The mammalian adult cardiomyocyte (CM) harbors a typical rod shape specifically dedicated to the function of the adult heart. Understanding the maturation of the adult rod-shaped CM can provide important insights for regenerative medicine, especially for the differentiation of hiPSC cells into fully mature rod-shaped adult CMs, which still remains an obstacle. To date, the molecular events leading to the setting of the CM rod shape during the postnatal stage are still unknown.

Indeed, despite fetal and adult CMs being extensively studied, the postnatal stage has only recently garnered an unprecedented interest with the discovery of the potential of adult CMs to proliferate and regenerate the heart (Bergmann et al., 2009). Thus, strategies in this field have focused on boosting this regenerative process by exploiting factors specifically involved in the early CM proliferation arrest that occurs during the postnatal period (Karra and Poss, 2017). However, despite the postnatal maturation period characterizing the exit of the CM from the cell cycle, it also coincides with a morphogenesis step during which the CM switches from a proliferative rounded shape to a nonproliferative mature rod shape (Anversa et al., 1980). In situ, mammalian CMs stop dividing and start their morphogenesis maturation around postnatal day 7 (P7) (Porrello et al., 2011; Porrello et al., 2013).

The postnatal morphogenesis stage of the CM relies on a polarization process that results in the asymmetric organization of the plasma membrane components underlying specific functions with an atypical basolateral polarity. It begins with a longitudinal elongation process of the CM to progressively evolve into the rod-shaped characteristic of the mature adult state. Contrary to epithelial cells harboring a basolateral and apical side, the adult CM lacks the apical side and looks like a barrel surrounded by a unique basal side with a basement membrane connecting the fibrillar extracellular matrix (ECM) and flanked by two intercalated disks (ID) involved in the CM-CM tight interactions, shaping the longitudinal alignment of myofibers within the tissue (Kanzaki et al., 2010; Kanzaki et al., 2012). The ID phenocopies the lateral side of polarized epithelial cells with the presence of tight, adherent, gap junctions and desmosomes that play a specific role in the anchorage of the contractile myofilaments but also in the synchronization of the contraction. One architectural feature of the basal side of the adult CM, also called the lateral membrane, also relies on its important intracellular invaginations into transverse T-tubules, which play a key role in both action potential propagation and Ca²⁺ handling/excitation–contraction coupling Ibrahim et al., 2011. Likewise, the extracellular side of the lateral membrane seems more complex than initially suspected since, besides the presence of a costamere structure expressing classical transmembrane receptors (integrin and DGC dystroglycan-glycoprotein complex) that connect the ECM components to the intracellular myofibrils, we and others have reported the atypical presence of transmembrane proteins, claudin-5 and ephrin-B1 (Genet et al., 2012; Sanford et al., 2005), more likely involved in cell–cell communication. This finding was unexpected since, contrary to the ID, the lateral membrane was until recently viewed as a CM side lacking physical interactions with neighboring CMs. However, these last years, using high-resolution nanoscale imaging, i.e., SCIM, AFM, and MET, we and Gorelik’s lab have described a highly organized architecture of the lateral membrane on adult CMs with periodic crests (Dague et al., 2014; Guilbeau-Frugier et al., 2019; Nikolaev et al., 2010) filled with subsarcolemmal mitochondria (SSM) whose role is unknown. Furthermore, we provided evidence for the existence, in the 3D cardiac tissue, of intermittent lateral crest–crest contacts all along the lateral membrane through claudin-5/claudin-5 tight junctional interactions (Guilbeau-Frugier et al., 2019), thus reconciling the presence of such cell–cell communication proteins on the lateral face of the adult CM. However, exactly when and how the lateral membrane crests of the CM maturate is completely unknown.

In this study, we investigated the maturation of the CM crests and their role during the postnatal period. We provide evidence for a late postnatal development stage, following the set-up of the rod shape, during which crests fully maturate through SSM swelling. We also show that this maturation step of the crests is ephrin-B1-dependent and specifically regulates the diastolic function of the adult heart.

In this study, we describe a new developmental stage occurring in the late postnatal period between P20 and P60, during which crests of the CM lateral membrane maturate through SSM biogenesis, swelling, and crest–crest interactions within the tissue through an ephrin-B1/claudin-5 mechanism, thus allowing CM lateral stretching and a global compaction of the cardiac tissue (Figure 9). We demonstrate that this mechanism regulates the adult diastolic function. Hence, these results shed light on the molecular mechanism by which ephrin-B1 regulates the CM lateral membrane that we described before (Genet et al., 2012). Taken together, our findings identify crest subdomains of the adult CM lateral surface as novel specific determinants of cardiac diastole.

Figure 9

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Postnatal maturation of the heart in mammals has been paid much less attention than embryonic and fetal development. This would be a prerequisite for future pediatric clinical trials, which are seriously lacking. It also contributes to a significant knowledge gap that impedes research progression in regenerative medicine since this postnatal maturation coincides with the proliferation blockage of the CM. To date, at the cellular level, postnatal cardiac maturation has been essentially described until P20 in rodents, most likely related to the implementation of the typical adult rod shape of the CM. Very few studies have examined the specific P20-adult stage window, assuming that the genetic maturation of the heart is completed by P20 and that the heart merely undergoes a substantial growth beyond P20 until the young adult stage (Piquereau et al., 2010). A recent study analyzed early gene expression of rodent hearts and of CMs during different postnatal days, including P21 and P56 (young adult), and while the authors clearly identified different transcriptomic signatures between these two periods, they focused their study on the P1-P7 transition (Li et al., 2022). However, this P20-Adult period coincides with the weaning time in rodents (~P21) and thus with a critical nutritional/metabolic switch in the organism likely to influence heart function. So far, research has focused on the P0 (birth) to P20 postnatal window, during which the heart switches from a hyperplasic growth (CM proliferation) (~P3-P5) to an hypertrophic growth (increase in CM size) (P20-21) (Bishop et al., 2021; Leu et al., 2001; Li et al., 1996). Recent omics studies have detailed the molecular changes associated with the postnatal development of the mouse heart but only until P20 (DeLaughter et al., 2016; Talman et al., 2018). Thus, the P0-P20 postnatal development period essentially relies on the ECM remodeling of the cardiac tissue and, at the CM level, myofibril and Ca²⁺ handling maturation, metabolic switch from glycolysis to major fatty acid oxidation and the transition from CM proliferation to CM hypertrophy (Guo and Pu, 2020; Karbassi et al., 2020). This metabolic change most likely occurs as an adaptation of the postnatal heart to cardiac tissue oxygenation and the newborn diet, which essentially consists of mother’s milk and thus on high fatty acid availability. Our transcriptome analysis of mouse hearts reveals an additional developmental genetic program between P20 and P60 originating from all the cardiac cells of the left ventricle, thus indicating that the heart and the CM had not completed maturation by P20. Of interest, while the primary metabolic reliance of the heart on fatty acids and then glucose is already programmed between birth and P20, we found that the P20-P60 late postnatal stage programs the metabolic diversification of the heart. Such a new final metabolic adaptation of the heart coincides with the weaning process occurring around P20 in rodents, during which the newborn switches from milk to solid food (Sengupta, 2013). This step is also in line with the capacity of the heart to metabolize a large panel of substrates to meet the energy demands of the adult stage (Murashige et al., 2020). Remarkably, we found that the Bdh1 gene was increased by more than 37-fold between P20 and P60, most likely indicating that the capacity of the heart to oxidize KB (coming essentially from the liver) as a fuel is not only restricted to the adaptation of the failing heart, as previously shown (Horton et al., 2019), but is also necessary for the adult physiological state. These results also agree with recent findings demonstrating that the human adult heart can use a large panel of substrates as a fuel, including a large proportion of KB (Murashige et al., 2020). Horton et al. did not report a major cardiac phenotype under basal conditions in CM-specific Bdh1 KO mice (Horton et al., 2019). However, more in-depth cardiac phenotyping of these mice would undoubtedly be necessary to depict the role of KB in the adult cardiac physiology, such as diastolic function.

An intriguing finding from our study is the physiological cardiac hypertrophy of the heart between P20 and P60, which, from a CM lateral standpoint, does not rely on a classical myofibril addition in the CM but, at least in part, on an ephrin-B1-dependent- (1) crest maturation through SSM swelling at the CM surface and (2) lateral stretching of the CM. During postnatal development, heart growth occurs primarily through CM proliferation (hyperplasia) but transitions rapidly after birth (~P5-7) to CM growth (hypertrophy) (Leu et al., 2001; Li et al., 1996) through new myofibril biogenesis. Although physiological CM hypertrophy has been described beyond P20 and is related to increased cardiac mass (Piquereau et al., 2010; Anversa et al., 1986), the underlying molecular mechanisms have never been explored. Piquereau et al., 2010 already reported and questioned such atypical hypertrophy of the rat heart after P21 without fiber addition, which was not classically related to the increase in heart weight to body weight index but conversely to a marked decrease. Here, we show that the P20-P60 hypertrophy relies on both an enlargement of the short and long axes of the CM. Interestingly, we demonstrated that the short-axis elongation is dependent on the architectural maturation of the CM surface trough an ephrin-B1 mechanism. Thus, the ephrin-B1 lateral membrane protein, a partner and regulator of claudin-5⁹, participates in P20-P60 lateral CM hypertrophy, likely by bringing claudin-5 into the vicinity of neighboring CM, allowing intermittent but direct lateral crest–crest interactions (claudin-5/claudin-5 interactions), crest/SSM maturation, and the ensuing stretching of the CM lateral membrane (Figure 9). In agreement with this model, we previously showed that CMs from Efnb1^CM-/- KO mice exhibit substantially decreased levels of claudin-5 expression (Genet et al., 2012), likely accounting for the lack of crest maturation and lateral crest–crest interactions in these adult KO mice. However, other mechanisms also likely contribute to the short-axis elongation since it was only partially prevented by ephrin-B1 deletion. More specifically, lateral membrane interactions with the ECM, i.e., through integrin or the dystroglycan complex, which we previously showed to be independent of ephrin-B1⁹, could also play a role. In line with this assumption, our transcriptomic analysis identified the regulation of genes from the ECM remodeling pathway during the P20-P60 maturation period and the dystrobrevin-encoding gene (DTNA, Figure 4—figure supplement 3) from the dystroglycan complex. Apart from the short axis, P20-P60 CM hypertrophy also depends on the elongation of the CM long axis, which we show here to be independent from ephrin-B1 and which probably depends on the assembly of new sarcomeres at the myofibril extremities, thus contributing to the classical heart hypertrophy.

A new finding of our study is the specific maturation of SSM during the late P20-P60 postnatal period of the CM. Coinciding with this late cardiac mitochondria maturation in the CM, (Piquereau et al., 2010) previously reported a substantial increase in maximum respiratory capacity occurring after P21 and the adult stage in cardiac tissues from rats while the postnatal maturation of IFM occurred earlier. Biogenesis/maturation of cardiac mitochondria occur early during the embryogenesis, concurrently with the energy demand of the heart during the development period (Lopaschuk and Jaswal, 2010; Zhao et al., 2019.) Thus, they can adapt their morphology and function according to the energy need and metabolic conditions of the cell (Packer, 1963; Schönfeld et al., 2000). In this field, most of the works on the postnatal period have focused on the characterization of the IFM (the most abundant in the adult CM) or the global cardiac mitochondria activity dedicated to the energy supply to the CMs for the contractile machinery, without distinguishing the different mitochondria subpopulations of the adult CM (Hollander et al., 2014). IFM maturation during the P0-P7 stage occurs both through swelling and through architectural reorganization along the myofibrils (Piquereau et al., 2010), concomitantly with the well-known metabolic shift of the heart from glycolysis to a central oxidative metabolism more efficient for adult CM contraction (Lopaschuk and Jaswal, 2010). It follows that IFM function is primarily dedicated to supplying the CM with the energy necessary for adult contraction. The delayed maturation of SSM at the CM surface compared to intracellular IFM supports the concept that these mitochondria regulate different CM functions. In agreement with this notion, we demonstrated in this study that crests/SSM specifically regulate heart diastole. Several results support this conclusion: (1) young adult CM-specific Efnb1 KO mice with immature SSM display diastolic defects with no impairment of systolic function, and (2) systolic function is already mature by P20 in rat hearts while the diastolic function is highly variable. Moreover, supporting our results about the late maturation of diastole, Zhou et al. previously reported that the diastolic function in the left ventricle of mice matures around the weaning period (Zhou et al., 2003). In the future, it would be interesting to investigate whether cardiac SSM defects are a specific feature of diastolic dysfunction pathologies, such as HFpEF frequently associated with a metabolic syndrome (Valero-Muñoz et al., 2017). In support of this concept, a recent study of myocardial gene expression signatures in human HFpEF reported that the ephrin-B1-encoding gene, which we demonstrated here as a specific determinant of the CM crests/SSM, is specifically downregulated in HFpEF heart patients compared with HFrEF (Hahn et al., 2021). Unfortunately, while several works have reported the influence of different cardiac pathologies on specific subpopulations of cardiac mitochondria (Hollander et al., 2014), these results require some caution, given the technical difficulty of specifically purifying and distinguishing the populations in the absence of reliable markers and due to the fact that these mitochondria are morphologically highly similar (Guilbeau-Frugier et al., 2019). Today, electron microscopy still remains the gold standard for accurately examining the cardiac mitochondria subpopulations.

An essential and new finding of our study is the identification of the ephrin-B1/crest/SSM module at the lateral membrane of the CM as a specific determinant of the physiological diastolic function of the adult heart. So far, the diastolic determinants have been proposed only in the context of diastolic dysfunction in cardiac pathologies such as HFpEF (Lewis et al., 2017). However, until rather recently, the lack of specific and compelling therapeutics in HFpEF underlines our limited knowledge of the control of diastole. This is overcomplicated in the context of HFpEF due to the contributions of several comorbidities delineating highly heterogeneous clinical features (Lewis et al., 2017). Here, our study demonstrates that Efnb1 deletion specifically in the CM recapitulates at the young adult stage (2 months) some features of the diastolic dysfunction depicted in HFpEF, i.e., an elevated EDP and altered filling patterns combined with exercise intolerance. One important concern is understanding how ephrin-B1 at the lateral membrane of the adult CM can impact diastolic function. We previously demonstrated that ephrin-B1 controls the architecture of the lateral membrane and the overall adult rod shape of the CM (Genet et al., 2012). Here, we now further demonstrated that ephrin-B1 controls the maturity of the crest/SSM architectural motif at the lateral membrane, thus playing a key role in the adult crest–crest interactions between neighboring CMs and in overall tissue cohesion. These lateral CM interactions likely dictate a mechanical lateral stretch of the CM, allowing perfect stacking between myofibril layers. Consequently, crest–crest interactions might contribute to controlling the relaxation length of the sarcomere, a mechanism that we previously suggested to be dependent on crest height (Guilbeau-Frugier et al., 2019). This ephrin-B1-dependent lateral stretch of the CM is also necessary for the spatial arrangement of the T-tubules and most likely its ensuing function during the P20-P60 development, as supported by the T-tubule disorganization in the CM-specific Efnb1 KO mice. Thus, by altering the T-tubule structure, lack of ephrin-B1 could influence the Ca²⁺ entry/Ca²⁺ exit. It is worth noting that T-tubule disorganization in the CMs of Efnb1^CM-/- KO mice is progressive with mild disorganization correlating with diastolic dysfunction only, while extensive disorganization is observed in HFrEF. Although defects in T-tubule architecture/function are a hallmark of HFrEF (Guo et al., 2013), it has been poorly examined in HFpEF, only one recent study reported that this mechanism is etiology-dependent (Frisk et al., 2021). An exciting feature of the CM-specific Efnb1 KO mice is the progressive cardiac phenotype starting from a primarily diastolic defect that progressively switches toward a mild and then severe HFrEF and finally to death, thus highlighting the substantial cardioprotective role of the surface crests/SSM of the lateral membrane. Although this switch toward HFrEF is not a common feature of HFpEF patients (Lupón et al., 2019), definitive conclusions cannot be reached on the natural evolution of HFpEF, given that HFpEF patients received medication for their different comorbidities, which could protect them from HFrEF. In the future, an accurate characterization of the CM surface crests/SSM in different HFpEF models with diastolic dysfunction will undoubtedly shed light on whether crest disruption might be a hallmark of HFpEF and could thus contribute to the setting of the pathology.

Transcriptomic data have been deposited in GEO under the accession number GSE196257. Source data files have been provided for Figures 1B, C, 3 A, B, 4 A-G, 5 A-G, 6 A-D, 7B-D, 8 A-E and Figure 1-figure supplement 5, 8C, Figure 4-figure supplement 1, 2, 3 A-B, Figure 7-figure supplement 1.

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Author details

1. Clement Karsenty

   1. INSERM, UMR 1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France
   2. Department of Pediatric Cardiology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

2. Celine Guilbeau-Frugier

   1. INSERM, UMR 1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France
   2. Department of Forensic Medicine, Centre Hospitalier Universitaire de Toulouse, Université de Toulouse, Toulouse, France

   Contribution

   Conceptualization, Supervision, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

3. Gaël Genet

   Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, United States

   Contribution

   Conceptualization, Formal analysis, Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0016-5887

4. Marie-Helene Seguelas

   INSERM, UMR 1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France

   Contribution

   Investigation

   Competing interests

   No competing interests declared

5. Philippe Alzieu

   Université de Bordeaux, INSERM, Biologie des maladies cardiovasculaires, Pessac, France

   Contribution

   Supervision, Validation, Investigation

   Competing interests

   No competing interests declared

6. Olivier Cazorla

   Université de Montpellier, INSERM, CNRS, PhyMedExp, Montpellier, France

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

7. Alexandra Montagner

   INSERM, UMR 1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France

   Contribution

   Data curation, Formal analysis, Supervision, Validation, Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

8. Yuna Blum

   IGDR UMR 6290, CNRS, Université de Rennes 1, Rennes, France

   Contribution

   Conceptualization, Data curation, Validation, Investigation, Methodology

   Competing interests

   No competing interests declared

9. Caroline Dubroca

   CARDIOMEDEX, Escalquens, France

   Contribution

   Formal analysis, Supervision, Validation, Investigation, Methodology, Writing – review and editing

   Competing interests

   Dubroca, Julie Maupoint and Thierry Sulpice are employees of Cardiomedex

10. Julile Maupoint

    CARDIOMEDEX, Escalquens, France

    Contribution

    Formal analysis, Supervision, Validation, Investigation, Methodology

    Competing interests

    Dubroca, Julie Maupoint and Thierry Sulpice are employees of Cardiomedex

11. Blandine Tramunt

    1. INSERM, UMR 1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France
    2. Department of Diabetology, Metabolic Diseases & Nutrition, Centre Hospitalier Universitaire de Toulouse, Toulouse, France

    Contribution

    Investigation, Writing – review and editing

    Competing interests

    No competing interests declared

12. Marie Cauquil

    INSERM, UMR 1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France

    Contribution

    Supervision, Investigation, Writing – review and editing

    Competing interests

    No competing interests declared

13. Thierry Sulpice

    CARDIOMEDEX, Escalquens, France

    Contribution

    Supervision, Funding acquisition, Writing – review and editing

    Competing interests

    Dubroca, Julie Maupoint and Thierry Sulpice are employees of Cardiomedex

14. Sylvain Richard

    Université de Montpellier, INSERM, CNRS, PhyMedExp, Montpellier, France

    Contribution

    Data curation, Formal analysis, Investigation, Writing – review and editing

    Competing interests

    No competing interests declared

15. Silvia Arcucci

    INSERM, UMR 1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France

    Contribution

    Data curation, Formal analysis, Validation, Investigation, Writing – review and editing

    Competing interests

    No competing interests declared

16. Remy Flores-Flores

    INSERM, UMR 1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France

    Contribution

    Validation, Investigation, Methodology

    Competing interests

    No competing interests declared

17. Nicolas Pataluch

    INSERM, UMR 1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France

    Contribution

    Data curation, Investigation

    Competing interests

    No competing interests declared

18. Romain Montoriol

    Department of Forensic Medicine, Centre Hospitalier Universitaire de Toulouse, Université de Toulouse, Toulouse, France

    Contribution

    Investigation

    Competing interests

    No competing interests declared

19. Pierre Sicard

    Université de Montpellier, INSERM, CNRS, PhyMedExp, Montpellier, France

    Contribution

    Data curation, Validation, Investigation

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-5837-3916

20. Antoine Deney

    INSERM, UMR 1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France

    Contribution

    Formal analysis, Validation, Investigation

    Competing interests

    No competing interests declared

21. Thierry Couffinhal

    1. Université de Bordeaux, INSERM, Biologie des maladies cardiovasculaires, Pessac, France
    2. Service des Maladies Cardiaques et Vasculaires, CHU de Bordeaux, Bordeaux, France

    Contribution

    Data curation, Formal analysis, Supervision, Validation, Writing – review and editing

    Competing interests

    No competing interests declared

22. Jean-Michel Senard

    1. INSERM, UMR 1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France
    2. Department of Clinical Pharmacology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France

    Contribution

    Conceptualization, Formal analysis, Supervision, Validation, Methodology, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-7679-1281

23. Celine Galés

    INSERM, UMR 1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France

    Contribution

    Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Methodology, Writing – original draft, Project administration, Writing – review and editing

    For correspondence

    celine.gales@inserm.fr

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-4938-1583

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