In heart muscle cells, energy is transferred from mitochondria to multiple locations in the cell, where it is utilized to perform mechanical work and maintain ion balance. On the molecular diffusion pathway, several intracellular structures impose restrictions, which are prominent in healthy cells and, some data suggests, disappear in disease. While the restrictions and some clinical data point towards a major role of creatine kinase (CK) assisted energy transfer in the cell, data from loss-of-function animal models are equivocal. In this project, we will develop and use state-of-the-art experimental and mathematical modeling approaches to characterize the diffusion environment within cardiomyocytes and quantify the role of CK in the healthy heart. By identifying the adaptations in transgenic mice, we expect to identify new treatment targets for heart failure patients with reduced CK flux.