Expression of the familial hypertrophic cardiomyopathy alpha-TM 175 mutation in transgenic mice caused severe impairment of contractility and relaxation, and increased myofilament Ca2+ sensitivity.
Does the expression of mutant alpha-TM (Asp175Asn) cause cardiac dysfunction and histological changes in a mouse model of familial hypertrophic cardiomyopathy?
The generation of a transgenic mouse model expressing the alpha-TM Asp175Asn mutation successfully recapitulates the physiological and histological features of familial hypertrophic cardiomyopathy.
To investigate the functional consequences of a tropomyosin (TM) mutation associated with familial hypertrophic cardiomyopathy (FHC), we generated transgenic mice that express mutant alpha-TM in the adult heart. The missense mutation, which results in the substitution of asparagine for aspartic acid at amino acid position 175, occurs in a troponin T binding region of TM. S1 nuclease mapping and Western blot analyses demonstrate that increased expression of the alpha-TM 175 transgene in different lines causes a concomitant decrease in levels of endogenous alpha-TM mRNA and protein expression. In vivo physiological analyses show a severe impairment of both contractility and relaxation in hearts of the FHC mice, with a significant change in left ventricular fractional shortening. Myofilaments that contain alpha-TM 175 demonstrate an increased activation of the thin filament through enhanced Ca2+ sensitivity of steady-state force. Histological analyses show patchy areas of mild ventricular myocyte disorganization and hypertrophy, with occasional thrombi formation in the left atria. Thus, the FHC alpha-TM transgenic mouse can serve as a model system for the examination of pathological and physiological alterations imparted through aberrant TM isoforms.
Muthuchamy et al. (Fri,) conducted a other in Familial hypertrophic cardiomyopathy. Mutant alpha-TM 175 transgene expression was evaluated on Cardiac contractility, relaxation, and histological alterations. Expression of the familial hypertrophic cardiomyopathy alpha-TM 175 mutation in transgenic mice caused severe impairment of contractility and relaxation, and increased myofilament Ca2+ sensitivity.