Dilated cardiomyopathy mutant tropomyosin mice develop cardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity

Mutations in striated muscle α-tropomyosin (α-TM), an essential thin filament protein, cause both dilated cardiomyopathy (DCM) and familial hypertrophic cardiomyopathy. Two distinct point mutations within α-tropomyosin are associated with the development of DCM in humans: Glu40Lys and Glu54Lys. To investigate the functional consequences of α-TM mutations associated with DCM, we generated transgenic mice that express mutant α-TM (Glu54Lys) in the adult heart. Results showed that an increase in transgenic protein expression led to a reciprocal decrease in endogenous α-TM levels, with total myofilament TM protein levels remaining unaltered. Histological and morphological analyses revealed development of DCM with progression to heart failure and frequently death by 6 months. Echocardiographic analyses confirmed the dilated phenotype of the heart with a significant decrease in the left ventricular fractional shortening. Work-performing heart analyses showed significantly impaired systolic, and diastolic functions and the force measurements of cardiac myofibers revealed that the myofilaments had significantly decreased Ca sensitivity and tension generation. Real-time RT-PCR quantification demonstrated an increased expression of β-myosin heavy chain, brain natriuretic peptide, and skeletal actin and a decreased expression of the Ca handling proteins sarcoplasmic reticulum Ca-ATPase and ryanodine receptor. Furthermore, our study also indicates that the α-TM54 mutation decreases tropomyosin flexibility, which may influence actin binding and myofilament Ca sensitivity. The pathological and physiological phenotypes exhibited by these mice are consistent with those seen in human DCM and heart failure. As such, this is the first mouse model in which a mutation in a sarcomeric thin filament protein, specifically TM, leads to DCM.