex. ConclusionThe ob/ob model does not recapitulate the main hallmarks of metabolic HFpEF and does not display any change in MAM Ca2+ coupling. On the contrary, a MAM Ca2+ uncoupling was detected both in the human T2D heart and in the heart of the HFHSD-induced metabolic HFpEF mouse, suggesting the reticulum-mitochondria Ca2+ coupling as a critical therapeutic target in metabolic HFpEF.