Differential interactions of thin filament proteins in two cardiac troponin T mouse models of hypertrophic and dilated cardiomyopathies

Abstract

Differential interactions among the sarcomeric proteins containing cTnT-Q92 or cTnT-W141 are responsible for the contrasting phenotypes of HCM or DCM, respectively.

Human stem cells as a model for cardiac differentiation and disease

“…A knock-in mouse model of DK210-cTnT resulted in cardiac enlargement with marked ventricular dilation and systolic dysfunction in mice, which closely resembles the phenotype of DCM in humans [77]. In addition, two independent groups generated mice harboring a human R141W cTnT and showed clinical features of DCM [78,79].…”

Actin in striated muscle: recent insights into assembly and maintenance

“…While the effects of specific point mutations on the functional characteristics of the proteins are beginning to be elucidated (e.g. Dyer et al 2009;Song et al 2011), and can in some cases be correlated to a certain type of disease (Chang et al 2005;Debold et al 2010;Lombardi et al 2008), the complexity of thin filament assembly and regulation eluded to in this review would indicate that we are just at the beginning of understanding its mechanisms.…”

Genetics and sudden death

“…Potential pathways include altered calcium cycling and sarcomeric calcium sensitivity, disturbed biomechanical sensing, impaired energy homeostasis and impaired protein degradation [23 && , [25][26][27][28]; paracrine factors deriving from mutant cardiomyocytes may stimulate myocardial fibrosis [29].…”

“…All these proximal defects cause contractile dysfunction, which finally induces cardiomyocyte death and reparative fibrosis [71]. Sarcomeric DCM mutations affect force production by decreasing calcium sensitivity and ATPase activity [26,72], or force transmission from the myocytes to extracellular matrix or between adjacent sarcomeres by destabilizing the sarcolemma-cytoskeleton-sarcomere or the titin-Z-disc interactions, respectively [22,[72][73][74]. Impaired calcium reuptake, with consequent decreased calcium release by the sarcoplasmic reticulum, weakens contraction in phospholamban mutations [75].…”