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      Augmenting workload drives T-tubule assembly in developing cardiomyocytes

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          Abstract

          Contraction of cardiomyocytes is initiated at subcellular elements called dyads, where L-type Ca 2+ channels in t-tubules are located within close proximity to ryanodine receptors in the sarcoplasmic reticulum. While evidence from small rodents indicates that dyads are assembled gradually in the developing heart, it is unclear how this process occurs in large mammals. We presently examined dyadic formation in fetal and newborn sheep ( Ovis aries), and the regulation of this process by fetal cardiac workload. By employing advanced imaging methods, we demonstrated that t-tubule growth and dyadic assembly proceed gradually during fetal sheep development, from 93 days of gestational age until birth (147 days). This process parallels progressive increases in fetal systolic blood pressure, and includes step-wise colocalization of L-type Ca 2+ channels and the Na +/Ca 2+ exchanger with ryanodine receptors. These proteins are upregulated together with the dyadic anchor junctophilin-2 during development, alongside changes in the expression of amphiphysin-2 (BIN1) and its partner proteins myotubularin and dynamin-2. Increasing fetal systolic load by infusing plasma or occluding the post-ductal aorta accelerated t-tubule growth. Conversely, reducing fetal systolic load with infusion of enalaprilat, an angiotensin converting enzyme inhibitor, blunted t-tubule formation. Interestingly, altered t-tubule densities did not relate to changes in dyadic junctions, or marked changes in the expression of dyadic regulatory proteins, indicating that distinct signals are responsible for maturation of the sarcoplasmic reticulum. In conclusion, augmenting blood pressure and workload during normal fetal development critically promotes t-tubule growth, while additional signals contribute to dyadic assembly.

          Graphical Abstract

          In the sheep heart, t-tubule growth begins in the fetal stage of development. Even at this early stage, growing t-tubules contain both L-type Ca 2+ channels (LTCCs) and Na +/Ca 2+ exchanger (NCX), which are colocalized with ryanodine receptors (RyRs) in dyadic junctions with the sarcoplasmic reticulum (SR). Progressive dyadic maturation is linked to upregulation of junctophilin-2 and BIN1, and this structural organization continues after birth. T-tubule development is highly workload sensitive. Indeed, in the healthy developing heart, gradually increasing blood pressure drives t-tubule maturation, and this process can be accelerated or blunted by interventions which increase or reduce fetal systolic load, respectively.

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          Most cited references85

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          Thyroid and Glucocorticoid Hormones Promote Functional T-Tubule Development in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

          Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are increasingly being used for modeling heart disease and are under development for regeneration of the injured heart. However, incomplete structural and functional maturation of hiPSC-CM, including lack of T-tubules, immature excitation-contraction coupling, and inefficient Ca-induced Ca release remain major limitations.
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            Functional partnership between amphiphysin and dynamin in clathrin-mediated endocytosis.

            Amphiphysin, a protein that is highly concentrated in nerve terminals, has been proposed to function as a linker between the clathrin coat and dynamin in the endocytosis of synaptic vesicles. Here, using a cell-free system, we provide direct morphological evidence in support of this hypothesis. Unexpectedly, we also find that amphiphysin-1, like dynamin-1, can transform spherical liposomes into narrow tubules. Moreover, amphiphysin-1 assembles with dynamin-1 into ring-like structures around the tubules and enhances the liposome-fragmenting activity of dynamin-1 in the presence of GTP. These results show that amphiphysin binds lipid bilayers, indicate a potential function for amphiphysin in the changes in bilayer curvature that accompany vesicle budding, and imply a close functional partnership between amphiphysin and dynamin in endocytosis.
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              Amphiphysin 2 (Bin1) and T-tubule biogenesis in muscle.

              In striated muscle, the plasma membrane forms tubular invaginations (transverse tubules or T-tubules) that function in depolarization-contraction coupling. Caveolin-3 and amphiphysin were implicated in their biogenesis. Amphiphysin isoforms have a putative role in membrane deformation at endocytic sites. An isoform of amphiphysin 2 concentrated at T-tubules induced tubular plasma membrane invaginations when expressed in nonmuscle cells. This property required exon 10, a phosphoinositide-binding module. In developing myotubes, amphiphysin 2 and caveolin-3 segregated in tubular and vesicular portions of the T-tubule system, respectively. These findings support a role of the bilayer-deforming properties of amphiphysin at T-tubules and, more generally, a physiological role of amphiphysin in membrane deformation.
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                Author and article information

                Journal
                0266262
                5187
                J Physiol
                J Physiol
                The Journal of physiology
                0022-3751
                1469-7793
                3 February 2024
                September 2024
                21 May 2023
                24 September 2024
                : 602
                : 18
                : 4461-4486
                Affiliations
                [1 ]Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
                [2 ]K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, Norway
                [3 ]Center for Developmental Health, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA
                [4 ]Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, OR, USA
                [5 ]VA Portland Health Care System Portland, OR, USA
                Author notes

                Author contributions

                Animal work, tissue harvesting, and cellular imaging were performed at the Centre for Developmental Health, Knight Cardiovascular Institute, Oregon Health and Science University. Image and molecular analyses were performed at the Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo. O.M., G.D.G., K.L.T., and W.E.L. were responsible for the conception and design of the study. S.L., S.S.J., G.D.G., and K.L.T. organized and performed animal surgery, and harvested tissue. S.L. isolated cardiomyocytes, and O.M. conducted cellular imaging studies. O.M. and M.F. performed image analysis. H.P-D. designed and performed PCR experiments. O.M. and W.E.L. wrote the paper with critical input from all authors. Funding for the study was provided by G.D.G., K.L.T., O.M., and W.E.L. All authors approved the final version of the manuscript. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

                Corresponding authors O. Manfra and W. E. Louch: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Ullevål, PB 4956 Nydalen, NO-0424 Oslo, Norway. ornella.manfra@ 123456medisin.uio.no , w.e.louch@ 123456medisin.uio.no
                Author information
                http://orcid.org/0000-0002-3802-6690
                http://orcid.org/0000-0002-2628-0085
                http://orcid.org/0000-0002-1097-2562
                http://orcid.org/0000-0002-5561-4785
                http://orcid.org/0000-0002-0511-6112
                Article
                NIHMS1962206
                10.1113/JP284538
                10854476
                37128962
                740617b3-6f68-4f81-949f-e0cac707e8a9

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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                Categories
                Article

                Human biology
                cardiomyocytes,fetal development,ryanodine receptors,t-tubule,workload
                Human biology
                cardiomyocytes, fetal development, ryanodine receptors, t-tubule, workload

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