title: Dilated cardiomyopathy mutant tropomyosin mice develop cardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity.
abstract: Mutations in striated muscle alpha-tropomyosin (alpha-TM), an essential thin filament protein, cause both dilated cardiomyopathy (DCM) and familial hypertrophic cardiomyopathy. Two distinct point mutations within alpha-tropomyosin are associated with the development of DCM in humans: Glu40Lys and Glu54Lys. To investigate the functional consequences of alpha-TM mutations associated with DCM, we generated transgenic mice that express mutant alpha-TM (Glu54Lys) in the adult heart. Results showed that an increase in transgenic protein expression led to a reciprocal decrease in endogenous alpha-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 beta-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 alpha-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.
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati Medical Center, Cincinnati, OH 45267-0524, USA.
authors.forename: Sudarsan
authors.initials: S
authors.lastname: Rajan
authors.forename: Rafeeq P H
authors.initials: RP
authors.lastname: Ahmed
authors.forename: Ganapathy
authors.initials: G
authors.lastname: Jagatheesan
authors.forename: Natalia
authors.initials: N
authors.lastname: Petrashevskaya
authors.forename: Greg P
authors.initials: GP
authors.lastname: Boivin
authors.forename: Dalia
authors.initials: D
authors.lastname: Urboniene
authors.forename: Grace M
authors.initials: GM
authors.lastname: Arteaga
authors.forename: Beata M
authors.initials: BM
authors.lastname: Wolska
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
authors.forename: David F
authors.initials: DF
authors.lastname: Wieczorek
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000199:Actins / Q000096:biosynthesis; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004452:Echocardiography; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019837:Ryanodine Receptor Calcium Release Channel / Q000096:biosynthesis; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D014335:Tropomyosin / Q000235:genetics / Q000378:metabolism*; D024723:Ventricular Myosins / Q000378:metabolism
chemical_list: D000199:Actins; D019837:Ryanodine Receptor Calcium Release Channel; C490774:Tpm1 protein, mouse; D014335:Tropomyosin; D020097:Natriuretic Peptide, Brain; D024723:Ventricular Myosins; D000252:Calcium-Transporting ATPases; D002118:Calcium