Regulation of Cardiomyocyte T-Tubular Structure: Opportunities for Therapy

Manfra, Ornella; Frisk, Michael; Louch, William E.

doi:10.1007/s11897-017-0329-9

Cited by 42 publications

(50 citation statements)

References 120 publications

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“…; Manfra et al . ), we observed here that this structural reorganization shows reversion to an immature phenotype. During HF, t‐tubule changes specifically include loss of transverse elements and an increasing density of longitudinal elements, features which are robustly present in developing cells (Fig.…”

Section: Resultssupporting

confidence: 65%

“…; Manfra et al . ). Plasticity of t‐tubule structure is also supported by previous work examining effects of cardiac resynchronization therapy (Sachse et al .…”

Section: Discussionmentioning

confidence: 97%

“…; Manfra et al . ). We and others have shown that considerable reorganization of the t‐tubule network during heart failure (HF) is linked to slower, more dyssynchronous Ca 2+ release and weaker contraction (Louch et al .…”

Section: Introductionmentioning

confidence: 97%

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Cardiomyocyte substructure reverts to an immature phenotype during heart failure

Lipsett

Frisk

Aronsen

et al. 2019

The Journal of Physiology

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Key points As reactivation of the fetal gene program has been implicated in pathological remodelling during heart failure (HF), we examined whether cardiomyocyte subcellular structure and function revert to an immature phenotype during this disease. Surface and internal membrane structures appeared gradually during development, and returned to a juvenile state during HF. Similarly, dyadic junctions between the cell membrane and sarcoplasmic reticulum were progressively ‘packed’ with L‐type Ca2+ channels and ryanodine receptors during development, and ‘unpacked’ during HF. Despite similarities in subcellular structure, dyads were observed to be functional from early developmental stages, but exhibited an impaired ability to release Ca2+ in failing cardiomyocytes. Thus, while immature and failing cardiomyocytes share similarities in subcellular structure, these do not fully account for the marked impairment of Ca2+ homeostasis observed in HF. Abstract Reactivation of the fetal gene programme has been implicated as a driver of pathological cardiac remodelling. Here we examined whether pathological remodelling of cardiomyocyte substructure and function during heart failure (HF) reflects a reversion to an immature phenotype. Using scanning electron microscopy, we observed that Z‐grooves and t‐tubule openings at the cell surface appeared gradually during cardiac development, and disappeared during HF. Confocal and super‐resolution imaging within the cell interior revealed similar structural parallels; disorganization of t‐tubules in failing cells was strikingly reminiscent of the late stages of postnatal development, with fewer transverse elements and a high proportion of longitudinal tubules. Ryanodine receptors (RyRs) were observed to be laid down in advance of developing t‐tubules and similarly ‘orphaned’ in HF, although RyR distribution along Z‐lines was relatively sparse. Indeed, nanoscale imaging revealed coordinated packing of L‐type Ca2+ channels and RyRs into dyadic junctions during development, and orderly unpacking during HF. These findings support a ‘last in, first out’ paradigm, as the latest stages of dyadic structural development are reversed during disease. Paired imaging of t‐tubules and Ca2+ showed that the disorganized arrangement of dyads in immature and failing cells promoted desynchronized and slowed Ca2+ release in these two states. However, while developing cells exhibited efficient triggering of Ca2+ release at newly formed dyads, dyadic function was impaired in failing cells despite similar organization of Ca2+ handling proteins. Thus, pathologically deficient Ca2+ homeostasis during HF is only partly linked to the re‐emergence of immature subcellular structure, and additionally reflects lost dyadic functionality.

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Section: Resultssupporting

confidence: 65%

“…; Manfra et al . ). Plasticity of t‐tubule structure is also supported by previous work examining effects of cardiac resynchronization therapy (Sachse et al .…”

Section: Discussionmentioning

confidence: 97%

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Cardiomyocyte substructure reverts to an immature phenotype during heart failure

Lipsett

Frisk

Aronsen

et al. 2019

The Journal of Physiology

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“…Notably, maturation on Matrigel mattress was required for t-tubule formation, as T3+Dex treated cells plated without thick Matrigel mattress were not different from control cells (Figure 1B). Cellular staining for bridging-integrator 1 (BIN1), junctophilin-2 (JP2), and caveolin-3 (Cav3), three regulators of t-tubule genesis 16, 17 , demonstrated striking changes in their subcellular localization. Whereas these t-tubule markers were located mostly perinuclear in vehicle-treated cells, after T3+Dex treatment staining was much more prominent throughout the whole cell (Online Figure IA).…”

Section: Resultsmentioning

confidence: 99%

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

Parikh

Blackwell

Gómez-Hurtado³

et al. 2017

Circulation Research

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307

229

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Rationale 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 (EC) coupling, and inefficient Ca-induced Ca release (CICR) remain major limitations. Objective Thyroid and glucocorticoid hormones are critical for heart maturation. We hypothesized that their addition to standard protocols would promote t-tubule development and mature EC coupling of hiPSC-CM when cultured on extracellular matrix with physiological stiffness (Matrigel mattress). Methods and Results HiPSC-CM were generated using a standard chemical differentiation method supplemented with triiodo-L-thyronine (T3) and/or dexamethasone (Dex) during days 16–30 followed by single-cell culture for 5 days on Matrigel mattress. HiPSC-CM treated with T3+Dex, but not with either T3 or Dex alone, developed an extensive t-tubule network. Notably, Matrigel mattress was necessary for t-tubule formation. Compared to adult human ventricular CM, t-tubules in T3+Dex-treated hiPSC-CM were less organized and had more longitudinal elements. Confocal line scans demonstrated spatially and temporally uniform Ca release that is characteristic of EC coupling in the heart ventricle. T3+Dex enhanced elementary Ca release measured by Ca sparks as well as promoted ryanodine receptor (RyR2) structural organization. Simultaneous measurements of L-type Ca current and intracellular Ca release confirmed enhanced functional coupling between L-type Ca channels and RyR2 in T3+Dex cells. Conclusions Our results suggest a permissive role of combined thyroid and glucocorticoid hormones during the cardiac differentiation process which, when coupled with further maturation on Matrigel mattress, is sufficient for t-tubule development, enhanced CICR, and more ventricular-like EC coupling. This new hormone maturation method could advance the utility of hiPSC-CM for disease modeling and cell-based therapy.

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“…Then, depolarization triggers L‐type calcium channel (LTCC) opening and extracellular calcium entry into the cell, increasing the number of intracellular calcium ions . Increased intracellular Ca 2+ activates ryanodine receptors (RyRs) to release a large number of Ca 2+ from the intracellular sarcoplasmic reticulum (SR) store, and this process is called calcium‐induced calcium release (CICR) . This process depends on subcellular structures called dyads, where invaginations of the surface membrane, or transverse tubules (T‐tubules), form functional junctions with the SR. Dyads can exhibit compensatory remodelling when they are required to promote impaired contractility and arrhythmogenesis in cardiac disease .…”

Section: Introductionmentioning

confidence: 99%

Effect of BIN1 on cardiac dysfunction and malignant arrhythmias

et al. 2019

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Heart failure (HF) is the end‐stage syndrome for most cardiac diseases, and the 5‐year morbidity and mortality of HF remain high. Malignant arrhythmia is the main cause of sudden death in the progression of HF. Recently, bridging integrator 1 (BIN1) was discovered as a regulator of transverse tubule function and calcium signalling in cardiomyocytes. BIN1 downregulation is linked to abnormal cardiac contraction, and it increases the possibility of malignant arrhythmias preceding HF. Because of the detectability of cardiac BIN1 in peripheral blood, BIN1 may serve as a predictor of HF and may be useful in therapy development. However, the mechanism of BIN1 downregulation in HF and how BIN1 regulates normal cardiac function under physiological conditions remain unclear. In this review, recent progress in the biological studies of BIN1‐related cardiomyocytes and the effect of cardiac dysfunction and malignant arrhythmia will be discussed.

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Regulation of Cardiomyocyte T-Tubular Structure: Opportunities for Therapy

Cited by 42 publications

References 120 publications

Cardiomyocyte substructure reverts to an immature phenotype during heart failure

Cardiomyocyte substructure reverts to an immature phenotype during heart failure

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

Effect of BIN1 on cardiac dysfunction and malignant arrhythmias

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