The Formin FHOD1 in Cardiomyocytes

Abstract

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.

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“…Pointing to their clinical relevance, one allele of the human formin gene fhod3 has been associated with increased incidence of hypertrophic cardiomyopathy, while another allele was present in one case of adult onset dilated cardiomyopathy [20,21]. Moreover, expression of FHOD3 and the related FHOD1 formin change differentially during human cardiomyopathies [10,22], suggesting they may play a role in disease progression, or perhaps compensation.…”

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“…In addition, an increase in actin anchoring components and also of F-actin is detected [63]. This may in part be due to the increased presence of a formin, FHOD1, at the intercalated discs of DCM hearts [64]. However, not all formins are upregulated in their expression in DCM, since FHOD3, which plays a role in myofibril maintenance in the embryo [65] and in cultured cardiomyocytes [17] was seen to be downregulated in human cardiomyopathy, potentially contributing to myofibril loss.…”

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“…Confocal microscopy images show that, while FHOD1 is a component of the sarcomeres (Dwyer et al 2015), it is mainly located at the intercalated discs, which are the tight cell-cell contacts between cardiomyocytes that are often associated with cardiomyopathies.…”