Impact of detubulation on force and kinetics of cardiac muscle contraction

Ferrantini, Cecilia; Coppini, Raffaele; Sacconi, Leonardo; Tosi, Benedetta; Zhang, Mei Luo; Wang, Guoliang; Vries, Ewout de; Hoppenbrouwers, Ernst; Pavone, Francesco S.; Cerbai, Elisabetta; Tesi, Chiara; Poggesi, Corrado; Keurs, H. E. D. J. Ter

doi:10.1085/jgp.201311125

Cited by 48 publications

(105 citation statements)

References 55 publications

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“…T-tubular loss was considered a main contributor to these Ca 2+ transients abnormalities (7), resulting in a weaker and slower contraction (5,32). Here we find a global delay of Ca 2+ transient occurring even close to electrically coupled TTs.…”

Section: Discussionmentioning

confidence: 52%

Defects in T-tubular electrical activity underlie local alterations of calcium release in heart failure

Crocini¹,

Coppini

Ferrantini

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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110

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Action potentials (APs), via the transverse axial tubular system (TATS), synchronously trigger uniform Ca 2+ release throughout the cardiomyocyte. In heart failure (HF), TATS structural remodeling occurs, leading to asynchronous Ca 2+ release across the myocyte and contributing to contractile dysfunction. In cardiomyocytes from failing rat hearts, we previously documented the presence of TATS elements which failed to propagate AP and displayed spontaneous electrical activity; the consequence for Ca 2+ release remained, however, unsolved. Here, we develop an imaging method to simultaneously assess TATS electrical activity and local Ca 2+ release. In HF cardiomyocytes, sites where T-tubules fail to conduct AP show a slower and reduced local Ca 2+ transient compared with regions with electrically coupled elements. It is concluded that TATS electrical remodeling is a major determinant of altered kinetics, amplitude, and homogeneity of Ca 2+ release in HF. Moreover, spontaneous depolarization events occurring in failing T-tubules can trigger local Ca 2+ release, resulting in Ca 2+ sparks. The occurrence of tubuledriven depolarizations and Ca 2+ sparks may contribute to the arrhythmic burden in heart failure.cardiac disease | voltage imaging | calcium imaging | nonlinear microscopy

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Section: Discussionmentioning

confidence: 52%

Defects in T-tubular electrical activity underlie local alterations of calcium release in heart failure

Crocini¹,

Coppini

Ferrantini

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

110

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“…Ion transport is important for cardiac muscle contraction (28), which can be affected by cranial radiotherapy in individuals that survived childhood cancer (29). In the present study, the DEGs involved in the aforementioned processes were significantly upregulated by radiotherapy, suggesting the effects of radiotherapy on cardiac muscle contraction.…”

Section: Discussionsupporting

confidence: 48%

Identification of molecular characteristics induced by radiotherapy in rectal cancer based on microarray data

Chen

et al. 2017

Oncology Letters

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Abstract. The present study aimed to reveal the molecular characteristics induced by radiotherapy in rectal cancer at the transcriptome level. Microarray data (ID, GSE26027) downloaded from the Gene Expression Omnibus database were re-analyzed to identify differentially expressed genes (DEGs) between rectal cancer tissues during and prior to radiotherapy. The DEGs were then inputted into the database for annotation, visualization and integrated discovery, an online tool to perform enrichment analyses, and into the search tool for the retrieval of interacting genes/proteins database to identify protein-protein interactions (PPIs). Subsequently, a PPI network was constructed, which was screened for densely connected modules. Furthermore, protein domain enrichment analysis was performed. In total, 690 DEGs, including 179 upregulated and 511 downregulated DEGs, were found in rectal cancer tissues during and prior to radiotherapy. The upregulated DEGs were significantly enriched in 'positive regulation of transport' and 'regulation of cardiac muscle contraction', while the downregulated DEGs were most markedly enriched in 'cell migration', 'cell-cell signaling', 'extracellular matrix organization' and 'blood vessel development', including prostaglandin-endoperoxide synthase 2, transforming growth factor β-induced, 68 kDa endothelin receptor type A, brain-derived neurotrophic factor, TIMP metallopeptidase inhibitor 1, and serpin family E member 1, which were the top 6 hub nodes in the PPI network. Furthermore, 2 protein domains were significantly enriched by PPI modules, including: The collagen triple helix repeat (CTHR) family members collagen type (COL) 5A2, COL9A3, COL6A3, COL21A1, COL5A3, COL11A1, COL7A1 and CTHR-containing-1; and the olfactory receptor family (OR) members OR7E24, OR7A17, OR6A2, OR1F1, OR10H3 and OR7A10. A total of 7 upregulated DEGs were characterized as tumor suppressor genes, and 8 downregulated DEGs were characterized as oncogenes. The biological processes or protein domains enriched by upregulated or downregulated DEGs may improve the understanding of molecular characteristics in response to radiotherapy.

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“…Isolated cardiomyocytes are gradually readapted to calcium, adding steps of 50 or 100 μM CaCl 2 every 5-8 min, until a concentration of 0.5 mM CaCl 2 is reached. Detubulation is induced by osmotic shock as previously described (8,9). Briefly, 1.5 M formamide is added to the cell suspension for 15-20 min; the cells are then resuspended rapidly in standard solution (CaCl 2 -free).…”

Section: Methodsmentioning

confidence: 99%

“…Finally, in view of the formal analogy that exists between diffusion and electrical conduction, the apparent diffusion coefficient is linked to the effective electrical conductivity of the network. The methodology is first validated using an acutely detubulated cellular model (8,9) and then applied to assessing the effective electrical conductivity in diseased cardiomyocytes where structural (10) and functional (11)(12)(13)(14)(15) defects of the TATS have been described.…”

Section: Significancementioning

confidence: 99%

Quantitative assessment of passive electrical properties of the cardiac T-tubular system by FRAP microscopy

Scardigli

Crocini

Ferrantini

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Well-coordinated activation of all cardiomyocytes must occur on every heartbeat. At the cell level, a complex network of sarcolemmal invaginations, called the transverse-axial tubular system (TATS), propagates membrane potential changes to the cell core, ensuring synchronous and uniform excitation-contraction coupling. Although myocardial conduction of excitation has been widely described, the electrical properties of the TATS remain mostly unknown. Here, we exploit the formal analogy between diffusion and electrical conductivity to link the latter with the diffusional properties of TATS. Fluorescence recovery after photobleaching (FRAP) microscopy is used to probe the diffusion properties of TATS in isolated rat cardiomyocytes: A fluorescent dextran inside TATS lumen is photobleached, and signal recovery by diffusion of unbleached dextran from the extracellular space is monitored. We designed a mathematical model to correlate the time constant of fluorescence recovery with the apparent diffusion coefficient of the fluorescent molecules. Then, apparent diffusion is linked to electrical conductivity and used to evaluate the efficiency of the passive spread of membrane depolarization along TATS. The method is first validated in cells where most TATS elements are acutely detached by osmotic shock and then applied to probe TATS electrical conductivity in failing heart cells. We find that acute and pathological tubular remodeling significantly affect TATS electrical conductivity. This may explain the occurrence of defects in action potential propagation at the level of single T-tubules, recently observed in diseased cardiomyocytes.cardiac disease | transverse-axial tubular system | diffusion | electrical conductivity | porous rock T he sequential and coherent recruitment of all cardiomyocytes that occurs on every heartbeat is fundamental for proper contraction of the heart. Every heartbeat is triggered by a depolarizing event, the action potential (AP), spontaneously generated in cardiac pacemaker cells, which propagates through the conductive tissue and the working myocardium. The well-coordinated activation of all cardiomyocytes involves a spreading AP wave, conducted from cell to cell throughout the lattice of interconnections called gap junctions. The 3D electrical network of cardiomyocytes includes a finer order of complexity that involves a system of deep sarcolemmal membrane invaginations within each cell. As a network within a network, these sarcolemmal invaginations occur transversely with a periodicity roughly corresponding to that of sarcomere z-lines (transverse tubules, or T-tubules) and branch in the longitudinal direction (axial tubules) to form a complex system in atrial and ventricular cells, named the transverse-axial tubular system (TATS) (1, 2). The TATS allows membrane potential changes to propagate rapidly into the cardiomyocyte core and is considered an ultimate structural player for excitation-contraction coupling. During rapid depolarization, such as seen during the AP, Ca 2+ enters the cytos...

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Impact of detubulation on force and kinetics of cardiac muscle contraction

Abstract: T-tubule uncoupling from the plasma membrane leads to myocardial contractile abnormalities.

Cited by 48 publications

References 55 publications

Defects in T-tubular electrical activity underlie local alterations of calcium release in heart failure

Defects in T-tubular electrical activity underlie local alterations of calcium release in heart failure

Identification of molecular characteristics induced by radiotherapy in rectal cancer based on microarray data

Quantitative assessment of passive electrical properties of the cardiac T-tubular system by FRAP microscopy

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