*2.4.2.1 Sarcomere protein location: force generation and transmission*

The sarcomere is the contracting unit of the myocyte. The thin filaments of the sarcomere emanate from the Z-disc. They consist of filamentous α-actin (gene name ACTC 1) and calcium-sensitive troponin-tropomyosin regulatory apparatus (encoded by TPM1), which includes the three troponin subunits (encoded by TNNT2, TNNC1, and TNNI3) [52, 53]. The thick filament core is formed by the β-myosin heavy chain (encoded by MYH7), the molecular motor of the thick filament, and the myosin-binding protein C (β-MYBPC3) [52, 53]. Titin (encoded by TTN), which is the largest human protein, spans the half length of the sarcomere,

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 and decrease contractile strength [55].
