Super-Resolution 3D Imaging Reveals Disarray of Dyadic Calcium Ion Channels in Failing Hearts Expressing Low Thyroid...

Area of Science:

• Cardiology
• Cell Biology
• Molecular Biology

Background:

• Heart failure (HF) involves ventricular remodeling and structural disarray of T-tubule (TT)-sarcoplasmic reticulum (SR) junctions.
• This disruption impairs the close apposition of L-type Ca2+ channels (CaV1.2) and ryanodine receptors (RyR2), crucial for calcium release and myofilament contraction.
• Low thyroid hormone (TH) function is observed in a rat ischemic heart failure model, potentially exacerbating these issues.

Purpose of the Study:

• To investigate the impact of TH deficiency on the structural organization of cardiac T-tubules and dyadic ion channels in heart failure.
• To evaluate the therapeutic potential of T3 (active TH form) in preserving TT structure and dyadic ion channel organization during HF progression.
• To understand the role of junctophilin-2 (Jph2) in mediating these structural and functional changes.

Main Methods:

• Utilized a rat ischemic heart failure model with low TH function.
• Employed 3D stochastic optical reconstruction microscopy (STORM) to image RyR2 clusters, CaV1.2 channels, and Jph2.
• Confocal microscopy assessed T-tubule density using ANEPPS membrane dye in isolated cardiomyocytes (CMs).

Main Results:

• Diseased CMs exhibited significantly decreased TT density, while T3 treatment attenuated TT disorganization.
• Analysis revealed reduced RyR2 cluster size and number, with decreased Jph2 co-localization in failing CMs.
• T3 treatment showed a trend towards increased RyR2 cluster numbers and volumes, with enhanced Jph2 co-clustering, and improved CaV1.2 co-localization.

Conclusions:

• Maintaining TH homeostasis is crucial for optimizing the nanoscale organization of Ca2+ ion channels in cardiomyocytes.
• Proper organization of CaV1.2 and RyR2 at dyadic junctions is vital for triggering Ca2+ release and myofibrillar contraction.
• TH therapy may offer a strategy to improve cardiac function by preserving dyadic structure in heart disease.