Crest maturation at the cardiomyocyte surface contributes to a new late postnatal development stage that controls the diastolic function of the adult heart

karsenty, c.; frugier, c.; GENET, G.; SEGUELAS, M.-H.; Alzieu, P.; Cazorla, O.; Montagner, A.; Blum, Y.; Dubroca, c.; Maupoint, J.; Tramunt, B.; Cauquil, M.; Sulpice, T.; Richard, S.; Arcucci, S.; Flores-Flores, R.; Pataluch, N.; Montoriol, R.; Sicard, P.; Deney, A.; Couffinhal, T.; Senard, J.-M.; Gales, C.

doi:10.1101/2022.02.11.480042

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bioRxiv · 10.1101/2022.02.11.480042

Crest maturation at the cardiomyocyte surface contributes to a new late postnatal development stage that controls the diastolic function of the adult heart

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Abstract

RATIONALEIn addition to its typical rod-shape, the mammalian adult cardiomyocyte (CM) harbors a unique lateral membrane surface architecture with periodic crests, relying on the presence of subsarcolemmal mitochondria (SSM) the role of which is still unknown. OBJECTIVETo investigate the development and functional role of CM crests during the postnatal period. METHODS AND RESULTSElectron/confocal microscopy and western-blot of left ventricular tissues from rat hearts indicated a late CM surface crest maturation, between postnatal day 20 (P20) and P60, as shown by substantial SSM swelling and increased claudin-5 cell surface expression. The P20-P60 postnatal stage also correlates with an ultimate maturation of the T-Tubules and the intercalated disk. At the cellular level, we identified an atypical CM hypertrophy characterized by an increase in long- and short-axes without myofibril addition and with sarcomere lateral stretching, indicative of lateral stretch-based CM hypertrophy. We confirmed the P20-P60 hypertrophy at the organ level by echocardiography but also demonstrated a transcriptomic program after P20 targeting all the cardiac cell populations. At the functional level, using Doppler echocardiography, we found that the P20-P60 period is specifically dedicated to the improvement of relaxation. Mechanistically, using CM-specific knock-out mice, we identified ephrin-B1 as a determinant of CM crest maturation after P20 controlling lateral CM stretch-hypertrophy and relaxation. Interestingly, while young adult Efnb1CMspe-/- mice essentially show a relaxation impairment with exercise intolerance, they progressively switch toward heart failure with 100% KO mice dying after 13 months. CONCLUSIONSThis study highlights a new late P20-P60 postnatal developmental stage of the heart in rodents during which the CM surface crests mature through an ephrin-B1-dependant mechanism and regulate the diastolic function. Moreover, we demonstrate for the first time that the CM crest architecture is cardioprotective.

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karsenty, c., frugier, c., GENET, G., SEGUELAS, M.-H., Alzieu, P., Cazorla, O., Montagner, A., Blum, Y., Dubroca, c., Maupoint, J., Tramunt, B., Cauquil, M., Sulpice, T., Richard, S., Arcucci, S., Flores-Flores, R., Pataluch, N., Montoriol, R., Sicard, P., Deney, A., Couffinhal, T., Senard, J.-M., Gales, C.. 2022-02-11. Crest maturation at the cardiomyocyte surface contributes to a new late postnatal development stage that controls the diastolic function of the adult heart. https://doi.org/10.1101/2022.02.11.480042

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