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

Hypothyroidism (Hypo) is a risk factor for cardiovascular diseases, including heart failure. Hypo rapidly induces Ca 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 cycling characterization in VM is missing, and contribution of other structural and functional changes to the mechanism underlying Ca mishandling and CD, as transverse tubules (T-T) remodeling, mitochondrial density (D) and energy availability, is unclear. Therefore, in a rat model of Hypo, we aimed to characterize systolic and diastolic Ca signaling, T-T remodeling, D, 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 (19%) and blunted Ca transient amplitude (41%). Moreover, assessing the rate of SR Ca release (dRel/dt), we found that early and maximum dRel/dt decreased, and this correlated with staggered Ca transients. However, dRel/dt persisted during Ca transient relaxation due to abundant late Ca sparks. Isoproterenol significantly up-regulated systolic Ca cycling. T-T were unchanged, hence, cannot explain staggered Ca transients and altered dRel/dt. Therefore, we suggest that these might be caused by RyR2 clusters desynchronization, due to diminished Ca-dependent sensitivity of RyR2, which also caused a decrease in diastolic SR Ca leak. Furthermore, D was unchanged and CS activity slightly decreased (14%), however, the ratio phosphocreatine/ATP did not change, therefore, energy deficiency cannot account for Ca and contractility dysregulation. We conclude that decreased SR Ca, due to slower SERCA, disrupts systolic RyR2 synchronization, and this underlies CD.