Journal
BASIC RESEARCH IN CARDIOLOGY
Volume 115, Issue 6, Pages -Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00395-020-00835-7
Keywords
Diabetic cardiomyopathy; Ca2+ flux; Metabolic syndrome disease; Protein database; Mitochondria-associated membranes MAM; Proteomic analysis of cardiac MAM proteome
Categories
Funding
- Fondation de France [00056853]
- Fondation Leducq [16CVD04]
- Fondation Lefoulon-Delalande
- Fondation pour la Recherche Medicale [ARF20160936149]
- Innovative Medicines Initiative 2 Joint Undertaking [821508]
- European Union
- EFPIA
- OPeRa program [ANR-10-IBHU-0004 OPeRa]
- RHU MARVELOUS program [ANR-16-RHUS-0009]
- National Council for Scientific Research of Lebanon (CNRS-L)
- Agence Universitaire de la Francophonie (AUF)
- Lebanese University
- Azm and Saade association
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Type 2 diabetic cardiomyopathy features Ca2+ signaling abnormalities, notably an altered mitochondrial Ca2+ handling. We here aimed to study if it might be due to a dysregulation of either the whole Ca2+ homeostasis, the reticulum-mitochondrial Ca2+ coupling, and/or the mitochondrial Ca2+ entry through the uniporter. Following a 16-week high-fat high-sucrose diet (HFHSD), mice developed cardiac insulin resistance, fibrosis, hypertrophy, lipid accumulation, and diastolic dysfunction when compared to standard diet. Ultrastructural and proteomic analyses of cardiac reticulum-mitochondria interface revealed tighter interactions not compatible with Ca2+ transport in HFHSD cardiomyocytes. Intramyocardial adenoviral injections of Ca2+ sensors were performed to measure Ca2+ fluxes in freshly isolated adult cardiomyocytes and to analyze the direct effects of in vivo type 2 diabetes on cardiomyocyte function. HFHSD resulted in a decreased IP3R-VDAC interaction and a reduced IP3-stimulated Ca2+ transfer to mitochondria, with no changes in reticular Ca2+ level, cytosolic Ca2+ transients, and mitochondrial Ca2+ uniporter function. Disruption of organelle Ca2+ exchange was associated with decreased mitochondrial bioenergetics and reduced cell contraction, which was rescued by an adenovirus-mediated expression of a reticulum-mitochondria linker. An 8-week diet reversal was able to restore cardiac insulin signaling, Ca2+ transfer, and cardiac function in HFHSD mice. Therefore, our study demonstrates that the reticulum-mitochondria Ca2+ miscoupling may play an early and reversible role in the development of diabetic cardiomyopathy by disrupting primarily the mitochondrial bioenergetics. A diet reversal, by counteracting the MAM-induced mitochondrial Ca2+ dysfunction, might contribute to restore normal cardiac function and prevent the exacerbation of diabetic cardiomyopathy.
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