Type 2 Diabetes disrupts T-tubule and RyR2 organisation in male but not female rat ventricular muscle

Authors:

Maryam Rahmani, Andrew J. Taberner, Kenneth Tran, David J. Crossman, June-Chiew Han

Keywords:

Type 2 Diabetes; T-tubule organisation; RyR2 organisation; ventricular muscle; cardiovascular; cardiac excitation-contraction coupling proteins; myocardial ECC structures;

Abstract:

Females with diabetes often experience more severe cardiovascular outcomes than males with diabetes. It is unclear whether these sex-specific outcomes are rooted in distinct cellular alterations of key cardiac excitation-contraction coupling (ECC) proteins, specifically transverse tubules (T-tubules), ryanodine receptors (RyR2), and filamentous actin (F-actin). This study investigated myocardial ECC structures in both sexes under type 2 diabetic conditions and measured cardiac functional outcomes at muscle level. Type 2 diabetes was induced in male and female Wistar rats using a high-fat diet and low-dose streptozotocin protocol. Left ventricular trabeculae were isolated and subjected to mechano calorimetric experiments to quantify heat output and twitch force production. The same trabeculae were imaged using high-resolution Stimulated Emission Depletion (STED) microscopy to assess structural organisations of the T-tubule, RyR2, and F-actin. Diabetic rats of both sexes developed hyperglycaemia and glucose intolerance, without evidence of ventricular hypertrophy. Mechano energetic indices including activation heat, crossbridge economy, and twitch force kinetics were unaffected by diabetes in either sex. F-actin organisation was not affected by diabetes. However, compared with their respective controls, diabetic males, but not diabetic females, exhibited structural differences in cardiac ECC proteins: reduced T-tubule area and skeleton length, and enlarged RyR2 clusters and Calcium Release Units (CRU) with increased RyR2 density. These results show that structural reorganisation of cardiac RyR2 proteins occurred in diabetic males and not females, despite absence of ventricular hypertrophy and mechano-energetic dysfunction in the muscles of these two groups.

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