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

Pasi Tavi1, Maria Sjögren, Per Kristian Lunde

  • 1Department of Physiology and Pharmacology, Karolinska Institute, SE-171 77 Stockholm, Sweden.

Journal of Molecular and Cellular Cardiology
|April 6, 2005
PubMed

Insights

Thyroid hormone receptor alpha 1 (TRalpha1) mutations cause heart dysfunction, mimicking hypothyroidism. TRalpha1+m mice show slowed cardiomyocyte contractions and calcium transients, revealing critical roles for TRalpha1 in cardiac function.

Area of Science:

  • Cardiology
  • Endocrinology
  • Molecular Biology

Background:

  • Thyroid hormone (TH) profoundly impacts cardiac development and function via thyroid hormone receptors (TR) alpha(1) and beta(1).
  • While TRbeta(1) mutations are documented in patients, TRalpha(1) mutations remain undiscovered, potentially due to normal TH levels in affected individuals.
  • TRalpha(1)+/m mice possess a dominant-negative TRalpha(1) mutation, offering a model to study TRalpha(1) function in vivo.

Purpose of the Study:

  • To investigate the functional consequences of a dominant-negative TRalpha(1) mutation on cardiomyocyte calcium (Ca2+) handling and contractility.
  • To compare the cardiac phenotype of TRalpha(1)+/m mice with wildtype (WT) littermates and assess responses to varying stimulation frequencies and beta-adrenergic stimulation.
  • To elucidate the role of TRalpha(1) in regulating cardiac function and identify potential therapeutic targets.

Main Methods:

  • Isolation and functional assessment of cardiomyocytes from TRalpha(1)+/m mice and WT littermates.
  • Measurement of intracellular Ca2+ transients and cell shortening (contractions) under various stimulation conditions (frequency, beta-adrenergic stimulation).
  • Assessment of TH treatment effects and analysis of phospholamban (PLB) expression in excised hearts.

Main Results:

  • TRalpha(1)+/m cardiomyocytes exhibited significantly slowed Ca2+ transients and contractions, mirroring a hypothyroid phenotype.
  • Increased stimulation frequency or beta-adrenergic stimulation partially normalized differences but induced diastolic Ca2+ abnormalities and spontaneous Ca2+ release in TRalpha(1)+/m cells.
  • TH treatment normalized cardiac function in both TRalpha(1)+/m and WT cardiomyocytes, while TRalpha(1)+/m hearts showed increased PLB expression.

Conclusions:

  • Isolated TRalpha(1)+/m cardiomyocytes display significant functional deficits, characterized by impaired Ca2+ handling and contractility.
  • These findings highlight the critical role of TRalpha(1) in maintaining normal cardiac electrophysiology and contractility.
  • The TRalpha(1)+/m mouse model provides valuable insights into TRalpha(1)-mediated cardiac dysfunction and potential therapeutic strategies.

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