The costamere³ is a structural and functional component of striated myocytes. This proteic complex consists of cytoskeletal proteins and signaling kinases. It couples the sarcomere to the sarcolemma. This subsarcolemmal proteic assembly encircles the myocyte and is circumferentially aligned with the Z disc, as it anchors myofibrils from the Z disc to the sarcolemma and extracellular matrix. Costameres are sites of force transmission [328].

The costamere is composed of the dystrophin-associated glycoprotein complex (DGC) and the integrin complex (Table 4.2). The dystrophin-associated glycoprotein complex is a structural unit and scaffold for signaling molecules at the sarcolemma. It is composed of dystroglycans and sarcoglycans as well as focal adhesion constituents. It maintains the structural integrity of myofibers by linking the extracellular matrix to the subsarcolemmal cytoskeleton. The costamere coordinates force transduction and intracellular signaling.
The dystrobrevin family comprises α- and β-dystrobrevin that are encoded by the DTNA and DTNB genes, respectively. The former is expressed predominantly in muscle and brain and the latter in nonmyocyte cells.

α-dystrobrevin is a component of the DGC that directly tethers to dystrophin. In striated myocytes, dystrobrevin and dystrophin localize to the cytoplasmic face of the sarcolemma. α-dystrobrevin also binds to intermediate filaments as well as syntrophin, a modular adaptor protein.⁴

α-syntrophin is the major isoform in skeletal and cardiac myocytes [329]. Syntrophin can coordinate the assembly of nitric oxide synthase NOS1, P38MAPKγ, transient receptor potential channels (TRPC), which modulates cation (calcium) entry, and calmodulin to the DGC.

α-dystrobrevin experiences alternative splicing that impacts its subcellular distribution and function in myocytes. Among the three major α-dystrobrevin isoforms, α-dystrobrevin-1 and α-dystrobrevin-2 localize to the sarcolemma. The former colocalizes with both dystrophin and utrophin and the latter only with dystrophin. α-dystrobrevin-1 to α-dystrobrevin-3 bind to the sarcoglycan complex [329]. α-dystrobrevin-1 and α-dystrobrevin-2 tether to dystrophin and syntrophin (but not α-dystrobrevin-3).

Additional α-dystrobrevin-binding partners include the constituents of the mechanical stabilizer intermediate filament syncoilin and β-synemin as well as dysbindin [329]. In striated myocytes, intermediate filaments encircle the Z disc, thereby connecting all adjacent myofibrils and linking the Z disc of the peripheral layer of cellular myofibrils to the sarcolemma. Syncoilin also binds to desmin, a muscle-specific intermediate filament protein. The α-dystrobrevin–syncoilin interaction provides another linkage between the DGC and cytoskeleton, which may be important for force transduction during contraction. β-synemin interacts with plectin, a linker protein of intermediate filaments to the Z disc. Dysbindin (or dystrobrevin-binding protein-1) is a ubiquitous sarcolemmal protein, the expression of which is relatively low in muscle [329]. It binds to α-dystrobrevin and myospryn.⁵ Myospryn may function as a docking platform for structural and signaling molecules, such as α-actinin-2 and protein kinase-A [329].

α-catulin is a ubiquitous binding partner of α-dystrobrevin-1 that localizes to nerve bundles and blood vessels. It may regulate α1d-adrenergic receptor signaling.

α-actinin binds to: (1) actin and the CRSP3–Tcap–titin complex⁶ to organize the local cell architecture and (2) to talin and vinculin to connect the sarcomeres to costameres and, hence, to integrins and the extracellular matrix constituents (e.g., collagen and laminin). The mechanosensor and mechanotransducer vinculin is also connected to intercellular junctions, not only integrin-based adhesion complexes, but also tight, adherens, and gap junctions.

The cytoplasmic domain of β-integrin binds integrin-linked kinase (ILK) and melusin. The former has structural and functional roles at the costamere, as it recruits various adaptors (e.g., LIM and senescent cell antigen-like domain-containing proteins [LIMS], ⁷ parvins [α-parvin, or actopaxin, and β-parvin, or affixin], and paxillin), cytoskeletal, and signaling molecules. In particular, it links to various kinases and phosphatases (e.g., protein Ser/Thr ILK-associated phosphatase [ILKAP], an inhibitor of ILK of the PPM1 category, 3-phosphoinositide-dependent [PI3K-dependent] protein kinase PDK1, which phosphorylates PKB, and PKB) [330]. Therefore, ILK is connected to the actin cytoskeleton, focal adhesion complex, and growth factor receptors.

Morerover, it phosphorylates protein kinase-B and other signaling effectors to regulate the muscular response to stretch [330].

In addition to their structural role, integrins and their associated adaptor proteins recruit to the plasma membrane signaling molecules used for the survival and growth of cardiomyocytes (e.g., focal adhesion kinase, ILK, P21-activated kinase, proline-rich tyrosine kinase PYK2, PKC, and Src) [330].

Furthermore, the focal adhesion complex can be linked to growth factor receptors, thereby enabling crosstalk between mechanotransduction and growth factor-mediated hypertrophic signals.

Costameric and sarcomeric proteins, particularly those of the Z disc, are components of the cardiac stretch sensor.

The mechanical stretch response can be impaired, whereas hypertrophic signaling triggered by humoral factors such as endothelin-1 can remain intact.

The N-cadherin complex links adjacent cardiomyocytes via adherens junctions (with α-, β-, and δ1-catenins and related partners), as do mechanosensory integrins vie focal adhesion complexes (with numerous cytoskeletal adaptors [e.g., filamin, paxillin, talin, and vinculin] and signaling effectors [e.g., focal adhesion kinase and small RhoA GTPase]), is sensitive to force transmission. Forces acting on N-cadherin–mediated adhesions elicit structural and functional changes in cardiomyocytes.

α-catenin is a major component of the mechanosensory cadherin–catenin complex that connects to the cell actin cytoskeleton. It homodimerizes or heterodimerizes with β-catenin. It localizes to regions of highest mechanical stress on cardiomyocytes [331]. Localization of α-catenin depends on N-cadherin topography, and hence on the degree of internal stress at the intercellular junction, that is, on changes in contractility. The α-catenin–cadherin complex indeed serves as a mechanosensory regulator of the cardiomyocyte cytoskeletal structure.

Sarcomeric remodeling depends on whether adhesion and force transmission is mediated by cadherins or integrins. Inhibition of myosin bound by integrins to fibronectin disrupts myofibril organization. On the other hand, inhibition of myosin bound by N-cadherins disturbs to a lower extent myofibril arrangement. These two mechanosensory cell adhesion types provide independent mechanisms for regulating sarcomeric organization. Lower myosin activity is preferential for cadherin-dependent assembly and preservation of sarcomeres [331]. Cadherin- and integrin-based junctions can sustain stresses of similar magnitudes, but subsequent cytoskeletal remodeling differs due to the specific function of proteic components and their interaction in assembling and orienting actin bundles in response to mechanical stresses.

More than 900 mutations in genes expressed in the cardiomyocyte can cause cardiomyopathies [332]. More than 400 mutations in 13 sarcomeric proteins are linked to cardiomyopathies (Table 4.3). Mutations in genes encoding sarcomeric constituents (e.g., cardiac α-actin, myosin light chain, cardiac β-myosin heavy chain, cardiac myosin-binding protein-C, cardiac troponin-I and -T, titin, and tropomyosin) are usually inherited in an autosomal-dominant manner and are missense mutations. Mutations in both the essential and regulatory myosin light chains cause a rare form of midventricular hypertrophic cardiomyopathy.

Mutations of several sarcomeric components are associated with dilated cardiomyopathy and skeletal muscle myopathy. Major forms of muscular dystrophies are caused by abnormalities of the dystrophin-associated glycoprotein complex. Mutations in the dystrophin gene generate Duchenne and Becker muscular dystrophy. Duchenne muscular dystrophy in skeletal muscles and heart is characterized by the absence or slight production of functional dystrophin (Table 4.4). In Becker muscular dystrophy, a partly functional dystrophin is synthesized.

Mutations in the sarcoglycan genes cause several types of sarcoglycan-deficient limb-girdle muscular dystrophy (SDLGMD).

Mutations in several Z-disc proteins of the cardiomyocyte sarcomere, which lead to disruption and dysfunction of the contractile apparatus, cause cardiomyopathies [333].

Ischemic and nonischemic cardiomyopathies share expression of some genes compared with controls, but numerous genes are differently expressed with respect to cardiomyopathy types and controls [334]. Among extracellular stimuli (ions, hormones, and mechanical stress), pathological myocardial remodeling is mainly induced by neurohormonal factors (angiotensin-2, endothelin-1, and catecholamines) via the Gq–PLCβ axis that activates the IP–Ca–PP3–NFAT and DAG–PKC pathways.

On the other hand, adaptive cardiac (exercise-induced) hypertrophy that is particularly induced by growth hormone and insulin-like growth factor is associated with the PI3K–PKB–GSK3α/β pathway. Phosphoinositide 3-kinase-α downstream from the IGF1 receptor mediates adaptive cardiac growth (normal postnatal growth as well as growth in response to chronic exercise training) and protects the heart against pressure overload, dilated cardiomyopathy, and myocardial infarction.

Numerous inherited and acquired cardiomyopathies has been described, in addition to unclassified cardiomyopathies. They are categorized mainly into dilated, hypertrophic, and restrictive cardiomyopathies and arrhythmogenic right ventricular cardiomyopathy.

Many causes of cardiomyopathies exist (Table 4.5). Acquired cardiomyopathies can result from stress, diabetes, some chemotherapeutic agents, pregnancy, and alcohol intake. The most common cause is ischemic cardiomyopathy.

Cardiomyopathies are generally categorized into two groups: extrinsic and intrinsic cardiomyopathies.

Intrinsic cardiomyopathies are usually classified into four main categories (Table 4.6;[210]):

Like in normal hearts, two populations of mitochondria exist in cardiomyopathies at least in hamsters [335]: (1) subsarcolemmal mitochondria beneath the sarcolemma and (2) interfibrillar mitochondria among the myofibrils.

Mitochondrial enzymes (enoylCoA hydratase, hydroxyacylCoA dehydrogenase, and citrate synthase) are depressed in cardiomyopathies. The content of coenzyme-A remains unaltered, but carnitine amount is reduced.

The two heart mitochondrial populations are distinctly affected, as they react differently in cardiomyopathy. Oxidative phosphorylation in subsarcolemmal mitochondria is normal, whereas it decays in interfibrillar mitochondria. The amount of mitochondrial respiratory supercomplexes mtRSC1 (cI–cIII–cIV) of the electron transport chain, the major form of the so-called respirasome, can decay, thereby reducing the efficiency of electron transfer and energy production.

Compensatory responses, such as changes in gene expression and cellular morphology and metabolic shifts in cardiomyocytes, can initially maintain the cardiac function in cardiomyopathy.