Actin-associated proteins and cardiomyopathy—the ‘unknown’ beyond troponin and tropomyosin

Actin-associated proteins and cardiomyopathy—the ‘unknown’ beyond troponin and tropomyosin It has been known for several decades that mutations in genes that encode for proteins involved in the control of actomyosin interactions such as the troponin complex, tropomyosin and MYBP-C and thus regulate contraction can lead to hereditary hypertrophic cardiomyopathy. In recent years, it has become apparent that actin-binding proteins not directly involved in the regulation of contraction also can exhibit changed expression levels, show altered subcellular localisation or bear mutations that might lead to hereditary cardiomyopathies. The aim of this review is to look beyond the troponin/tropomyosin mechanism and to give an overview of the different types of actin-associated proteins and their potential roles in cardiomyocytes. It will then discuss recent findings relevant to their involvement in heart disease. . . . . Keywords Actin-binding proteins Formin Cytoskeleton Cardiomyopathy Intercalated disc Introduction disc (Lange et al. 2016). While about 75% of mutations that lead to hereditary HCM are found in the genes encoding for Two major different types of cardiomyopathy can be defined sarcomeric myosin heavy chain (MYH7) and myosin-binding in human patients, hypertrophic cardiomyopathy (HCM) and protein-C (MYBPC3; McNally et al. 2013), other components dilated cardiomyopathy (DCM; for review, see Seidman and of the myofibrils can be mutated such as the troponins and Seidman 2001). While HCM shows obvious signs of myocyte alpha-tropomyosin (Tardiff 2011). Initially, it was believed disarray in conventional histology, the phenotype of DCM is that HCM was a disease of the sarcomere. However, with more subtle and can usually only be elucidated by immuno- the identification of mutations in more genes that encode for histochemistry and electron microscopy (Pluess and Ehler proteins that do not stably associate with myofibrils (Geier et 2015). The major changes in DCM appear to occur at the al. 2008), this was probably an over-simplification. Similarly, intercalated disc, the specialised cell-cell contact between the hypothesis that hereditary DCM is caused solely by mu- cardiomyocytes. These changes lead to an altered molecular tations in cytoskeletal proteins had to be abandoned, since composition and include an increased expression of actin- mutations in genes that encode for sarcomeric proteins result anchoring proteins (Ehler et al. 2001). In addition, signalling in this disease phenotype, too (McNally et al. 2013). It may be molecules such as PKCalpha are recruited to the intercalated more the position of the mutation in the molecule or the com- bination with mutations in other genes that results in a HCM versus a DCM phenotype (McNally and Mestroni 2017; This article is part of a Special Issue on ‘Heart Failure Due to Non- Tardiff 2011). Myofibrillar Defects’ edited by Elisabeth Ehler and Katja Gehmlich. As far as components of the thin (actin) filaments are con- * Elisabeth Ehler cerned, mutations were described for tropomyosin, troponin elisabeth.ehler@kcl.ac.uk T, troponin I and troponin C as well as for cardiac actin itself (Hoffmann et al. 2001;Kimura etal. 1997; Olson et al. 1998; Randall Centre for Cell and Molecular Biophysics (School of Basic Watkins et al. 1995). However, more recently, it was also and Medical Biosciences), London, UK shown that mutations in actin-interacting proteins that are School of Cardiovascular Medicine and Sciences, British Heart not directly involved in contraction or its regulation, such as Foundation Research Excellence Centre, King’s College London, FHOD3, alpha-actinin or filamin C, can cause hereditary car- Room 3.26A, New Hunt’s House, Guy’s Campus, London SE1 1UL, UK diomyopathies (Arimura et al. 2013; Girolami et al. 2014; Biophys Rev Tucker et al. 2017;Wootenetal. 2013). These reports myofibrils, although cytoplasmic actin isoforms are expressed prompted the writing of this review on actin and its associated at very low levels and can be detected in the vicinity of mem- proteins beyond the sarcomere. branes and at the Z-disc (Benz et al. 2013; Dwyer et al. 2012; Actin is a highly conserved eukaryotic protein that exists as Kee et al. 2009; Tondeleir et al. 2009,Fig. 2). In the early six distinct isoforms: alpha-cardiac, alpha-skeletal, alpha- embryonic heart, alpha-cardiac and alpha-smooth muscle ac- smooth muscle, beta-cytoplasmic, gamma-cytoplasmic and tin are co-expressed in the same thin filaments (Ehler et al. gamma-smooth muscle actin (Vandekerckhove and Weber 2004). Confocal microscopy suggests that while the length of 1978). Actin monomers (G-actin) can associate to form fila- the cardiac actin filaments is determined quite early, there ments (F-actin; see Fig. 1) that have the appearance of two exists a population of actin filaments that extends beyond helically entwined pearl strings (Hanson and Lowy 1963). the I-band, which may be mainly composed of alpha-smooth However, this is an energetically unfavourable process, which muscle actin (Ehler et al. 2004). Currently, it is unknown is massively enhanced by factors that promote actin filament whether there are mixed actin filament populations and wheth- formation such as the Arp2/3 complex or members of the er the length-determining factor is functional rather than mo- formin family (Chesarone and Goode 2009). Once filaments lecular, since tropomodulin and leiomodin are absent at the are formed, they can be stabilised laterally via the association pointed ends or not expressed at this developmental stage of tropomyosin in one of its numerous isoforms (Gunning et (Ehler et al. 2004; Tsukada et al. 2010). Similar to other foetal al. 2015). Based on their distinct dynamics, the ends of an marker genes, an upregulation of alpha-smooth and even actin filament are termed plus end (where incorporation of alpha-skeletal muscle actin can be detected in hypertrophic new actin monomers happens; also called barbed end based cardiomyopathy (Copeland et al. 2010; Suurmeijer et al. on the decoration with myosin heads) and minus end (also 2003). An inbred mouse strain, the Balb/c mouse, also has a called pointed end, where actin monomers are lost in the pro- higher expression level of alpha-skeletal actin and shows in- cess of treadmilling). These ends can be protected by the as- creased contractility (Hewett et al. 1994). sociation of capping proteins such as CapZ at the barbed end or tropomodulin and leiomodin at the pointed end (Fig. 2). In addition, actin filaments can be crosslinked to meshworks or Actin filament assembly and maintenance bundled to parallel filaments and there are severing proteins in cardiomyocytes that lead to their disassembly (for a landmark review on actin- binding proteins, see Pollard and Cooper 1986, and for a more As mentioned above, since actin filament assembly is an in- recent review, see dos Remedios et al. 2003). efficient process, there is a need for factors that might promote Adult cardiomyocytes mainly express the alpha-cardiac ac- it, especially as the half-life of actin and its associated proteins tin isoform, which is found almost exclusively in the in a cardiomyocyte range from 3 to 10 days (Martin 1981). Fig. 1 Overview of actin-binding proteins and their effect on actin. Actin- capping proteins. Disassembly of actin filaments is favoured by members binding proteins can enhance the formation of filaments from G-actin of the gelsolin family. Gene names are given below the roles; names in monomers, can stabilise and crosslink these filaments and can also disas- bold are highly expressed in cardiomyocytes. An asterisk after the name semble them. The end of the filaments are termed barbed (plus end) and indicates that these genes were shown to bear mutations that can cause pointed (minus end) and dissociation of G-actin is prevented by different hereditary cardiomyopathy Biophys Rev Fig. 2 Overview of the different types of actin filaments and subcellular different types of complexes, which are mostly represented in a very localisation of different actin-associated proteins in a cardiomyocyte. simplified fashion. Chevrons indicate the orientation of the actin Only one corner of the cell is shown. The legend below shows the filaments The cell migration field has pioneered this research and two severe in Daam1-Daam2 double knockout mice, suggesting a main basic ways were identified: (1) filament assembly by the certain redundancy between these proteins. Arp2/3 complex of proteins, which tends to support the for- The formin FHOD3 seems to play a role in early heart mation of filaments at an angle to the mother filaments and (2) development and subsequently in myofibril maintenance. filament assembly by members of the formin family, which FHOD3 knockout mice did not survive beyond E12.5 and promote the formation of linear filaments (Chesarone and showed hypokinetic ventricles with myofibrillar disarray and Goode 2009). Not much is known about Arp2/3 in the heart, Z-disc malformations (Kan-o et al. 2012a). However, a con- but in the skeletal muscle, a role for an Arp2/3 family member, ditional knockout of FHOD3 expression in adult mice did not Arpc5L, was shown for the coordination between gamma- lead to a lethal phenotype, but just to a mild impairment of actin filaments, the desmin cytoskeleton and nuclear position- cardiac function (Ushijima et al. 2018). Experiments with ing (Roman et al. 2017). More and more of the 15 members of knockdown of FHOD3 expression in cultured cardiomyocytes the formin family are characterised as having a role in the also demonstrated a failure to maintain myofibrils and reduced heart (Li et al. 2011; Rosado et al. 2014; Taniguchi et al. expression levels in samples from human heart failure patients 2009; reviewed in Randall and Ehler 2014). (Iskratsch et al. 2010). Currently, the exact role of FHOD3 in Knockout mice for the formin Daam1 mainly reveal a more cardiomyocytes is as unclear as its subcellular localisation. We general role in heart morphogenesis with a noncompaction and others detected FHOD3 exclusively at the Z-discs of iso- phenotype and septal defects (Ajima et al. 2015;Lietal. lated adult cardiomyocytes and in adult heart tissue from mice 2011). This is especially interesting, since a recent report and humans (Iskratsch et al. 2010; Rosado et al. 2014), which showed a potential association of a deletion of a DAAM1 would fit well with a role as barbed-end facilitator of actin copy with congenital heart disease (Bao et al. 2012). assembly, while others have reported a broader localisation, Myofibrils are assembled, but are disorganised, and there which overlaps the A-band (Kan-o et al. 2012b). In our hands, may be a problem with their maintenance (Ajima et al. this kind of FHOD3 localisation is only detected in the em- 2015). The major phenotype is seen at the intercalated discs, bryonic heart and in cultured neonatal rat cardiomyocytes that where cardiomyocyte attachment is severely impaired (Ajima are adapting to life in two dimensions in a culture dish et al. 2015). This is in agreement with localisation data for (Iskratsch et al. 2010). On the other hand, a recently identified Daam1 close to the plasma membrane and its potential role interaction between FHOD3 and MyBP-C, which associates in the Wnt effector Dishevelled and thus the planar cell polar- with a subset of the myosin heads, favours the A-band localisation (Matsuyama et al. 2018). Patients with mutations ity signalling pathway (Li et al. 2011). The phenotype is more Biophys Rev in the FHOD3 gene can develop HCM or DCM (Arimura et whether it indeed plays a role in excessive actin filament syn- al. 2013; Wooten et al. 2013). Potentially, FHOD3 is not firm- thesis in DCM (Dwyer et al. 2014). ly integrated into the sarcomere and exerts its role by influenc- ing MyBP-C, which is a regulator of the thick filament on-off state (Kampourakis et al. 2014), or it may affect the ratio of What happens at the ends of the thin available actin monomers. This could explain its detrimental filaments? effect on the activation of the transcription factor SRF in the case of the DCM mutant (Arimura et al. 2013). Actin-capping proteins determine the length of thin fil- aments in healthy cardiomyocytes both at the barbed end at the Z-disc and at the pointed end near the inner edges of the H-zone (reviewed by Dwyer et al. 2012; What happens at the anchorage sites Fowler and Dominguez 2017). of the myofibrils, the intercalated discs? CapZ binds to the barbed ends of thin filaments (Casella et al. 1987) and its dynamics in myocytes is increased by exer- As mentioned above, the major subcellular changes observed cise and during hypertrophy (Lin et al. 2013; Lin et al. 2016). in DCM occur at the intercalated disc. Both in mouse models Among the signalling pathways that affect CapZ dynamics are for this disease and in human DCM samples, we observed PIP2 (phosphatidylinositol-4,5 bisphosphate), phosphoryla- increased expression of all proteins involved in anchoring of tion by PKC (protein kinase C) and acetylation (Hartman et actin filaments (i.e. the myofibrils in the cardiomyocytes): the al. 2009; Lin et al. 2016). CapZ transgenic hearts that express transmembrane cadherins, and at the cytoplasmic face the reduced amounts of CapZ are protected against ischemia- catenins and N-RAP (Ehler et al. 2001; Pluess et al. 2015). reperfusion injury and show alterations in PKC signalling The increased width of signal for these proteins that was seen (Yang and Pyle 2012). In addition to its adaptive dynamic at the intercalated disc by confocal microscopy was due to a behaviour upon cardiomyocyte stress, CapZ also interacts higher degree of membrane convolution, as demonstrated by with classical stress signals such as the co-chaperone BAG3 ultrastructural analysis (Wilson et al. 2014). Analysis of the and the small heat shock protein Hsc70 (Hishiya et al. 2010). actin signal using the F-actin stain phalloidin in 0.25-μm-thick Gain of function (overexpression of tropomodulin) and loss cryosections also revealed a higher intensity at the intercalated of function experiments (interfering with tropomodulin bind- disc in mouse models for DCM, suggesting that the increased ing) have shown that the tight control of thin filament length at amount of actin-anchoring proteins mirrors an increased pres- its pointed end is crucial for a healthy cardiomyocyte (Fritz- ence of filamentous actin there (Ehler et al. 2001). Currently, it Six et al. 2003;Gregorioetal. 1995; Sussman et al. 1998)and is not known which protein is involved in generating more tropomodulin seems to be the major protein responsible for filamentous actin at the intercalated disc, but the observation capping the pointed ends. However, in recent years, a related that the formin FHOD1 locates to this subcellular domain (Al protein, called leiomodin, was described, which is also needed Hajetal. 2015) and its signal is also increased in DCM to maintain myofibrils (Chereau et al. 2008) and results in a (Dwyer et al. 2014) makes it a promising candidate. FHOD1 DCM phenotype with early postnatal death in knockout mice was thought to be unable to promote the formation of actin (Pappas et al. 2015). Interestingly, there seems to be crosstalk filaments and to act just as an actin capper and actin bundler between tropomodulin, leimodin2 and an actin-monomer- (Schönichen et al. 2013). However, FHOD1 participates in the binding protein, Hspb7, that was reported to be mutated in nucleation of actin filaments from early integrin clusters in DCM (Stark et al. 2010). Knockout mice for Hspb7 have fibroblasts and is associated with integrins in cardiomyocytes longer thin filaments in their sarcomeres that even seem to (Al Haj et al. 2015; Iskratsch et al. 2013). Recent evidence connect two neighbouring Z-discs and are crosslinked by al- also shows that FHOD1’s actin polymerising activity depends pha-actinin. Lmod2 expression is upregulated, suggesting that on the actin isoform and that while it is inactive with sarco- its uncontrolled activity contributes to the excessive actin fil- meric actins (which most people use for in vitro polymerisa- ament synthesis and the signal for tropomodulin becomes dif- tion assays), it does promote filament formation with cytoplas- fuse (Wu et al. 2017). mic actin isoforms (Patel et al. 2018). Filamentous actin lead- ing up from the transitional junction to the intercalated disc does not seem to contain alpha-cardiac actin (Bennett et al. What happens at the Z-discs? 2006) and may well be composed of cytoplasmic actins (Benz et al. 2013). Thus, FHOD1 could be an important controlling Mutations in several Z-disc proteins are associated with a factor. FHOD1 at the intercalated disc is in an active state, HCM phenotype (Bos and Ackerman 2010). For example, since it can be stained with an antibody against a phosphory- missense mutations in the gene ACTN2 were described, lated epitope at T1141. However, it remains to be shown which encodes the actin-crosslinking protein alpha-actinin, Biophys Rev the marker protein for Z-discs (Chiu et al. 2010). Thorough knockout mouse was generated, which expressed only molecular characterisation of these mutations is still under 40% of cofilin-2 compared to wild-type littermates. way, but first results indicate that at least in the case of These mice displayed dilation and wall thinning of the left A119T and G111V mutations, the dynamic behaviour of ventricle (Subramanian et al. 2015). The reduced contrac- alpha-actinin and its readiness to incorporate into the Z-disc tile function was attributed to disorganised sarcomeres in may be affected (Haywood et al. 2016). A second major Z- the heterozygous cofilin-2 mice (Subramanian et al. 2015). disc-associated actin-binding protein that was shown to cause These data suggest that cofilin-2 has a regulatory role also cardiomyopathy when mutated is filamin C. Missense muta- in cardiomyocytes and that its expression must be tightly tions of filamin C cause familial restrictive cardiomyopathy controlled to prevent cardiomyopathy. and lead to a loss of filamin C signal at the Z-disc (Tucker et Profilin is a protein that sequesters actin monomers and al. 2017). Truncating variants of filamin C and its co- governs their ATP-associated state, leading to a higher affinity chaperone BAG3 are associated with DCM (Janin et al. for the barbed ends (for a review, see dos Remedios et al. 2017). Interestingly, BAG3 stimulates filamin transcription 2003). Interestingly, the barbed ends are classically assumed and also spatially regulates mTORC1 signalling to simulta- to be the major site of activity of formins. Formins are neously induce autophagy of damaged filamin and activate characterised by two formin homology (FH) domains, FH1 protein synthesis upon mechanical stress in cardiomyocytes and FH2. The FH2 domains of two formins dimerise into a (Kathage et al. 2017). Again, these results indicate that actin- doughnut-like structure that forms the business end for associated proteins are not just static glue at their respective formin-promoted actin assembly (Goode and Eck 2007), sites but closely interweave with signalling pathways that are while the FH1 domain interacts with profilin and may help relevant for the cardiomyocyte stress response. to shunt profilin-bound actin monomers to the neighbouring FH2 domain. Since profilin dissociates from actin in the pres- ence of PIP and PIP2, the environment of the Z-disc, which is Proteins involved in actin filament turnover enriched in PIP2 (Pyle et al. 2006; Ribeiro et al. 2014), would and their role in cardiac disease and repair be an ideal location to release the actin from profilin and make it available for polymerisation. A recent study has demonstrat- Cofilin-2 is a member of the ADF/cofilin family of pro- ed that the expression of profilin is increased in a variety of teins that acts preferentially at the pointed ends of actin rodent models for hypertrophy in situ and in vitro, but de- filaments and increases the off-rate by 30-fold (for a creased in end-stage heart failure patients (Kooij et al. 2016). review, see dos Remedios et al. 2003). In cultured In vivo experiments in Drosophila showed that overexpres- cardiomyocytes, cofilin-2 was shown to localise towards sion of profilin leads to longer thin filaments than in control strains and results in a functional phenotype resembling dilat- the M-band region of the sarcomeres, where the pointed ends are found (Kremneva et al. 2014). In a healthy car- ed cardiomyopathy (Kooij et al. 2016). Knockdown of diomyocyte in situ, cofilin-2 should not affect the structure profilin expression in cultured cardiomyocytes prevented their of thin filaments too much, since the pointed ends are hypertrophic response, probably by impaired activation of protected by tropomodulin or leiomodin and cofilin’s ERK1/ERK2 signalling (Kooij et al. 2016). In conclusion, depolymerising activity is known to be inhibited by the profilin appears likely to be crucial for hypertrophic growth presence of tropomyosins (dos Remedios et al. 2003). in the heart, potentially by delivering actin monomers for as- However, when cofilin-2 expression is knocked down in sembly by members of the formin family. cultured cardiomyocytes, a marked elongation of thin fila- Another small actin monomer-binding protein, thymosin ments is observed and proper I-band striations are lost beta 4 (Tbeta4), has recently entered the limelight by its ability (Kremneva et al. 2014). In a mouse model for DCM, the to enhance cardiac repair in the adult heart following injury calsarcin knockout mouse, cofilin-2 expression was in- (Smart et al. 2011). Tbeta4 was administered to the mice by creased due to a decrease in miRNA miR-301a expression intraperitoneal injection and somehow seemed to activate a and was subsequently shown to be a direct target for this population of stem cells in the epicardial surface of the heart miRNA (Rangrez et al. 2017). Cofilin-2 function is regu- that differentiated into blood vessels but also to a much lower lated by phosphorylation, and fasudil, an inhibitor of extent into cardiomyocytes. The exact role of Tbeta4 in ROCK (Rho kinase), which has a protective effect against cardiomyocytes is somewhat unclear at the moment, since cardiac dysfunction, prevents its phosphorylation and pro- Tbeta4 knockout mice had no cardiac phenotype (Banerjee motes the organisation of actin filaments (Lai et al. 2017). et al. 2012). Therefore, its contribution to improved cardiac In human idiopathic DCM, aggregates of cofilin-2 in its repair may be mainly due to its enhancement of vascularisa- phosphorylated state were detected in the heart samples tion of the injured heart. On the other hand, another group of patients (Subramanian et al. 2015). To model reduced reported shorter sarcomere length, expression of shorter titin cofilin-2 activity, a heterozygous cardiac specific cofilin-2 isoforms and a limited contractile reserve in their Tbeta4 Biophys Rev Bao B, Zhang L, Hu H, Yin S, Liang Z (2012) Deletion of a single-copy knockout mice, suggesting that Tbeta4 may be somehow in- DAAM1 gene in congenital heart defect: a case report. BMC Med volved in the regulation of alternative splicing of titin, poten- Genet 13:63 tially via RBM20 (Guo et al. 2012; Smart et al. 2017). Bennett PM, Maggs AM, Baines AJ, Pinder JC (2006) The transitional junction: a new functional subcellular domain at the intercalated disc. 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However, it is obvious that the actin cytoskeleton is dynamic and that subtle changes that affect Casella JF, Craig SW, Maack DJ, Brown AE (1987) Cap Z(36/32), a barbed end actin-capping protein, is a component of the Z-line of this dynamics and its amount will alter the function of a skeletal muscle. J Cell Biol 105:371–379 cardiomyocyte. Chereau D, Boczkowska M, Skwarek-Maruszewska A, Fujiwara I, Hayes DB, Rebowski G, Lappalainen P, Pollard TD, Dominguez Acknowledgements I would like to thank the collaborators past and pres- R (2008) Leiomodin is an actin filament nucleator in muscle cells. ent for their hard work and fruitful discussions. Science 320:239–243 Chesarone MA, Goode BL (2009) Actin nucleation and elongation fac- Funding The research in my laboratory was financially supported by the tors: mechanisms and interplay. Curr Opin Cell Biol 21:28–37 British Heart Foundation and the Medical Research Council. 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J Mol Cell Cardiol 52:761–772 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Biophysical Reviews Springer Journals

Actin-associated proteins and cardiomyopathy—the ‘unknown’ beyond troponin and tropomyosin

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Life Sciences; Biochemistry, general; Biological and Medical Physics, Biophysics; Cell Biology; Membrane Biology; Biological Techniques; Nanotechnology
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Abstract

It has been known for several decades that mutations in genes that encode for proteins involved in the control of actomyosin interactions such as the troponin complex, tropomyosin and MYBP-C and thus regulate contraction can lead to hereditary hypertrophic cardiomyopathy. In recent years, it has become apparent that actin-binding proteins not directly involved in the regulation of contraction also can exhibit changed expression levels, show altered subcellular localisation or bear mutations that might lead to hereditary cardiomyopathies. The aim of this review is to look beyond the troponin/tropomyosin mechanism and to give an overview of the different types of actin-associated proteins and their potential roles in cardiomyocytes. It will then discuss recent findings relevant to their involvement in heart disease. . . . . Keywords Actin-binding proteins Formin Cytoskeleton Cardiomyopathy Intercalated disc Introduction disc (Lange et al. 2016). While about 75% of mutations that lead to hereditary HCM are found in the genes encoding for Two major different types of cardiomyopathy can be defined sarcomeric myosin heavy chain (MYH7) and myosin-binding in human patients, hypertrophic cardiomyopathy (HCM) and protein-C (MYBPC3; McNally et al. 2013), other components dilated cardiomyopathy (DCM; for review, see Seidman and of the myofibrils can be mutated such as the troponins and Seidman 2001). While HCM shows obvious signs of myocyte alpha-tropomyosin (Tardiff 2011). Initially, it was believed disarray in conventional histology, the phenotype of DCM is that HCM was a disease of the sarcomere. However, with more subtle and can usually only be elucidated by immuno- the identification of mutations in more genes that encode for histochemistry and electron microscopy (Pluess and Ehler proteins that do not stably associate with myofibrils (Geier et 2015). The major changes in DCM appear to occur at the al. 2008), this was probably an over-simplification. Similarly, intercalated disc, the specialised cell-cell contact between the hypothesis that hereditary DCM is caused solely by mu- cardiomyocytes. These changes lead to an altered molecular tations in cytoskeletal proteins had to be abandoned, since composition and include an increased expression of actin- mutations in genes that encode for sarcomeric proteins result anchoring proteins (Ehler et al. 2001). In addition, signalling in this disease phenotype, too (McNally et al. 2013). It may be molecules such as PKCalpha are recruited to the intercalated more the position of the mutation in the molecule or the com- bination with mutations in other genes that results in a HCM versus a DCM phenotype (McNally and Mestroni 2017; This article is part of a Special Issue on ‘Heart Failure Due to Non- Tardiff 2011). Myofibrillar Defects’ edited by Elisabeth Ehler and Katja Gehmlich. As far as components of the thin (actin) filaments are con- * Elisabeth Ehler cerned, mutations were described for tropomyosin, troponin elisabeth.ehler@kcl.ac.uk T, troponin I and troponin C as well as for cardiac actin itself (Hoffmann et al. 2001;Kimura etal. 1997; Olson et al. 1998; Randall Centre for Cell and Molecular Biophysics (School of Basic Watkins et al. 1995). However, more recently, it was also and Medical Biosciences), London, UK shown that mutations in actin-interacting proteins that are School of Cardiovascular Medicine and Sciences, British Heart not directly involved in contraction or its regulation, such as Foundation Research Excellence Centre, King’s College London, FHOD3, alpha-actinin or filamin C, can cause hereditary car- Room 3.26A, New Hunt’s House, Guy’s Campus, London SE1 1UL, UK diomyopathies (Arimura et al. 2013; Girolami et al. 2014; Biophys Rev Tucker et al. 2017;Wootenetal. 2013). These reports myofibrils, although cytoplasmic actin isoforms are expressed prompted the writing of this review on actin and its associated at very low levels and can be detected in the vicinity of mem- proteins beyond the sarcomere. branes and at the Z-disc (Benz et al. 2013; Dwyer et al. 2012; Actin is a highly conserved eukaryotic protein that exists as Kee et al. 2009; Tondeleir et al. 2009,Fig. 2). In the early six distinct isoforms: alpha-cardiac, alpha-skeletal, alpha- embryonic heart, alpha-cardiac and alpha-smooth muscle ac- smooth muscle, beta-cytoplasmic, gamma-cytoplasmic and tin are co-expressed in the same thin filaments (Ehler et al. gamma-smooth muscle actin (Vandekerckhove and Weber 2004). Confocal microscopy suggests that while the length of 1978). Actin monomers (G-actin) can associate to form fila- the cardiac actin filaments is determined quite early, there ments (F-actin; see Fig. 1) that have the appearance of two exists a population of actin filaments that extends beyond helically entwined pearl strings (Hanson and Lowy 1963). the I-band, which may be mainly composed of alpha-smooth However, this is an energetically unfavourable process, which muscle actin (Ehler et al. 2004). Currently, it is unknown is massively enhanced by factors that promote actin filament whether there are mixed actin filament populations and wheth- formation such as the Arp2/3 complex or members of the er the length-determining factor is functional rather than mo- formin family (Chesarone and Goode 2009). Once filaments lecular, since tropomodulin and leiomodin are absent at the are formed, they can be stabilised laterally via the association pointed ends or not expressed at this developmental stage of tropomyosin in one of its numerous isoforms (Gunning et (Ehler et al. 2004; Tsukada et al. 2010). Similar to other foetal al. 2015). Based on their distinct dynamics, the ends of an marker genes, an upregulation of alpha-smooth and even actin filament are termed plus end (where incorporation of alpha-skeletal muscle actin can be detected in hypertrophic new actin monomers happens; also called barbed end based cardiomyopathy (Copeland et al. 2010; Suurmeijer et al. on the decoration with myosin heads) and minus end (also 2003). An inbred mouse strain, the Balb/c mouse, also has a called pointed end, where actin monomers are lost in the pro- higher expression level of alpha-skeletal actin and shows in- cess of treadmilling). These ends can be protected by the as- creased contractility (Hewett et al. 1994). sociation of capping proteins such as CapZ at the barbed end or tropomodulin and leiomodin at the pointed end (Fig. 2). In addition, actin filaments can be crosslinked to meshworks or Actin filament assembly and maintenance bundled to parallel filaments and there are severing proteins in cardiomyocytes that lead to their disassembly (for a landmark review on actin- binding proteins, see Pollard and Cooper 1986, and for a more As mentioned above, since actin filament assembly is an in- recent review, see dos Remedios et al. 2003). efficient process, there is a need for factors that might promote Adult cardiomyocytes mainly express the alpha-cardiac ac- it, especially as the half-life of actin and its associated proteins tin isoform, which is found almost exclusively in the in a cardiomyocyte range from 3 to 10 days (Martin 1981). Fig. 1 Overview of actin-binding proteins and their effect on actin. Actin- capping proteins. Disassembly of actin filaments is favoured by members binding proteins can enhance the formation of filaments from G-actin of the gelsolin family. Gene names are given below the roles; names in monomers, can stabilise and crosslink these filaments and can also disas- bold are highly expressed in cardiomyocytes. An asterisk after the name semble them. The end of the filaments are termed barbed (plus end) and indicates that these genes were shown to bear mutations that can cause pointed (minus end) and dissociation of G-actin is prevented by different hereditary cardiomyopathy Biophys Rev Fig. 2 Overview of the different types of actin filaments and subcellular different types of complexes, which are mostly represented in a very localisation of different actin-associated proteins in a cardiomyocyte. simplified fashion. Chevrons indicate the orientation of the actin Only one corner of the cell is shown. The legend below shows the filaments The cell migration field has pioneered this research and two severe in Daam1-Daam2 double knockout mice, suggesting a main basic ways were identified: (1) filament assembly by the certain redundancy between these proteins. Arp2/3 complex of proteins, which tends to support the for- The formin FHOD3 seems to play a role in early heart mation of filaments at an angle to the mother filaments and (2) development and subsequently in myofibril maintenance. filament assembly by members of the formin family, which FHOD3 knockout mice did not survive beyond E12.5 and promote the formation of linear filaments (Chesarone and showed hypokinetic ventricles with myofibrillar disarray and Goode 2009). Not much is known about Arp2/3 in the heart, Z-disc malformations (Kan-o et al. 2012a). However, a con- but in the skeletal muscle, a role for an Arp2/3 family member, ditional knockout of FHOD3 expression in adult mice did not Arpc5L, was shown for the coordination between gamma- lead to a lethal phenotype, but just to a mild impairment of actin filaments, the desmin cytoskeleton and nuclear position- cardiac function (Ushijima et al. 2018). Experiments with ing (Roman et al. 2017). More and more of the 15 members of knockdown of FHOD3 expression in cultured cardiomyocytes the formin family are characterised as having a role in the also demonstrated a failure to maintain myofibrils and reduced heart (Li et al. 2011; Rosado et al. 2014; Taniguchi et al. expression levels in samples from human heart failure patients 2009; reviewed in Randall and Ehler 2014). (Iskratsch et al. 2010). Currently, the exact role of FHOD3 in Knockout mice for the formin Daam1 mainly reveal a more cardiomyocytes is as unclear as its subcellular localisation. We general role in heart morphogenesis with a noncompaction and others detected FHOD3 exclusively at the Z-discs of iso- phenotype and septal defects (Ajima et al. 2015;Lietal. lated adult cardiomyocytes and in adult heart tissue from mice 2011). This is especially interesting, since a recent report and humans (Iskratsch et al. 2010; Rosado et al. 2014), which showed a potential association of a deletion of a DAAM1 would fit well with a role as barbed-end facilitator of actin copy with congenital heart disease (Bao et al. 2012). assembly, while others have reported a broader localisation, Myofibrils are assembled, but are disorganised, and there which overlaps the A-band (Kan-o et al. 2012b). In our hands, may be a problem with their maintenance (Ajima et al. this kind of FHOD3 localisation is only detected in the em- 2015). The major phenotype is seen at the intercalated discs, bryonic heart and in cultured neonatal rat cardiomyocytes that where cardiomyocyte attachment is severely impaired (Ajima are adapting to life in two dimensions in a culture dish et al. 2015). This is in agreement with localisation data for (Iskratsch et al. 2010). On the other hand, a recently identified Daam1 close to the plasma membrane and its potential role interaction between FHOD3 and MyBP-C, which associates in the Wnt effector Dishevelled and thus the planar cell polar- with a subset of the myosin heads, favours the A-band localisation (Matsuyama et al. 2018). Patients with mutations ity signalling pathway (Li et al. 2011). The phenotype is more Biophys Rev in the FHOD3 gene can develop HCM or DCM (Arimura et whether it indeed plays a role in excessive actin filament syn- al. 2013; Wooten et al. 2013). Potentially, FHOD3 is not firm- thesis in DCM (Dwyer et al. 2014). ly integrated into the sarcomere and exerts its role by influenc- ing MyBP-C, which is a regulator of the thick filament on-off state (Kampourakis et al. 2014), or it may affect the ratio of What happens at the ends of the thin available actin monomers. This could explain its detrimental filaments? effect on the activation of the transcription factor SRF in the case of the DCM mutant (Arimura et al. 2013). Actin-capping proteins determine the length of thin fil- aments in healthy cardiomyocytes both at the barbed end at the Z-disc and at the pointed end near the inner edges of the H-zone (reviewed by Dwyer et al. 2012; What happens at the anchorage sites Fowler and Dominguez 2017). of the myofibrils, the intercalated discs? CapZ binds to the barbed ends of thin filaments (Casella et al. 1987) and its dynamics in myocytes is increased by exer- As mentioned above, the major subcellular changes observed cise and during hypertrophy (Lin et al. 2013; Lin et al. 2016). in DCM occur at the intercalated disc. Both in mouse models Among the signalling pathways that affect CapZ dynamics are for this disease and in human DCM samples, we observed PIP2 (phosphatidylinositol-4,5 bisphosphate), phosphoryla- increased expression of all proteins involved in anchoring of tion by PKC (protein kinase C) and acetylation (Hartman et actin filaments (i.e. the myofibrils in the cardiomyocytes): the al. 2009; Lin et al. 2016). CapZ transgenic hearts that express transmembrane cadherins, and at the cytoplasmic face the reduced amounts of CapZ are protected against ischemia- catenins and N-RAP (Ehler et al. 2001; Pluess et al. 2015). reperfusion injury and show alterations in PKC signalling The increased width of signal for these proteins that was seen (Yang and Pyle 2012). In addition to its adaptive dynamic at the intercalated disc by confocal microscopy was due to a behaviour upon cardiomyocyte stress, CapZ also interacts higher degree of membrane convolution, as demonstrated by with classical stress signals such as the co-chaperone BAG3 ultrastructural analysis (Wilson et al. 2014). Analysis of the and the small heat shock protein Hsc70 (Hishiya et al. 2010). actin signal using the F-actin stain phalloidin in 0.25-μm-thick Gain of function (overexpression of tropomodulin) and loss cryosections also revealed a higher intensity at the intercalated of function experiments (interfering with tropomodulin bind- disc in mouse models for DCM, suggesting that the increased ing) have shown that the tight control of thin filament length at amount of actin-anchoring proteins mirrors an increased pres- its pointed end is crucial for a healthy cardiomyocyte (Fritz- ence of filamentous actin there (Ehler et al. 2001). Currently, it Six et al. 2003;Gregorioetal. 1995; Sussman et al. 1998)and is not known which protein is involved in generating more tropomodulin seems to be the major protein responsible for filamentous actin at the intercalated disc, but the observation capping the pointed ends. However, in recent years, a related that the formin FHOD1 locates to this subcellular domain (Al protein, called leiomodin, was described, which is also needed Hajetal. 2015) and its signal is also increased in DCM to maintain myofibrils (Chereau et al. 2008) and results in a (Dwyer et al. 2014) makes it a promising candidate. FHOD1 DCM phenotype with early postnatal death in knockout mice was thought to be unable to promote the formation of actin (Pappas et al. 2015). Interestingly, there seems to be crosstalk filaments and to act just as an actin capper and actin bundler between tropomodulin, leimodin2 and an actin-monomer- (Schönichen et al. 2013). However, FHOD1 participates in the binding protein, Hspb7, that was reported to be mutated in nucleation of actin filaments from early integrin clusters in DCM (Stark et al. 2010). Knockout mice for Hspb7 have fibroblasts and is associated with integrins in cardiomyocytes longer thin filaments in their sarcomeres that even seem to (Al Haj et al. 2015; Iskratsch et al. 2013). Recent evidence connect two neighbouring Z-discs and are crosslinked by al- also shows that FHOD1’s actin polymerising activity depends pha-actinin. Lmod2 expression is upregulated, suggesting that on the actin isoform and that while it is inactive with sarco- its uncontrolled activity contributes to the excessive actin fil- meric actins (which most people use for in vitro polymerisa- ament synthesis and the signal for tropomodulin becomes dif- tion assays), it does promote filament formation with cytoplas- fuse (Wu et al. 2017). mic actin isoforms (Patel et al. 2018). Filamentous actin lead- ing up from the transitional junction to the intercalated disc does not seem to contain alpha-cardiac actin (Bennett et al. What happens at the Z-discs? 2006) and may well be composed of cytoplasmic actins (Benz et al. 2013). Thus, FHOD1 could be an important controlling Mutations in several Z-disc proteins are associated with a factor. FHOD1 at the intercalated disc is in an active state, HCM phenotype (Bos and Ackerman 2010). For example, since it can be stained with an antibody against a phosphory- missense mutations in the gene ACTN2 were described, lated epitope at T1141. However, it remains to be shown which encodes the actin-crosslinking protein alpha-actinin, Biophys Rev the marker protein for Z-discs (Chiu et al. 2010). Thorough knockout mouse was generated, which expressed only molecular characterisation of these mutations is still under 40% of cofilin-2 compared to wild-type littermates. way, but first results indicate that at least in the case of These mice displayed dilation and wall thinning of the left A119T and G111V mutations, the dynamic behaviour of ventricle (Subramanian et al. 2015). The reduced contrac- alpha-actinin and its readiness to incorporate into the Z-disc tile function was attributed to disorganised sarcomeres in may be affected (Haywood et al. 2016). A second major Z- the heterozygous cofilin-2 mice (Subramanian et al. 2015). disc-associated actin-binding protein that was shown to cause These data suggest that cofilin-2 has a regulatory role also cardiomyopathy when mutated is filamin C. Missense muta- in cardiomyocytes and that its expression must be tightly tions of filamin C cause familial restrictive cardiomyopathy controlled to prevent cardiomyopathy. and lead to a loss of filamin C signal at the Z-disc (Tucker et Profilin is a protein that sequesters actin monomers and al. 2017). Truncating variants of filamin C and its co- governs their ATP-associated state, leading to a higher affinity chaperone BAG3 are associated with DCM (Janin et al. for the barbed ends (for a review, see dos Remedios et al. 2017). Interestingly, BAG3 stimulates filamin transcription 2003). Interestingly, the barbed ends are classically assumed and also spatially regulates mTORC1 signalling to simulta- to be the major site of activity of formins. Formins are neously induce autophagy of damaged filamin and activate characterised by two formin homology (FH) domains, FH1 protein synthesis upon mechanical stress in cardiomyocytes and FH2. The FH2 domains of two formins dimerise into a (Kathage et al. 2017). Again, these results indicate that actin- doughnut-like structure that forms the business end for associated proteins are not just static glue at their respective formin-promoted actin assembly (Goode and Eck 2007), sites but closely interweave with signalling pathways that are while the FH1 domain interacts with profilin and may help relevant for the cardiomyocyte stress response. to shunt profilin-bound actin monomers to the neighbouring FH2 domain. Since profilin dissociates from actin in the pres- ence of PIP and PIP2, the environment of the Z-disc, which is Proteins involved in actin filament turnover enriched in PIP2 (Pyle et al. 2006; Ribeiro et al. 2014), would and their role in cardiac disease and repair be an ideal location to release the actin from profilin and make it available for polymerisation. A recent study has demonstrat- Cofilin-2 is a member of the ADF/cofilin family of pro- ed that the expression of profilin is increased in a variety of teins that acts preferentially at the pointed ends of actin rodent models for hypertrophy in situ and in vitro, but de- filaments and increases the off-rate by 30-fold (for a creased in end-stage heart failure patients (Kooij et al. 2016). review, see dos Remedios et al. 2003). In cultured In vivo experiments in Drosophila showed that overexpres- cardiomyocytes, cofilin-2 was shown to localise towards sion of profilin leads to longer thin filaments than in control strains and results in a functional phenotype resembling dilat- the M-band region of the sarcomeres, where the pointed ends are found (Kremneva et al. 2014). In a healthy car- ed cardiomyopathy (Kooij et al. 2016). Knockdown of diomyocyte in situ, cofilin-2 should not affect the structure profilin expression in cultured cardiomyocytes prevented their of thin filaments too much, since the pointed ends are hypertrophic response, probably by impaired activation of protected by tropomodulin or leiomodin and cofilin’s ERK1/ERK2 signalling (Kooij et al. 2016). In conclusion, depolymerising activity is known to be inhibited by the profilin appears likely to be crucial for hypertrophic growth presence of tropomyosins (dos Remedios et al. 2003). in the heart, potentially by delivering actin monomers for as- However, when cofilin-2 expression is knocked down in sembly by members of the formin family. cultured cardiomyocytes, a marked elongation of thin fila- Another small actin monomer-binding protein, thymosin ments is observed and proper I-band striations are lost beta 4 (Tbeta4), has recently entered the limelight by its ability (Kremneva et al. 2014). In a mouse model for DCM, the to enhance cardiac repair in the adult heart following injury calsarcin knockout mouse, cofilin-2 expression was in- (Smart et al. 2011). Tbeta4 was administered to the mice by creased due to a decrease in miRNA miR-301a expression intraperitoneal injection and somehow seemed to activate a and was subsequently shown to be a direct target for this population of stem cells in the epicardial surface of the heart miRNA (Rangrez et al. 2017). Cofilin-2 function is regu- that differentiated into blood vessels but also to a much lower lated by phosphorylation, and fasudil, an inhibitor of extent into cardiomyocytes. The exact role of Tbeta4 in ROCK (Rho kinase), which has a protective effect against cardiomyocytes is somewhat unclear at the moment, since cardiac dysfunction, prevents its phosphorylation and pro- Tbeta4 knockout mice had no cardiac phenotype (Banerjee motes the organisation of actin filaments (Lai et al. 2017). et al. 2012). Therefore, its contribution to improved cardiac In human idiopathic DCM, aggregates of cofilin-2 in its repair may be mainly due to its enhancement of vascularisa- phosphorylated state were detected in the heart samples tion of the injured heart. On the other hand, another group of patients (Subramanian et al. 2015). To model reduced reported shorter sarcomere length, expression of shorter titin cofilin-2 activity, a heterozygous cardiac specific cofilin-2 isoforms and a limited contractile reserve in their Tbeta4 Biophys Rev Bao B, Zhang L, Hu H, Yin S, Liang Z (2012) Deletion of a single-copy knockout mice, suggesting that Tbeta4 may be somehow in- DAAM1 gene in congenital heart defect: a case report. BMC Med volved in the regulation of alternative splicing of titin, poten- Genet 13:63 tially via RBM20 (Guo et al. 2012; Smart et al. 2017). Bennett PM, Maggs AM, Baines AJ, Pinder JC (2006) The transitional junction: a new functional subcellular domain at the intercalated disc. Mol Biol Cell 17:2091–2100 Benz PM, Merkel CJ, Offner K, Abesser M, Ullrich M, Fischer T, Bayer B, Wagner H, Gambaryan S, Ursitti JA, Adham IM, Linke WA, Concluding remarks Feller SM, Fleming I, Renne T, Frantz S, Unger A, Schuh K (2013) Mena/VASP and alphaII-Spectrin complexes regulate cyto- With the advance of next-generation sequencing, it can be plasmic actin networks in cardiomyocytes and protect from conduc- expected that many more point mutations will be identified tion abnormalities and dilated cardiomyopathy. Cell Commun Signal 11:56 in actin-associated proteins in patients with cardiomyopathy, Bos JM, Ackerman MJ (2010) Z-disc genes in hypertrophic cardiomyop- whose contribution to the observed functional phenotypes will athy: stretching the cardiomyopathies? J Am Coll Cardiol 55:1136– have to be validated. However, it is obvious that the actin cytoskeleton is dynamic and that subtle changes that affect Casella JF, Craig SW, Maack DJ, Brown AE (1987) Cap Z(36/32), a barbed end actin-capping protein, is a component of the Z-line of this dynamics and its amount will alter the function of a skeletal muscle. J Cell Biol 105:371–379 cardiomyocyte. Chereau D, Boczkowska M, Skwarek-Maruszewska A, Fujiwara I, Hayes DB, Rebowski G, Lappalainen P, Pollard TD, Dominguez Acknowledgements I would like to thank the collaborators past and pres- R (2008) Leiomodin is an actin filament nucleator in muscle cells. ent for their hard work and fruitful discussions. Science 320:239–243 Chesarone MA, Goode BL (2009) Actin nucleation and elongation fac- Funding The research in my laboratory was financially supported by the tors: mechanisms and interplay. Curr Opin Cell Biol 21:28–37 British Heart Foundation and the Medical Research Council. Chiu C, Bagnall RD, Ingles J, Yeates L, Kennerson M, Donald JA, Jormakka M, Lind JM, Semsarian C (2010) Mutations in alpha- actinin-2 cause hypertrophic cardiomyopathy: a genome-wide anal- Compliance with ethical standards ysis. J Am Coll Cardiol 55:1127–1135 Copeland O, Nowak KJ, Laing NG, Ravenscroft G, Messer AE, Bayliss Conflict of interest Elisabeth Ehler declares that she has no conflict of CR, Marston SB (2010) Investigation of changes in skeletal muscle interest. alpha-actin expression in normal and pathological human and mouse hearts. J Muscle Res Cell Motil 31:207–214 Ethical approval This article does not contain any studies with human dos Remedios CG, Chhabra D, Kekic M, Dedova IV, Tsubakihara M, participants or animals performed by the author. Berry DA, Nosworthy NJ (2003) Actin binding proteins: regulation of cytoskeletal microfilaments. Physiol Rev 83:433–473 Open Access This article is distributed under the terms of the Creative Dwyer J, Iskratsch T, Ehler E (2012) Actin in striated muscle: recent Commons Attribution 4.0 International License (http:// insights into assembly and maintenance. Biophys Rev 4:17–25 creativecommons.org/licenses/by/4.0/), which permits unrestricted use, Dwyer J, Pluess M, Iskratsch T, dos Remedios CG, Ehler E (2014) The distribution, and reproduction in any medium, provided you give appro- formin FHOD1 in cardiomyocytes. Anat Rec (Hoboken) 297:1560– priate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Ehler E, Horowits R, Zuppinger C, Price RL, Perriard E, Leu M, Caroni P, Sussman M, Eppenberger HM, Perriard JC (2001) Alterations at the intercalated disk associated with the absence of muscle LIM protein. 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