*2.4.2.4 Sarcoplasmic reticulum: calcium homeostasis*

*Visions of Cardiomyocyte - Fundamental Concepts of Heart Life and Disease*

and decrease contractile strength [55].

where it acts as a stretch sensor and myofibril stabilizer. It limits sarcomere stretch in early diastole and restores resting sarcomere length after contraction [52, 53]. Titin (TTN) mutations are the most prevalent genetic cause of idiopathic DCM (15–20%). In fact, DCM patients with TTN mutations have a worse outcome due to a higher arrhythmic risk and progressive functional deficits [54]. Mutations in human genes encoding protein components of the sarcomere cause either HCM or DCM. Deficits of force production and transmission are the two main mechanisms that lead to DCM due to sarcomere mutations [55]. Mutations of genes encoding myosin proteins (MYH 6, MYH7, and MYBPC3), actin proteins (ACTC 1 and ACTC 2), and tropomyosin protein (TPM 1) result in alterations of coupling-uncoupling mechanisms of actin to myosin [50]. Specifically, TPM1 mutations are associated with destabilization of actin interactions and compromise force transmission to neighboring sarcomeres. ACTC mutations impair the binding of actin to the Z-disc compromising force propagation [55]. Impaired contractile force may also occur from troponin mutations. Because troponin molecules modulate calcium-stimulated actomyosin ATPase activity, the mutation causes inefficient ATP hydrolysis

*2.4.2.2 Cytoskeleton protein location: force transmission and structural integrity*

another intermediate filament in cardiomyocytes, forms a 3D scaffold that extends across the entire diameter of the cardiomyocyte, surrounds the Z-discs and interlinks them together and integrates the contractile apparatus with the sarcolemma and the nucleus. Desmin helps to sense mechanical stretch and transduces downstream signals from extracellular to the nucleus. In addition, desmin plays a crucial role during myogenesis. Inhibition of desmin expression blocks myoblast fusion and myotube formation [58]. Mutations in the desmin genes are associated with an autosomal dominant skeletal myopathy, cardiac conduction block, and DCM [59]. Prevalence of desmin mutations in familial DCM have been

The Z-disc is an electron-dense structure, in which titin and the thin filaments anchor. Critical components include α-actinin, which aligns actin and titin from neighboring sarcomeres and interacts with muscle LIM protein (MLP encoded by CSRP3). Telethonin (encoded by TCAP) is another Z-disc component interacting with titin and MLP to support overall sarcomere function. In addition, Cipher/Zband alternatively spliced PDZ-motif protein (Cipher/ZASP encoded by LDB3), which interacts with α-actinin-2 through a PDZ domain, an abundant protein interaction modules that recognize short amino acid motifs of the C-termini of target proteins, and couples to protein kinase C (PKC)-mediated signaling via its LIM domains [55, 56]. Gene mutations of multiple Z-disc proteins like MLP, cardiac ankyrin repeat protein (CARP), myopalladin, α-actinin 2, TCAP, and nexilin may result in DCM [52]. Cipher/ZASP mutations have been associated to isolated left ventricular dilatation or DCM with NCCM phenotype [50]. Metavinculin (encoded by VCL) attaches the thin filaments to the plasma membrane and plays a key role in force transmission. Gene mutations in metavinculin cause DCM by disruption of disc structure and actin-filament organization [55]. The costamere, a rib-like structure of the cytoplasmatic and transmembrane proteins, interconnects the cytoskeleton to the plasma membrane and the extracellular matrix. Dystrophin and its associated proteins, sacroglycans and dystroglycan, enrich at the costamere and protect against contraction-induced injury [52]. The integrity of the dystrophin complex is critical for mechano-transduction and loss of function mutations trigger instability of the plasma membrane and myofiber loss. This mechanism leads to Duchenne and Becker muscular dystrophy [57]. Desmin,

**46**

reported in 1–2% [60].

Calcium enters the myocyte through voltage-gated L-type Ca2+-channels. This triggers the release of calcium from the sarcoplasmic reticulum (SR) via the ryanodine receptor 2 (RyR2). At low intracellular calcium concentrations, troponin I and actin interactions block actomyosin ATPase activity. With increasing intracellular concentration, calcium binds to troponin C, which releases troponin I inhibition and stimulates contraction. Calcium dissociates from troponin C in cardiac relaxation. Calcium concentration decreases by calcium reuptake in the SR through the phospholambanregulated cardiac sarcoplasmic reticulum CA2+-ATPase (SERCA2a) [55]. Mutations of phospholamban precipitate DCM by altering calcium homeostasis [54]. Specific phospholamban mutation R14del is associated with high risk of malignant ventricular arrhythmias and end-stage HF. Further, it is described in a phenotype of ARVC [62].
