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

Abstract

The rod-shaped adult cardiomyocyte (CM) harbors a unique lateral membrane surface architecture with periodic crests, relying on the presence of subsarcolemmal mitochondria (SSM) with unknown role. Here, we investigate the development and functional role of CM crests during the postnatal period. Using high-resolution imaging, biochemical, immunocytochemical studies in rodents, we demonstrate that CM crest maturation occurs late between postnatal day 20 (P20) and P60 (young adult), after the onset of the CM rod-shape, through both SSM biogenesis, swelling and crest-crest lateral interactions between adjacent CMs, thus promoting tissue compaction. Transcriptomics confirmed this specific P20-P60 late developmental stage that targets all cardiac cell populations. At the functional level, we show that the P20-P60 period is dedicated to the improvement of relaxation. It also contributes to a cardiac hypertrophy relying on a substantial increase in both the CM long- and short axes. However, we demonstrate that the P20-P60 lateral crest/SSM maturation contributes specifically to an atypical physiological CM hypertrophy of the short axis, without myofibril addition, but with sarcomere lateral stretching, indicative of lateral stretch-based CM hypertrophy. Mechanistically, using constitutive and conditional CM-specific knock-out (KO) mice, we identified ephrin-B1, a lateral membrane stabilizer, as a determinant of CM crest maturation during the P20-adult window, controlling specifically both the CM lateral stretch and the diastolic function. Interestingly, 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. This study characterized for the first time the molecular determinants and the biological implication of the 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.

Single-nucleus RNA/ATAC-seq in early-stage HCM models predicts SWI/SNF-activation in mutant-myocytes, and allele-specific differences in fibroblasts

“…These changes were due to stronger interactions between ventricular cardiomyocytes (C9), ECs (C14, C16) and fibroblasts (C21, C22) in mutant hearts, when compared to controls ( Suppl Fig 10a ). The mutant-TnT heart was highly enriched for ephrin B (which can influence diastolic function 43 ), and pro-fibrotic periostin, TGFβ signaling, whereas mutant-MyHC showed marked enrichment for pro-hypertrophic 44 neuregulin signaling ( Fig 7b – c ). PDGF and ANGPT signaling were predicted to be stronger in mutant-TnT, whereas VEGF signaling was similar in both mutants ( Fig 7b ).…”

Proteomic Signature of HIV-Associated Subclinical Left Atrial Remodeling and Incident Heart Failure

“…34 Though ephrin signaling has not been well-studied among PLWH, it has been linked to other viral infections 35 as well as cardiomyocyte development, systolic and diastolic function, and TGF-β mediated cardiac fibrosis. [36][37][38] Several of these higher interest proteins are related to tissue growth and development, angiogenesis, and ECM remodeling-including CRIM1, THBS2, and TIMP1. CRIM1 modulates activity of bone morphogenic proteins, members of the TGFβ superfamily that are known to play roles in cardiac development and disease pathophysiology in HF, pulmonary arterial hypertension, and atherosclerosis.…”