studies in developing embryos have made a significant contribution to our current knowledge of myofibril assembly and the importance of different components of the sarcomere , providing us with a molecular basis for a better comprehension of cardiac diseases . the highly orchestrated morphological and molecular events during early cardiac development have been the subject of research in different animal models , such as chick and mouse embryos . after gastrulation during embryonic development , cardiogenic cells from anterior lateral plate mesoderm can be distinguished in the so - called cardiac crescent ( first heart field ) . later , these cardiogenic cells migrate towards the ventral midline to form the primitive linear heart tube , giving rise to the definitive left ventricle and inflow tract . cardiogenic cells located medially to the cardiac crescent ( second heart field ) are recruited during heart tube elongation and looping stages , giving rise to the right ventricle and outflow tract myocardium . before fusion of cardiogenic cells to the linear heart tube is completed , contractile sarcomeric proteins such as -actinin are expressed . alpha - actinin is a major component of the sarcomere and localised at the z - disc , a structure that defines the boundaries of each sarcomeric unit and thus shared by neighbouring sarcomeres . besides the z - disc , other components of the sarcomere can be distinguished : the i - band ( isotropic ) surrounds the z - disc and is composed of only actin filaments , the a - band ( anisotropic ) is composed of actin and myosin filaments and the m - band ( middle ) forms the centre of each sarcomere . contraction is regulated by the coordinated action of the actin - containing thin filaments and the myosin - containing thick filaments , which slide over each other in an atp - dependent manner . in the heart the giant protein titin is the structural backbone of the sarcomere , indicated by the spanning of the entire z - disc by two molecules of titin . titin determines the stiffness of the sarcomere , retains the a - band in the middle of the sarcomere during contraction and is connected with -actinin at the z - disc . alpha - actinin , in its turn , forms homodimers in an antiparallel manner and cross - links actin . cardiomyopathy is a group of disorders of the heart that result in inadequate pumping of blood around the body . hypertrophic cardiomyopathy ( hcm ) and dilated cardiomyopathy ( dcm ) are mainly caused by mutations in sarcomeric proteins . hcm is characterised by left ventricular hypertrophy ( resulting from increased cell size or volume ) , increased systolic function and decreased diastolic function . at the histological level , hypertrophy and disarray of cardiomyocytes and interstitial fibrosis is observed . dcm , on the other hand , is characterised by ventricular dilation and contractile dysfunction of the left and/or right ventricles . depending on the location of the mutation , hcm or dcm is induced ; in hcm regions of sarcomeric proteins are mutated that are directly involved in force transmission , whereas the regions that are mutated in dcm are involved in force transmission from the sarcomere to the cytoskeleton . the majority of mutations in sarcomeric proteins are found in myosin heavy chain  and myosin binding protein c [ 2 , 3 ] . besides mutations in proteins that affect force generation and transmission , mutations in proteins at the z - disc ( and also the m - band ) that disrupt stress sensing and downstream signalling have also been implicated in cardiomyopathies and severe hypertrophic responses . for instance , calcineurin , muscle - specific lim protein ( mlp ) , t - cap , calsarcin-1 , cypher and enigma homologue protein ( enh ) interact with -actinin at the z - disc and have been associated with cardiomyopathies . the putative stress sensor mlp has been shown to be an essential component of the t - cap and titin complex , stabilising the interaction between these proteins , which can then sense an increase in stretch , followed by activation of downstream signals for the induction of hypertrophy . activated calcineurin dephosphorylates nuclear factor of activated t - cells ( nfat ) , which subsequently translocate to the nucleus to activate genes that are associated with stress , such as atrial natriuretic factor ( anf ) and brain natriuretic peptide ( bnp ) , and genes that encode foetal isoforms of contractile proteins , such as -myosin heavy chain ( -mhc ) . calcineurin transgenic ( tg ) mice , expressing a constitutively active form of the catalytic subunit of calcineurin in the heart , show massive hypertrophy , disorganised cardiomyocytes , fibrosis and enlarged nuclei . overexpression of calsarcin-1 , both in vitro and in vivo , has protective effects on hypertrophy by interfering with calcineurin - nfat signalling , while a lack of calsarcin-1 sensitises the calcineurin pathway and shows accelerated formation of cardiomyopathy in response to pathological stimuli . cypher ( or oracle / zasp ) is expressed in heart and skeletal muscle during mouse and zebrafish development and interacts with -actinin and calsarcin . deletion of cypher in mice and zebrafish resulted in disruption of the z - disc structure leading to dcm . however , in mice only deletion of the long isoform of cypher led to development of late - onset dcm , whereas deletion of the short isoform had no effect . these results indicate cypher as an essential component of the -actinin - calcineurin - calsarcin complex in order to maintain cardiac structure and function . enh is another pdz - lim protein , which interacts with -actinin , calsarcin and cypher . in enh mice expression of the short cypher isoform and calsarcin is lost , which leads to disruption of the z - disc and development of dcm . these data show an essential role for the z - disc in the development of cardiomyopathies and targeting these components could reveal strategies for possible new therapies for the treatment of these diseases . the actin cytoskeleton in striated muscles is organised in sarcomeres for generation of contractile force , as we have previously discussed . actin is also important in other cellular processes , including cytokinesis , migration , regulation of cell shape and gene expression during development and disease . in recent years , it has become clear that regulators of actin dynamics are crucial for the assembly and maintenance of functional sarcomeres . polymerisation of monomeric globular actin ( g - actin ) in filamentous actin ( f - actin ) is regulated by several actin - binding proteins . rho gtpases ( rhoa , rac and cdc42 ) induce actin polymerisation via the rho - associated kinase ( rock)-lim kinase - cofilin pathway . rhoa is highly expressed in embryonic hearts , down - regulated in adult hearts and re - expressed during cardiac hypertrophy . heart - specific overexpression of rhoa leads to the development of a dcm phenotype , whereas inhibiting rock protects the heart after aorta constriction . in addition , actin signalling has an important role in the regulation of transcriptional activity of various transcription factors , such as serum response factor ( srf ) , myocardin - related transcription factors ( mrtfs ) and mef2 . srf is a member of the mads ( mcm1 , agamous , deficiens , srf ) family of transcription factors , which share a conserved motif of 57 amino acids mediating homodimerisation , association with other factors and dna - binding activity . homodimeric srf binds to a palindromic dna sequence ( cc(a / t)6gg ) , which is called the carg box . several srf - mouse models have shown that srf is essential for cardiac development , as well as maintaining adult cardiomyocytes . srf is responsible for maintaining the sarcomeric integrity in cardiomyocytes and disruption of its expression results in dcm in mice . therefore , it is not surprising to find several sarcomeric genes , such as skeletal and cardiac actin , -mhc and -mhc , myosin light chain ( mlc)2a and 2v , myomesin , troponin c , and titin , to be targets of srf . myocardin , a co - activator of srf , is essential for smooth muscle differentiation and activates expression of smooth muscle genes in promoters with two adjacent carg boxes by binding these as homodimers . cardiac specific deletion ( using an -mhc - cre mouse line ) of myocardin leads to decreased expression of sarcomeric genes ( -cardiac actin , mlc2v , and tropomyosin ) and connexin 43 and desmin , which results in disruption of the structural organisation of the sarcomere and intercalated discs , respectively . furthermore , the hearts of -mhc - cre - myocardin showed left atrial enlargement , hypertrophy , interstitial fibrosis and a decreased cardiac function ( decreased ejection fraction ) . myocardin also has an essential function during pathophysiological events in the heart ; it is upregulated in several in vivo and in vitro models of hypertrophy , as well as in human patient hearts with idiopathic dcm . the hypertrophic marker anf is a direct target of myocardin and overexpression of myocardin in cardiomyocytes in vitro leads to a hypertrophic response , which can be abolished by expression of a dominant negative isoform lacking the transcriptional activation domain . four isoforms of mef2 exist ( a  d ) , of which isoforms a , c and d have distinct functions in the heart . knock - out studies show that mef2a is essential for energy metabolism and sarcomeric organisation in adult hearts , mef2c is involved in cardiac morphogenesis , and mef2d is a mediator of stress - dependent pathological remodelling of the adult heart . on the other hand , overexpression of these factors induced ( dilated ) cardiomyopathy in mice . transcriptional activity of srf is regulated by striated muscle activator of rho signalling ( stars ) . stars binds to actin and activates rhoa , which promotes actin polymerisation and depletion of the g - actin pool . subsequently , mrtfs translocate to the nucleus ( via decreased binding to g - actin binding domain ) and activate gene expression by acting as co - factor for srf . stars has been shown to be a direct target of mef2 in different models of hypertrophy . thus , the formation of actin bundles is not only necessary for cell movement and polarisation , but also leads to the induction of signal - transduction pathways important for cardiac development and hypertrophy . recently , following whole genome - wide microarray analysis of pluripotent human embryonic stem cell differentiating towards functional cardiomyocytes , we identified a novel gene , which we named cytoskeletal heart - enriched actin - associated protein ( chap ) ( also known synaptopodin-2-like ( synpo2l ) ) and which is highly expressed in heart and skeletal muscle . chap displays a significant homology to myopodin and synaptopodin ( 31  % and 30  % , respectively ) , which are both actin - bundling proteins that bind to -actinin . whereas synaptopodin is expressed in kidney and forebrain , myopodin is predominantly expressed in skeletal muscle and at lower levels in heart and smooth muscle cells . interestingly , myopodin is localised at the z - disc of skeletal muscle cells and cardiomyocytes , but can be translocated to the nucleus in a differentiation- and stress - dependent manner . phosphorylated synaptopodin and myopodin , mediated by inhibition of calcineurin activity , resulted in stabilisation of the actin cytoskeleton in kidney podocytes   and translocation from the z - disc to the nucleus in cardiomyocytes , respectively . based on the homology of chap with both myopodin and synaptopodin , we decided to further explore the role of chap in cardiomyocyte differentiation and more specifically in sarcomere organisation and function . we identified two isoforms of human and mouse chap : a long isoform chapa and a shorter isoform chapb . chapa and chapb isoforms are almost identical , containing a putative nuclear localisation signal ( nls ) and actin binding sites . one chap isoform has been identified , which shows homology with the human and mouse chapa gene . during mouse embryonic development , chapb is first expressed at the cardiac crescent stage ( e7.75 ) , later in the linear heart tube and in the looped heart . from embryonic day 10 onward , expression is also detected in somites ( giving rise to skeletal muscle ) . expression of chapb is downregulated in adult hearts , whereas chapa is expressed in adult heart and skeletal muscle . furthermore , chap is expressed in developing muscles , such as jaw , tongue and eye muscle . a similar expression pattern of chap in chick embryos was observed . in addition , we showed expression of mouse chap in skeletal muscle and smooth muscles of the aorta , carotid artery and coronary arteries . similar to myopodin , we demonstrated that chap was localised at the z - disc of cardiomyocytes and skeletal muscle cells , supported by co - localisation of -actinin and the lack of overlap in localisation with the m - band marker myomesin ( fig .  1 ) moreover , besides their co - localisation , we also showed that chap was able to interact with -actinin-2 . in a next step we studied the role of chap during zebrafish development . morpholino - mediated knock down of chap in zebrafish resulted in defects in heart looping , cardiac oedema and disturbed skeletal muscle development . mouse embryonic stem cells were differentiated to cardiomyocytes and immunostained with antibodies for the z - disc protein chap ( green , left ) , m - band marker myomesin ( red , middle ) . ( right ) it can be appreciated that chap and myomesin do not co - localise chap is localised at the z - disc . mouse embryonic stem cells were differentiated to cardiomyocytes and immunostained with antibodies for the z - disc protein chap ( green , left ) , m - band marker myomesin ( red , middle ) . ( right ) it can be appreciated that chap and myomesin do not co - localise in order to investigate the role of chap in adult mice , we generated transgenic mice by heart - specific overexpression of both isoforms of chap . chapb transgenic mice displayed a phenotype , which resembles dilated cardiomyopathy and was associated with abnormal atrial conduction ( unpublished data ) . interestingly , in a recent large - scale meta - analysis of multiple genome - wide association studies of european ancestry six new susceptibility loci for atrial fibrillation were identified , of which one locus was located 5  kb upstream of synpo2l ( chap ) and 20  kb upstream of myoz1 ( calsarcin-2 ) . it is evident that well - coordinated activities of the various components of the sarcomere are necessary for proper function of the heart muscle . changes in expression levels , localisation or function of these components may ultimately lead to heart failure . heart failure patients with impaired cardiac contractility can be treated with drugs that enhance -receptor camp - dependent protein kinase pathways , leading to increased phosphorylation of many different target proteins ( including sarcomeric proteins ) and increased cardiac contractility . however , detrimental side effects can be observed , because of the lack of selectivity of these drugs . nevertheless , recent successful development of selective activators of sarcomeric contractile and their regulatory proteins ( i.e. kinases ) demonstrate that the sarcomere is a potentially promising drug target . in addition , significant recent advances in ( human ) pluripotent stem cell biology now enable efficient generation of functional cardiomyocytes in vitro from patients and healthy individuals . studying abnormal cardiomyocyte function at the cellular level may provide a better understanding of the underlying mechanism(s ) responsible for the cardiac disease phenotype in patients . moreover , implementation of in vitro cardiac disease models for drug discovery may be valuable for screening and identification of effective and selective drugs , leading to improved therapeutic strategies . in conclusion , the perception of the sarcomere has considerably changed during the last two decades , going from a static contractile unit , responsible for generation and propagation of mechanical force , to a dynamic unit which , in addition to its essential role in contractility , is important for sensing mechanical stress or other changes in upstream signalling and the translation to adequate downstream signalling events . an increased knowledge in sarcomeric biology and function will be fundamental for unravelling signalling pathways that are important for both muscle development and disease . moreover , recent advances in pharmacological interventions with small molecule drugs have shown functional responses at the level of individual myosin and actin filaments , leading to an increased awareness of the potential of sarcomeric proteins as pharmacological targets . ultimately , this may lead to new therapeutic strategies for the treatment of a variety of muscle diseases .
sarcomeres are the smallest contractile units of heart and skeletal muscles and are essential for generation and propagation of mechanical force in these striated muscles . during the last decades it has become increasingly clear that components of sarcomeres also play a fundamental role in signal transduction in physiological and pathophysiological conditions . mutations or misexpression of both sarcomeric contractile and non - contractile proteins 
 have been associated with a variety of cardiac diseases . 
 moreover , re - expression of foetal sarcomeric proteins or isoforms during cardiac disease can be observed , emphasising the importance of understanding signalling in sarcomeres in both development and disease . 
 the prospective of pharmacological intervention at the level of the sarcomere is now emerging and may lead to novel therapeutic strategies for the treatment of cardiac and skeletal muscle diseases . 
 these aspects will be discussed in this brief review and recent findings , which led to novel insights into the role of the sarcomeric cytoskeleton in muscle development and disease , will be highlighted .