Cardiomyocyte growth and sarcomerogenesis at the intercalated disc

Abstract

Cardiomyocytes grow during heart maturation or disease-related cardiac remodeling. We present evidence that the intercalated disc (ID) is integral to both longitudinal and lateral growth: increases in width are accommodated by lateral extension of the plicate tread regions and increases in length by sarcomere insertion within the ID. At the margin between myofibril and the folded membrane of the ID lies a transitional junction through which the thin filaments from the last sarcomere run to the ID membrane and it has been suggested that this junction acts as a proto Z-disc for sarcomere addition. In support of this hypothesis, we have investigated the ultrastructure of the ID in mouse hearts from control and dilated cardiomyopathy (DCM) models, the MLP-null and a cardiac-specific β-catenin mutant, cΔex3, as well as in human left ventricle from normal and DCM samples. We find that the ID amplitude can vary tenfold from 0.2 μm up to a maximum of ~2 μm allowing gradual expansion during heart growth. At the greatest amplitude, equivalent to a sarcomere length, A-bands and thick filaments are found within the ID membrane loops together with a Z-disc, which develops at the transitional junction position. Here, also, the tops of the membrane folds, which are rich in αII spectrin, become enlarged and associated with junctional sarcoplasmic reticulum. Systematically larger ID amplitudes are found in DCM samples. Other morphological differences between mouse DCM and normal hearts suggest that sarcomere inclusion is compromised in the diseased hearts.

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

“…Our data show an unchanged crest‐crest distance of ≈2 μm in TAC cardiomyocytes, corresponding to the sarcomere length of quiescent myocytes. Because cell size was increased (increased cell capacitance; Figure 3C), sarcomeres were likely inserted during the development of hypertrophy in TAC hearts, as described previously by Wilson and coworkers in dilated cardiomyopathy 34. Although the number of sarcomeres and cell crests per cell increased, the mRNA and protein expression and density of sodium channel clusters remained unchanged.…”

“…Similar to natural growth occurring during cardiomyocyte development, growth during cardiac remodeling is achieved by the insertion of sarcomeres flanking the ID 34. Our data show an unchanged crest‐crest distance of ≈2 μm in TAC cardiomyocytes, corresponding to the sarcomere length of quiescent myocytes.…”

“…Electron microscopy images revealed extended membrane folds at the ID of TAC myocytes, in addition to disorganization of the plicate and interplicate regions. These increased interdigitations of the ID membrane likely contributed to an enlarged 3‐dimensional ID surface in failing myocytes34, 40, 41 and an increased spatial complexity of the overall ID area, with membrane foldings tightly packed next to each other. In this complex space, the separation between membrane foldings can be less than the distance that can be resolved using superresolution.…”

Three-Dimensional Structure of the Intercalated Disc Reveals Plicate Domain and Gap Junction Remodeling in Heart Failure

“…Therefore, despite an increase in the frequency of ICDs with a smaller surface area, the plicae are enlarged, which will act to provide local areas with increased contact surfaces between the two cells. An increase in plicae amplitude has also been recently described as part of the mechanism that promotes myocyte lengthening during development (34) with the scaffold protein N-RAP shown to be instrumental for myofibril assembly (35) and in the adult cardiac myocyte N-RAP is exclusively localized to the ICD (36). Here, we found that N-RAP was upregulated in HF.…”

Distribution of formins in cardiac muscle: FHOD1 is a component of intercalated discs and costameres

“…Before reaching the ICD the thin filaments pass or are attached to an additional structure named the "transitional element" (Bennett et al, 2006), which contains a high amount of a specialized spectrin variant (spectrin IVa; see Wilson et al, 2014). The transitional elements (TE) are further characterized as the region where the sarcomeric titin filaments end and by the presence of ␣-actinin, though of a much lower amount than in the classical Z-line (Wilson et al, 2014).…”