Increased calcium leak associated with reduced calsequestrin expression in hyperthyroid cardiomyocytes.

Area of Science:

• Cardiology
• Molecular Biology
• Physiology

Background:

• Diastolic calcium (Ca2+) leak via ryanodine receptors (RyRs) is crucial for cardiac function.
• Increased Ca2+ leak is implicated in hereditary arrhythmias.
• Little is known about Ca2+ leak and handling protein alterations in hyperthyroidism.

Purpose of the Study:

• Investigate modifications in diastolic Ca2+ leak in hyperthyroid rat cardiomyocytes.
• Examine changes in expression and activity of key Ca2+ handling proteins (RyRs, SERCA, calsequestrin).

Main Methods:

• ECG recordings in control and hyperthyroid rats.
• Confocal microscopy of Ca2+ sparks, waves, and transients in isolated cardiomyocytes.
• Biochemical assays for RyR binding, SERCA activity, and protein expression (Western blot, qPCR).

Main Results:

• Hyperthyroid rats exhibited extrasystoles and arrhythmogenic activity.
• Cardiomyocytes showed increased Ca2+ waves and wavelets without SR Ca2+ overload.
• Diastolic Ca2+ leak and arrhythmias correlated with decreased calsequestrin and increased SERCA pump activity.

Conclusions:

• Hyperthyroidism exacerbates diastolic Ca2+ leak and arrhythmogenic activity in cardiomyocytes.
• This is mediated by reduced calsequestrin and enhanced SERCA activity, leading to RyR gain-of-function.
• These changes contribute to the arrhythmogenic potential of hyperthyroidism.