Contraction and relaxation of the heart are dependent on the function of individual muscle cells, called cardiomyocytes. Within these cells are small structures called dyads, which are junctions between two cellular membranes. During the heartbeat, release of calcium occurs at these dyads, which triggers contraction, and relaxation occurs as calcium is removed. Prior to initiating the project, existing data indicated that dyads are broken down during diseases such as heart failure, which reduces the power of the heartbeat. In order to eventually treat these patients, we aimed to precisely understand how dyads work and what regulates their structure. We further sought to examine the specific consequences of changing dyadic structure, and to gain insight into approaches that may repair dyads in disease.
Using advanced microscopy, our work during this project has provided significant new knowledge of dyadic structure and function. We have observed the precise locations of different proteins which cycle calcium in the cell, providing information for how these proteins collaborate with each other. We have observed that these proteins are mobile and that they are carefully assembled into functional groups during cardiac development. However, these groupings are degraded during conditions such as heart failure. These changes in protein localization are paralleled by alterations in the membranes where they are located, as more membranes are grown in the developing and compensating heart, but are lost in the failing heart.
What regulates the formation and destruction of dyads? Our investigations have shown that the heart’s workload critically regulates the structure and function of dyads, and thus the function of the whole heart. In the developing heart, increasing workload drives the formation of dyads as cardiac function increases. In these hearts, we have specifically identified protein partners that work together to build new dyads. Interestingly, this functional reserve remains present in the healthy adult heart. Indeed, moderate increases in workload allow compensatory increases in dyad formation. However, excessive workload, as occurs during diseases such as heart failure, causes dyads to be broken down, weakening the heartbeat. Importantly, our observations have shown that this degradation of dyadic structure only occurs in forms of heart failure where the contractile power of the heart is reduced. These findings have important clinical implications, as interventions that reduce workload and/or mechanical signaling in cardiomyocytes have potential to treat some but not all forms of heart failure. We look forward to continuing our search for such therapies in our ongoing studies.
