Adverse transverse-tubule remodeling in a rat model of heart failure is attenuated with low-dose triiodothyronine treatment

An, Shimin; Gilani, Nimra; Huang, Yuan; Muncan, Adam; Zhang, Youhua; Tang, Yi-Da; Gerdes, A. Martin; Ojamaa, Kaie

doi:10.1186/s10020-019-0120-3

Cited by 10 publications

(10 citation statements)

References 66 publications

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“…A stream of evidence from human [1][2][3][4] and animal [5][6][7][8][9] studies has led to the prevailing recognition that the disorganization of the network of the transverse tubules (t-tubules) is a major contributor to many forms of heart failure. [10][11][12] In healthy myocardium, t-tubules are a highly organized network of invaginations of the cell surface membrane.…”

Section: Introductionmentioning

confidence: 99%

Disruption of transverse‐tubular network reduces energy efficiency in cardiac muscle contraction

et al. 2020

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Aim Altered organization of the transverse‐tubular network is an early pathological event occurring even prior to the onset of heart failure. Such t‐tubular remodelling disturbs the synchrony and signalling between membranous and intracellular ion channels, exchangers, receptors and ATPases essential in the dynamics of excitation‐contraction coupling, leading to ionic abnormality and mechanical dysfunction in heart disease progression. In this study, we investigated whether a disrupted t‐tubular network has a direct effect on cardiac mechano‐energetics. Our aim was to understand the fundamental link between t‐tubular remodelling and impaired energy metabolism, both of which are characteristics of heart failure. We thus studied healthy tissue preparations in which cellular processes are not altered by any disease event. Methods We exploited the “formamide‐detubulation” technique to acutely disrupt the t‐tubular network in rat left‐ventricular trabeculae. We assessed the energy utilization by cellular Ca2+ cycling and by crossbridge cycling, and quantified the change of energy efficiency following detubulation. For these measurements, trabeculae were mounted in a microcalorimeter where force and heat output were simultaneously measured. Results Following structural disorganization from detubulation, muscle heat output associated with Ca2+ cycling was reduced, indicating impaired intracellular Ca2+ homeostasis. This led to reduced force production and heat output by crossbridge cycling. The reduction in force‐length work was not paralleled by proportionate reduction in the heat output and, as such, energy efficiency was reduced. Conclusions These results reveal the direct energetic consequences of disrupted t‐tubular network, linking the energy disturbance and the t‐tubular remodelling typically observed in heart failure.

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Section: Introductionmentioning

confidence: 99%

Disruption of transverse‐tubular network reduces energy efficiency in cardiac muscle contraction

et al. 2020

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“…After 8 weeks of PTU treatment, rats were randomly assigned to continued PTU treatment (PTU group) or received triiodo-L-thyronine (T3; SigmaAldrich; St Louis, MO) in PTU-containing drinking water for an additional 2 weeks (PTU + T3 group). Stock T3 was prepared by dissolving in an ethanol/glycerol solution and then diluted in drinking water at a concentration calculated to deliver 10 μg/kg/d based on weekly measurements of body weight and water consumption as we previously published [20,34]. Control rats (euthyroid, EU group) consumed untreated water.…”

Section: Animal Model and Treatment Protocolsmentioning

confidence: 99%

“…As we have previously published [20], live cardiomyocytes adhered to laminin-coated glass coverslips were incubated with wheat germ agglutinin-conjugated to Alexa-488 (WGA-488; Molecular Probes) (5 μg/ml in HBSS, 10 mM BDM; Gibco, Life Technologies; ThermoFisher Scientific) for 20 min. at 37 • C, and then washed to remove unbound WGA-488.…”

Section: T-tubule Organization Imaged By Confocal Microscopymentioning

confidence: 99%

“…The higher the TT power value, the greater the TT organization (TTorg software is available as a plug-in on ImageJ [36]). Additionally as previously published [20], live cardiomyocytes adhered to glass bottom 35 mm culture dishes (Mat-Tek Corp., Ashland, MA) were stained with di-8-ANEPPS (5 μM in HBSS with BDM; Biotium Inc., Fremont, CA) for 20 min. at 37 • C. Live cells were imaged under oil immersion 63× objective of a DMI6000 SP5 Leica confocal microscope.…”

Section: T-tubule Organization Imaged By Confocal Microscopymentioning

confidence: 99%

“…Studies have documented that THs hormones promote transverse tubule (TT) development in induced pluripotent stem cells (iPSC)-derived cardiomyocytes and engineered heart tissue, thus promoting functional excitation-contraction (EC) coupling and dyadic organization of L-type Ca 2+ channels (LTCC) and ryanodine receptors (RyR2) [18,19]. Our recent studies have shown that low-dose T3 treatment of rats exhibiting heart failure induced by MI, attenuated TT disorganization observed in untreated HF animals, and that T3 normalized Ca 2+ transients and contractility [20]. T3 treatment also normalized expression of bridging integrator-1 (BIN1) and junctophilin (Jph2), two structural proteins that function to bridge SR and TT to produce functional dyads and efficient EC coupling [21,22].…”

Section: Introductionmentioning

confidence: 99%

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Triiodothyronine maintains cardiac transverse-tubule structure and function

Gilani

Wang

Muncan

et al. 2021

Journal of Molecular and Cellular Cardiology

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Subclinical hypothyroidism and low T3 syndrome are commonly associated with an increased risk of cardiovascular disease (CVD) and mortality. We examined effects of T3 on T-tubule (TT) structures, Ca 2+ mobilization and contractility, and clustering of dyadic proteins.Thyroid hormone (TH) deficiency was induced in adult female rats by propyl-thiouracil (PTU; 0.025%) treatment for 8 weeks. Rats were then randomized to continued PTU or triiodo-L-thyronine (T3; 10 μg/kg/d) treatment for 2 weeks (PTU + T3). After in vivo echocardiographic and hemodynamic recordings, cardiomyocytes (CM) were isolated to record Ca 2+ transients and contractility. TT organization was assessed by confocal microscopy, and STORM images were captured to measure ryanodine receptor (RyR2) cluster number and size, and L-type Ca 2+ channel (LTCC, Ca v 1.2) co-localization. Expressed genes including two integral TT proteins, junctophilin-2 (Jph-2) and bridging integrator-1 (BIN1), were analyzed in left ventricular (LV) tissues and cultured CM using qPCR and RNA sequencing. The T3 dosage used normalized serum T3, and reversed adverse effects of TH deficiency on in vivo measures of cardiac function. Recordings of isolated CM indicated that T3 increased rates of Ca 2+ release and re-uptake, resulting in increased velocities of sarcomere shortening and re-lengthening. TT periodicity was significantly decreased, with reduced transverse tubules but increased longitudinal tubules in TH-deficient CMs and LV tissue, and these structures were normalized by T3 treatment. Analysis of STORM data of PTU myocytes showed decreased RyR2 cluster numbers and RyR localizations within each cluster without significant changes in Ca v 1.2 localizations within RyR clusters. T3 treatment normalized RyR2 cluster size and number. qPCR and RNAseq analyses of LV and cultured CM showed that Jph2 expression was T3-responsive, and its increase with treatment may explain improved TT organization and RyR-LTCC coupling.

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Thyroid Hormone Signaling Mechanisms in the Heart and Vasculature

Ojamaa

Carrillo-Sepúlveda

2020

Thyroid and Heart

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Adverse transverse-tubule remodeling in a rat model of heart failure is attenuated with low-dose triiodothyronine treatment

Cited by 10 publications

References 66 publications

Disruption of transverse‐tubular network reduces energy efficiency in cardiac muscle contraction

Disruption of transverse‐tubular network reduces energy efficiency in cardiac muscle contraction

Triiodothyronine maintains cardiac transverse-tubule structure and function

Thyroid Hormone Signaling Mechanisms in the Heart and Vasculature

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