Mouse model of a familial hypertrophic cardiomyopathy mutation in alpha-tropomyosin manifests cardiac dysfunction. Academic Article uri icon

abstract

  • 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.

published proceedings

  • Circ Res

altmetric score

  • 3

author list (cited authors)

  • Muthuchamy, M., Pieples, K., Rethinasamy, P., Hoit, B., Grupp, I. L., Boivin, G. P., ... Wieczorek, D. F

citation count

  • 140

complete list of authors

  • Muthuchamy, M||Pieples, K||Rethinasamy, P||Hoit, B||Grupp, IL||Boivin, GP||Wolska, B||Evans, C||Solaro, RJ||Wieczorek, DF

publication date

  • July 1999