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.
