Impact of Mitochondrial Organisation on Cardiac Bioenergetics and Force Dynamics in Diabetic Myocardium

Abstract

The global prevalence of type 2 diabetes (T2D) remains substantial. T2D is characterised by insulin resistance and is associated with altered cardiac mitochondrial ultrastructure and cellular metabolism. However, it is unclear how these impairments collectively affect cardiac bioenergetics and force dynamics at the cell and tissue levels. To uncover this uncertainty, T2D was induced in rats with a 13-week high-fat (23.5%) diet and a single low-dose (27.5 mg/kg) injection of streptozotocin. Left-ventricular wall tissues and trabeculae were dissected, respectively, for evaluation of ultrastructure and force production. Wall tissue samples were fixed, heavy metal stained, and resin-embedded. They were imaged using transmission electron microscopy (TEM) to quantify mitochondrial and myofibril ultrastructure within cardiomyocytes. We found a significantly lower mitochondrial fractional area (15%) and a complementary higher myofibrillar fractional area (15%) in the diabetic tissues. These structural findings were not translatable to the functional performance at the trabecula level, where isometric force production was found to be preserved in diabetes. We thus combined structural image analysis and computational modelling in an attempt to explain these structure-function inconsistencies. We developed cell-specific finite element models of cardiomyocyte ultrastructure based on our TEM images. We embedded a model of mitochondrial respiration within our structural cell models, parameterised using data collected from oxidative phosphorylation experiments, and a model of cross-bridge contraction. We used the integrated model to explore whether observed diabetes-induced alterations in mitochondrial organisation and respiration can reach the threshold for inducing contractile dysfunction. Our simulation results reveal that mitochondrial structural derangement and depressed respiration led to larger gradients of metabolite concentrations across the diabetic cell. However, these alterations are not sufficient to bring about contractile dysfunction in diabetes.