Role of ultrastructural alterations in diabetic cardiomyopathy
Document TypePhD thesis
Access StatusOpen Access
© 2019 Dr. Shouryadipta Ghosh
Cardiomyocytes inside the heart are densely packed with parallel columns of myofibrils and mitochondria. Growing evidence indicates a strong correlation between alterations in this sub-cellular ultrastructure and the alterations in energy metabolism during various pathological conditions of heart. The central hypothesis explored in this thesis is that changes in cardiac sub-cellular architecture in pathological conditions can also affect cardiac bioenergetics by interfering with various mechanisms of intracellular energy transport. Type 1 diabetic cardiomyopathy is an ideal candidate for a model disease state to understand this hypothesized interplay between ultrastructure and metabolism. It exhibits many common conditions which accompany heart failure, such as increased mitochondrial reactive oxygen species production and decreased reserve of creatine phosphate. In a preliminary study, 2D electron microscope images collected from control and streptozotocin induced type I diabetic rat hearts were analysed. It was found that diabetic cardiomyopathy leads to an increased mitochondrial fission and formation of large mitochondrial clusters. Further analysis showed that effective surface-to-volume ratio of mitochondrial clusters increases by 22.5% in diabetic cells. Subsequently, a compartmental model of cardiac energy transfer was developed. This simple model predicted that this increase in the surface-to-volume ratio can have a moderate compensatory effect by elevating the availability of adenosine triphosphate (ATP) in the cytosol when ATP synthesis within the mitochondria is compromised. Next, 3D electron microscope images from control animals were investigated. The analysis revealed that cardiac mitochondria are arranged non-uniformly in parallel columns of varying sizes. Following this, the compartmental model was extended to a reaction diffusion based 2D finite element model incorporating a realistic description of the observed sub-cellular ultrastructure. The new model predicted that rapid diffusion of creatine and creatine phosphate acts to maintain homogenous ATP distribution and uniform force dynamics in the control cardiomyocytes, despite the heterogeneous mitochondrial organization. Subsequently, 3D electron microscope images of cardiomyocytes from streptozotocin (STZ) induced type I diabetic rats were compared with controls. The analysis revealed that mitochondrial distribution along the transverse sections was significantly more heterogeneous in type I diabetes compared to control cells. Moreover, mitochondrial area fraction in the studied type I diabetic cells was higher than the control cells. Finally, 2D models of cardiac energy metabolism were created based on the electron microscope images collected from the control and diabetics cells. The results indicated that an increased fraction of mitochondria in diabetic cells can compensate for the reduced ATP synthesising capacity of diabetic mitochondria. The models also predicted that lower activity of mitochondrial enzymes in type I diabetes, coupled with the observed non-uniform mitochondrial distribution, can lead to large spatial variation in concentration of ATP and adenosine diphosphate (ADP). The heterogeneous metabolic landscape in the diabetic cell cross sections was also reflected in large spatial gradients of myofibrillar ATP consumption rate. This finding is important since ATP consumption rate correlates with the speed of muscle shortening. Different parts of a diabetic cell might contract at different rates, which can decrease the energy efficiency of the cell and also damage the cell structure. Thus, this thesis, combining image analysis with computational modelling, provides new insights into how the ultrastructure regulates the metabolism of the cardiomyocytes in disease and health.
Keywordscardiomyocyte; cardiac muscle cell; mitochondria; type i diabetes; diabetic cardiomyopathy; electron microscopy; mitochondrial morphology; bioenergetics; finite element model; mathematical model; phosphocreatine shuttle; systems biology; bioengineering
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