JOURNAL ARTICLE

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

Sudarsan Rajan, Rafeeq P H Ahmed, Ganapathy Jagatheesan, Natalia Petrashevskaya, Greg P Boivin, Dalia Urboniene, Grace M Arteaga, Beata M Wolska, R John Solaro, Stephen B Liggett, David F Wieczorek
Circulation Research 2007 July 20, 101 (2): 205-14
17556658
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.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
17556658
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"