Diet reversal rescues mouse diabetic cardiomyopathy by counteracting the decreased reticulum-mitochondria interactions and the ensuing mitochondrial Ca2+ uptake impairment

Abstract

Type 2 diabetic cardiomyopathy has been linked to Ca2+ signaling alterations, notably a decreased mitochondrial Ca2+ uptake. Recent discovery of Ca2+ microdomains between cardiac mitochondria and reticulum launched a new investigation avenue for cardiometabolic diseases. Hereby, we aimed to investigate if the mitochondrial Ca2+ mishandling is due to a dysregulation of the reticulum-mitochondria interactions or of the mitochondrial Ca2+ uniporter in the diabetic mouse heart. Mice fed for 16 weeks with a high fat high sucrose diet (HFHSD) displayed a cardiac insulin resistance combined to cardiac fibrosis, hypertrophy and contractile dysfunction (decreased strain rate) versus standard diet-fed mice (SD). Fractionation of HFHSD mice hearts revealed a decreased protein content of their mitochondria associated-reticulum membranes, together with a lower expression of tethering proteins quantified by mass spectrometry. On functional terms, reduced IP3R-VDAC proximity and co-immunoprecipitation were associated with a reduced IP3-stimulated Ca2+ transfer to mitochondria in isolated HFHSD cardiomyocytes, yet no changes in mitochondrial calcium uniporter protein expression and function were detected. Moreover, HFHSD cardiomyocytes displayed no significant changes in the reticular Ca2+ release level and the amplitude of cytosolic Ca2+ transients. Eight weeks of diet reversal restored the cardiac insulin signaling, MAM content, Ca2+ transfer and cardiac function in HFHSD mice. Therefore, our data indicate that disruption of the cardiac reticulum-mitochondria interactions is an early and reversible event impairing mitochondrial Ca2+ handling and contributing to the cardiac contractile dysfunction in the diabetic mouse heart, which could be counteracted by diet reversal.