Ephrin-B1 regulates the adult diastolic function through a late postnatal maturation of cardiomyocyte surface crests

被引:4
作者
Karsenty, Clement [1 ,2 ]
Guilbeau-Frugier, Celine [1 ,3 ]
Genet, Gael [4 ]
Seguelas, Marie-Helene [1 ]
Alzieu, Philippe [5 ]
Cazorla, Olivier [6 ]
Montagner, Alexandra [1 ]
Blum, Yuna [7 ]
Dubroca, Caroline [8 ]
Maupoint, Julile [8 ]
Tramunt, Blandine [1 ,9 ]
Cauquil, Marie [1 ]
Sulpice, Thierry [8 ]
Richard, Sylvain [6 ]
Arcucci, Silvia [1 ]
Flores-Flores, Remy [1 ]
Pataluch, Nicolas [1 ]
Montoriol, Romain [3 ]
Sicard, Pierre [6 ]
Deney, Antoine [1 ]
Couffinhal, Thierry [5 ,10 ]
Senard, Jean-Michel [1 ,11 ]
Gales, Celine [1 ]
机构
[1] Univ Toulouse, Inst Malad Metab & Cardiovasc, INSERM, UMR 1297, Toulouse, France
[2] Ctr Hosp Univ Toulouse, Dept Pediat Cardiol, Toulouse, France
[3] Univ Toulouse, Ctr Hosp Univ Toulouse, Dept Forens Med, Toulouse, France
[4] Univ Virginia, Dept Cell Biol, Sch Med, Charlottesville, VA USA
[5] Univ Bordeaux, INSERM, Biol Malad Cardiovasc, Pessac, France
[6] Univ Montpellier, INSERM, CNRS, PhyMedExp, Montpellier, France
[7] Univ Rennes 1, IGDR UMR 6290, CNRS, Rennes, France
[8] CARDIOMEDEX, Escalquens, France
[9] Ctr Hosp Univ Toulouse, Dept Diabetol Metab Dis & Nutr, Toulouse, France
[10] CHU Bordeaux, Serv Malad Cardiaques & Vasc, Bordeaux, France
[11] Ctr Hosp Univ Toulouse, Dept Clin Pharmacol, Toulouse, France
关键词
cardiac postnatal devleopment; cardiomyocyte architecture; subsarcolemmal mitochondria; cardiac hypertrophy; diatolic function; ephrin-B1; Mouse; Rat; HEART-FAILURE; 3-DIMENSIONAL ARCHITECTURE; GENE-EXPRESSION; MITOCHONDRIA; HYPERTROPHY; GROWTH; HYPERPLASIA; MYOCARDIUM; MECHANISMS; MEMBRANE;
D O I
10.7554/eLife.80904
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
The rod-shaped adult cardiomyocyte (CM) harbors a unique architecture of its lateral surface with periodic crests, relying on the presence of subsarcolemmal mitochondria (SSM) with unknown role. Here, we investigated the development and functional role of CM crests during the postnatal period. We found in rodents that CM crest maturation occurs late between postnatal day 20 (P20) and P60 through both SSM biogenesis, swelling and crest-crest lateral interactions between adjacent CM, promoting tissue compaction. At the functional level, we showed that the P20-P60 period is dedicated to the improvement of relaxation. Interestingly, crest maturation specifically contributes to an atypical CM hypertrophy of its short axis, without myofibril addition, but relying on CM lateral stretching. Mechanistically, using constitutive and conditional CM-specific knock-out mice, we identified ephrin-B1, a lateral membrane stabilizer, as a molecular determinant of P20-P60 crest maturation, governing both the CM lateral stretch and the diastolic function, thus highly suggesting a link between crest maturity and diastole. Remarkably, while young adult CM-specific Efnb1 KO mice essentially exhibit an impairment of the ventricular diastole with preserved ejection fraction and exercise intolerance, they progressively switch toward systolic heart failure with 100% KO mice dying after 13 months, indicative of a critical role of CM-ephrin-B1 in the adult heart function. This study highlights the molecular determinants and the biological implication of a new late P20-P60 postnatal developmental stage of the heart in rodents during which, in part, ephrin-B1 specifically regulates the maturation of the CM surface crests and of the diastolic function.
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页数:31
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