Underlying mechanism of the contractile dysfunction in atrophied ventricular myocytes from a murine model of hypothyroidism. (June 2018)

• Record Type: Journal Article
• Authors: Montalvo, Dolores; Pérez-Treviño, Perla; Madrazo-Aguirre, Katheryne; González-Mondellini, Fabio A.; Miranda-Roblero, Hipólito O.; Ramonfaur-Gracia, Diego; Jacobo-Antonio, Mariana; Mayorga-Luna, Maritza; Gómez-Víquez, Norma. L.; García, Noemí; Altamirano, Julio
• Is Part Of: Cell calcium. Volume 72(2018)
• Page Start: 26
• Page End: 38
• Publication Date: 2018-06
• Subjects: α-MHC α-Myosin heavy chain -- β-MHC β-Myosin heavy chain -- β-AS β-adrenergic stimulation -- CICR Ca2+-induced Ca2+ release -- CL cell length -- CS citrate sintasa -- CV cell volume -- CW cell width -- CD contractile dysfunction -- Ctrl Control -- CSA cross-sectional area -- ΔF/F0 peak amplitude of field-stimulated cytosolic Ca2+ transient -- ΔFCaff/F0 peak amplitude of caffeine-evoked cytosolic Ca2+ transient -- Dmit mitochondrial density -- dRel/dt rate of SR Ca2+ release -- ECC excitation-contraction coupling -- FL femur length -- HF Heart failure -- HW heart weight -- Hypo hypothyroidism -- ISO isoproterenol -- ҡDecay rate of decay of the cytosolic Ca2+ transient -- λExc Emission wavelength -- λEmi Excitation wavelength -- LCC L-type Ca2+ channels -- ICa L-type Ca2+ channels current -- LVDP Left ventricular developed pressure -- +dLVP/dt maximum rate of rise of intraventricular pressure -- −dLVP/dt minimum rate of rise of intraventricular pressure -- MPI myocardium performance index -- PTU 6-propyl-2-thiouracil -- SR sarcoplasmic reticulum -- RyR2 ryanodine receptors type 2 -- SL saline solution -- SR sarcoplasmic reticulum -- PLB phospholamban -- PCr phosphocreatine -- TG thapsigargin -- T-Tubules Transverse Tubules -- TTPeriod T-Tubule period -- TTPower T-Tubule power -- T3 Triiodothyronine; SERCA -- Phospholamban -- Ryanodine receptors type 2 -- Transverse tubules -- Cardiac atrophy; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2018.01.005
• Languages: English
• ISSNs: 0143-4160

Abstract

Graphical abstract: Highlights: Within 3 weeks, hypothyroidism induced cardiac atrophy and contractile dysfunction. Blunted contractility was accompanied by slow SERCA due to reduced SERCA/PLB ratio. Staggered and blunted calcium transients and diminished diastolic calcium leak. Ventricular T-tubules, mitochondrial density and ATP availability were unchanged. Diminished calcium-dependent RyR2 sensitivity desynchronizes systolic SR release. Abstract: Hypothyroidism (Hypo) is a risk factor for cardiovascular diseases, including heart failure. Hypo rapidly induces Ca 2+ mishandling and contractile dysfunction (CD), as well as atrophy and ventricular myocytes (VM) remodeling. Hypo decreases SERCA-to-phospholamban ratio (SERCA/PLB), and thereby contributes to CD. Nevertheless, detailed spatial and temporal Ca 2+ cycling characterization in VM is missing, and contribution of other structural and functional changes to the mechanism underlying Ca 2+ mishandling and CD, as transverse tubules (T-T) remodeling, mitochondrial density (Dmit ) and energy availability, is unclear. Therefore, in a rat model of Hypo, we aimed to characterize systolic and diastolic Ca 2+ signaling, T-T remodeling, Dmit, citrate synthase (CS) activity and high-energy phosphate metabolites (ATP and phosphocreatine). We confirmed a decrease in SERCA/PLB (59%), which slowed SERCA activity (48%), reduced SR Ca 2+ (19%) and blunted Ca 2+ transient amplitude (41%). Moreover, assessing the rate of SR Ca 2+ release (dRel/dt), we found that early and maximum dRel/dt decreased, and this correlated with staggered Ca 2+ transients. However, dRel/dt persisted during Ca 2+ transient relaxation due to abundant late Ca 2+ sparks. Isoproterenol significantly up-regulated systolic Ca 2+ cycling. T-T were unchanged, hence, cannot explain staggered Ca 2+ transients and altered dRel/dt. Therefore, we suggest that these might be caused by RyR2 clusters desynchronization, due to diminished Ca 2+ -dependent sensitivity of RyR2, which also caused a decrease in diastolic SR Ca 2+ leak. Furthermore, Dmit was unchanged and CS activity slightly decreased (14%), however, the ratio phosphocreatine/ATP did not change, therefore, energy deficiency cannot account for Ca 2+ and contractility dysregulation. We conclude that decreased SR Ca 2+, due to slower SERCA, disrupts systolic RyR2 synchronization, and this underlies CD.