Triiodothyronine Maintains Cardiac Transverse-Tubule Structure and Function

Gilani, N., Wang, K., Muncan, A., Peter, J., An, S., Bhatti, S., Pandya, K., Zhang, Y., Tang, Y.-D., Gerdes, A. M., Stout, R. F., & Ojamaa, K.

Triiodothyronine Maintains Cardiac Transverse-Tubule Structure and Function

2021

Elsevier BV

Animals
Ca(2+)
Calcium Channels, L-Type metabolism
Calcium Signaling drug effects
Calcium metabolism
Cells, Cultured
Disease Models, Animal
Female
Gene Expression
Heart Ventricles drug effects metabolism
Hypothyroidism blood chemically induced drug therapy
Index Medicus
Junctophilin-2
Membrane Proteins genetics metabolism
Myocytes, Cardiac metabolism
Rats
Ryanodine Receptor Calcium Release Channel metabolism
Ryanodine receptors
STORM
SY7Q814VUP
Sarcolemma metabolism
Sarcomeres metabolism
Thyroid hormone
Transverse-tubules
Treatment Outcome
Triiodothyronine administration & dosage blood
Ventricular Function drug effects

English

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.

Journal of Molecular and Cellular Cardiology, Volume 160, November 2021, pages 1-14

Copyright © 2021 The Authors

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