Dilated Cardiomyopathy Mutant Tropomyosin Mice Develop Cardiac Dysfunction With Significantly Decreased Fractional Shortening and Myofilament Calcium Sensitivity

• DOI: 10.1161/circresaha.107.148379
• Publication Date: 2007-06-08T01:11:22Z
• Authors: Sudarsan Rajan; Rafeeq P.H. Ahmed; Ganapathy Jagathe...; Natalia Petrashev...; Greg P. Boivin; Dalia Urboniene; Grace M. Arteaga; Beata M. Wolska; R. John Solaro; Stephen B. Liggett; David F. Wieczorek
• Keywords: Cardiomyopathy, Dilated; 0301 basic medicine; Reverse Transcriptase Polymerase Chain Reaction; Muscle Fibers, Skeletal; Mutation, Missense; Mice, Transgenic; Ryanodine Receptor Calcium Release Channel; Calcium-Transporting ATPases; Actins; Mice, Mutant Strains; 3. Good health; Actin Cytoskeleton; Disease Models, Animal; Mice; 03 medical and health sciences; Gene Expression Regulation; Echocardiography; Natriuretic Peptide, Brain; Cardiomyopathy, Hypertrophic, Familial; Animals; Humans; Calcium; Muscle Contraction

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 2+ 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 2+ handling proteins sarcoplasmic reticulum Ca 2+ -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 2+ 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.