Difference between revisions of "Dia 2020 Basic Res Cardiol"
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|abstract=Type 2 diabetic cardiomyopathy features Ca<sup>2+</sup> signaling abnormalities, notably an altered mitochondrial Ca<sup>2+</sup> handling. We here aimed to study if it might be due to a dysregulation of either the whole Ca<sup>2+</sup> homeostasis, the reticulum-mitochondrial Ca<sup>2+</sup> coupling, and/or the mitochondrial Ca<sup>2+</sup> 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 Ca<sup>2+</sup> transport in HFHSD cardiomyocytes. Intramyocardial adenoviral injections of Ca<sup>2+</sup> sensors were performed to measure Ca<sup>2+</sup> 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 Ca<sup>2+</sup> transfer to mitochondria, with no changes in reticular Ca<sup>2+</sup> level, cytosolic Ca<sup>2+</sup> transients, and mitochondrial Ca<sup>2+</sup> uniporter function. Disruption of organelle Ca<sup>2+</sup> 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, Ca<sup>2+</sup> transfer, and cardiac function in HFHSD mice. Therefore, our study demonstrates that the reticulum-mitochondria Ca<sup>2+</sup> 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 Ca<sup>2+</sup> dysfunction, might contribute to restore normal cardiac function and prevent the exacerbation of diabetic cardiomyopathy. | |abstract=Type 2 diabetic cardiomyopathy features Ca<sup>2+</sup> signaling abnormalities, notably an altered mitochondrial Ca<sup>2+</sup> handling. We here aimed to study if it might be due to a dysregulation of either the whole Ca<sup>2+</sup> homeostasis, the reticulum-mitochondrial Ca<sup>2+</sup> coupling, and/or the mitochondrial Ca<sup>2+</sup> 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 Ca<sup>2+</sup> transport in HFHSD cardiomyocytes. Intramyocardial adenoviral injections of Ca<sup>2+</sup> sensors were performed to measure Ca<sup>2+</sup> 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 Ca<sup>2+</sup> transfer to mitochondria, with no changes in reticular Ca<sup>2+</sup> level, cytosolic Ca<sup>2+</sup> transients, and mitochondrial Ca<sup>2+</sup> uniporter function. Disruption of organelle Ca<sup>2+</sup> 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, Ca<sup>2+</sup> transfer, and cardiac function in HFHSD mice. Therefore, our study demonstrates that the reticulum-mitochondria Ca<sup>2+</sup> 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 Ca<sup>2+</sup> dysfunction, might contribute to restore normal cardiac function and prevent the exacerbation of diabetic cardiomyopathy. | ||
|editor=[[Plangger M]] | |editor=[[Plangger M]] | ||
|mipnetlab=FR Lyon Ovize M | |||
}} | }} | ||
{{Labeling | {{Labeling | ||
|area=Respiration | |area=Respiration | ||
|diseases=Diabetes | |||
|organism=Mouse | |||
|tissues=Heart | |||
|preparations=Intact cells | |||
|couplingstates=ROUTINE, ET | |||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
|additional=2020-12 | |additional=2020-12 | ||
}} | }} |
Latest revision as of 23:11, 11 December 2020
Dia M, Gomez L, Thibault H, Tessier N, Leon C, Chouabe C, Ducreux S, Gallo-Bona N, Tubbs E, Bendridi N, Chanon S, Leray A, Belmudes L, Couté Y, Kurdi M, Ovize M, Rieusset J, Paillard M (2020) Reduced reticulum-mitochondria Caysup>2+ transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy. Basic Res Cardiol 115:74. |
Dia M, Gomez L, Thibault H, Tessier N, Leon C, Chouabe C, Ducreux S, Gallo-Bona N, Tubbs E, Bendridi N, Chanon S, Leray A, Belmudes L, Couté Y, Kurdi M, Ovize M, Rieusset J, Paillard M (2020) Basic Res Cardiol
Abstract: 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.
• Bioblast editor: Plangger M • O2k-Network Lab: FR Lyon Ovize M
Labels: MiParea: Respiration
Pathology: Diabetes
Organism: Mouse Tissue;cell: Heart Preparation: Intact cells
Coupling state: ROUTINE, ET
HRR: Oxygraph-2k
2020-12