Impaired Ca2+ handling and contraction in cardiomyocytes from mice with a dominant negative thyroid hormone receptor α1

Abstract: The profound effects of thyroid hormone (TH) on heart development and function are mediated by the thyroid hormone receptors (TR) α1 and β1. While numerous patients with TRβ1 mutations have been identified, patients with similar mutations in TRα1 are yet to be discovered. Recently generated heterozygous mice with a dominant negative mutation in TRα1 (TRα1+/m mice) have normal TH levels, which may have hampered the discovery of patients with such mutations. We now measure intracellular Ca2+ and contraction in cardiomyocytes isolated from TRα1+/m mice and wildtype littermates (WT). TRα1+/m cardiomyocytes showed a phenotype similar to that in hypothyroidism with significant slowing of voltage-activated Ca2+ transients and contractions. Increased stimulation frequency (from 0.5 to 3 Hz) or β-adrenergic stimulation reduced the differences between TRα1+/m and WT cardiomyocytes. However, in TRα1+/m cells stimulation at 3 Hz gave a marked increase in diastolic Ca2+ and β-adrenergic stimulation triggered spontaneous Ca2+ release events during relaxation. Both TRα1+/m and WT cardiomyocytes responded to TH treatment by displaying a “hyperthyroid” phenotype with faster and larger Ca2+ transients and contractions. Excised TRα1+/m hearts showed an increased expression of phospholamban (PLB). In conclusion, isolated TRα1+/m cardiomyocytes display major dysfunctions with marked slowing of the Ca2+ transients and contractions. [Copyright &y& Elsevier]