Key result
PKP2 heterozygosity disrupts intercalated disc ultrastructure and reduces mechanical junctions in murine hearts.
Why the study?
Advances in tissue preservation, tomographic electron microscopy, and image analysis enable detailed morphometric description of the intercalated disc ultrastructure in adult murine ventricle, including in PKP2 heterozygous-null mice.
Warrants human validation studies in PKP2 carriers; leaves open clinical relevance and therapeutic implications.
AIMS: Progress in tissue preservation (high-pressure freezing), data acquisition (tomographic electron microscopy, TEM), and analysis (image segmentation and quantification) have greatly improved the level of information extracted from ultrastructural images. Here, we combined these methods and developed analytical tools to provide an in-depth morphometric description of the intercalated disc (ID) in adult murine ventricle. As a point of comparison, we characterized the ultrastructure of the ID in mice heterozygous-null for the desmosomal gene plakophilin-2 (PKP2; mice dubbed PKP2-Hz). METHODS AND RESULTS: Tomographic EM images of thin sections of adult mouse ventricular tissue were processed by image segmentation analysis. Novel morphometric routines allowed us to generate the first quantitative description of the ID intercellular space based on three-dimensional data. We show that complex invaginations of the cell membrane significantly increased the total ID surface area. In addition, PKP2-Hz samples showed increased average intercellular spacing, ID surface area, and membrane tortuosity, as well as reduced number and length of mechanical junctions compared with control. Finally, we observed membranous structures reminiscent of junctional sarcoplasmic reticulum at the ID, which were significantly more abundant in PKP2-Hz hearts. CONCLUSION: We have developed a systematic method to characterize the ultrastructure of the intercellular space in the adult murine ventricle and have provided a quantitative description of the structure of the intercellular membranes and of the intercellular space. We further show that PKP2 deficiency associates with ultrastructural defects. The possible importance of the intercellular space in cardiac behaviour is discussed.
No takes yet. Share an insight, caveat, or question.
Leo‐Macías et al. (2015) studied PKP2 deficiency. PKP2 heterozygous-null mutation (PKP2-Hz) vs. Wild-type control was evaluated on Ultrastructure of the intercalated disc (intercellular spacing, surface area, membrane tortuosity, mechanical junctions). PKP2-heterozygous-null murine hearts showed increased average intercellular spacing, intercalated disc surface area, and membrane tortuosity, along with reduced mechanical junctions compared to controls.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: