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The roles of E-Tmod in mechanotransduction and cardiac myofibrillogenesis


Sarcomeres comprise the backbone of striated muscles, serving structural roles and providing contractile drive essential to cardiac functions. Among the components of the actomyosin complex that form the building blocks of sarcomeres, Erythrocyte Tropomodulin (E-Tmod) belongs to a special category of capping proteins known to regulate actin monomer polymerization. While E-Tmod⁻ʹ⁻ is embryonically lethal with the phenotype of severe cardiac underdevelopment and impaired contractility, E-Tmod⁺ʹ⁻ mice survived through adulthood with a relatively mild phenotype of reduced right ventricular (RV) size. Through organ culture of the day post coitus (dpc) 9.5 E-Tmod⁻ʹ⁻ mouse hearts, we established that E-Tmod is required to sustain, but not to initiate, the heartbeats. Expression analysis also revealed that E-Tmod knockout caused the down-regulation of [alpha]-Tropomyosin ([alpha]-TM) and troponin, which are essential genes for Ca ²⁺ dependent contractile function. This finding suggested that E-Tmod influences cardiac contraction through modulating the TM- troponin complex. Hypertrophy is common adaptive response of postnatal cardiomyocytes subjected to stress overload, which requires the synthesis of additional sarcomere components to increase the cell size. Hypoxia stress overload remodels the underdeveloped RV of the E-Tmod⁺ʹ⁻ mice to the size of the wildtypes. Mechanical stretch and shear stress also elevated E-Tmod in both wildtype and siRNA E-Tmod knockdown myocytes. These results demonstrated that E-Tmod is up-regulated during hypertrophic process and that partial reduction of the E- Tmod (both E-Tmod⁺ʹ⁻ and siRNA-treated cardiomyocytes) does not affect the ability of the cardiomyocytes to undergo mechanically induced adaptive hypertrophy. We have provided the direct expression evidence for the critical role of E-Tmod in the correlation between developmental evolution of ventricular diastolic function and changes in ventricular myoarchitecture. The present investigation also showed for the first time that alteration in E-Tmod directly affects the expressions of TM, actin, and troponins during myofibrillogenesis, as well as mechanical stretch induced hypertrophy. Therefore, our study suggests that E-Tmod is not simply a passive structural molecule, but plays important roles in the transcriptional regulation of multiple components of the sarcomeric thin filament

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