Members of the formin family are known to be involved in the regulation of the actin cytoskeleton. We have recently identified a muscle specific splice variant of the formin FHOD3 and demonstrated its role in the maintenance of the contractile filaments of cardiomyocytes. Here, we characterize the expression and subcellular localization of FHOD3's closest relative, FHOD1, in the heart. Confocal microscopy shows that FHOD1 is mainly located at the intercalated disc, the special type of cell-cell contact between cardiomyocytes, but also partially associated with the myofibrils. Subcellular targeting of FHOD1 is probably mediated by its N-terminal domain, since expression constructs lacking this domain show aberrant localization in primary cultures of neonatal rat cardiomyocytes. Finally, we show that in contrast to FHOD3, FHOD1 shows increased expression levels in dilated cardiomyopathy, suggesting that the two formins play distinct roles and are differentially regulated in cardiomyocytes. Anat Rec, 297:1560Rec, 297: -1570Rec, 297: , 2014. V C 2014 Wiley Periodicals, Inc.Key words: formin; actin; intercalated disc; sarcomere Cardiomyocytes, which make up the bulk of heart mass, are characterized by an exquisitely organized cytoskeleton, which is the basis of maximal functional output (Ehler, 2010). The actin cytoskeleton comprises the thin filaments in the myofibrils, which mediate muscle contraction together with the thick (myosin) filaments, but in addition plays also a role in the organization of the plasma membrane cytoskeleton as well as in the anchoring of myofibrils at the specialized type of cell-cell contact in heart tissue, the intercalated disc (Dwyer et al., 2012). Despite this crucial role of actin in the function of cardiomyocytes, it is subjected to an impressive amount of protein turnover. Measurements in rat hearts have suggested that actin has a half-life of about 10 days (Martin, 1981). How the exchange of actin molecules is achieved in the continuously working cardiomyocyte is not well understood.We have recently focused our attention on a potential role of formins in the heart. Formins are proteins, which are mainly involved in the formation of linear actin filaments (Chesarone et al., 2010). They are characterized by the possession of an FH1 and an FH2 domain (for domain layout of formins see Fig. 1), which together make up the actin capturing and polymerization machinery and so far 15 different formins were described in mammals (Sch€ onichen and Geyer, 2010).One characteristic of formins is that they normally exist in an autoinhibited state, which is brought about Abbreviations used: DAD 5 Diaphanous autoregulatory domain; DCM 5 dilated cardiomyopathy; DID 5 Diaphanous inhibitory domain; FH 5 formin homology domain; GBD 5 GTPase binding domain; NRC 5 neonatal rat cardiomyocytes.

Hypertrophic cardiomyopathy is characterised by a histological phenotype of myocyte disarray, but heart tissue samples from patients with dilated cardiomyopathy (DCM) often look comparatively similar to those from healthy individuals apart from conspicuous regions of fibrosis and necrosis. We have previously investigated subcellular alterations in the cytoarchitecture of mouse models of dilated cardiomyopathy and found that both the organisation and composition of the intercalated disc, i.e. the specialised type of cell–cell contact in the heart, is altered. There is also is a change in the composition of the M-band of the sarcomere due to an expression shift towards the more extensible embryonic heart (EH)-myomesin isoform. Analysis of human samples from the Sydney Human Heart Tissue Bank have revealed similar structural findings and also provided evidence for a dramatic change in overall cardiomyocyte size control, which has also been seen in the mouse. Together these changes in cytoarchitecture probably contribute to the decreased functional output that is seen in DCM.

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