Charged residue alterations in the inner-core domain and carboxy-terminus of alpha-tropomyosin differentially affect mouse cardiac muscle contractility. Academic Article uri icon


  • Two important charge differences between the alpha- and beta-tropomyosin (TM) isoforms are the exchange of a serine residue in the inner-core region at position 229, and a histidine residue at the carboxy-terminal end at position 276, with glutamic acid and asparagine, respectively. We have recently shown that altering these two residues in alpha-TM to their beta-TM counterparts in transgenic (TG) mouse hearts causes a depression in both +dP/dt and -dP/dt and a decrease in calcium sensitivity. In this study, we address whether independent charge changes at these two residues in alpha-TM modulate cardiac function differentially. To test this hypothesis we generated two TG lines: alpha-TMSer229Glu and alpha-TMHis276Asn. Molecular analyses show that 98% of native alpha-TM is replaced by mutated protein in alpha-TM229 hearts whereas alpha-TM276 hearts show 82% replacement with the mutated protein. Isolated working heart data show that alpha-TM229 TG hearts exhibit a significant decrease in both +dP/dt (7%) and -dP/dt (8%) compared with nontransgenics (NTGs) and time to peak pressure (TPP) is also reduced in alpha-TM229 hearts. alpha-TM276 hearts show a decrease only in -dP/dt (14%) and TPP is increased. pCa(2+)-tension relationships in skinned fibre preparations indicate decreased calcium sensitivity in alpha-TM229 but no change in alpha-TM276 preparations. Force-[Ca(2+)](IC) measurements from intact papillary fibres indicate that alpha-TM276 fibres produce more force per given [Ca(2+)](IC) when compared to NTG fibres, while alpha-TM229 fibres produce less force per given [Ca(2+)](IC). These data demonstrate that changing charged residues at either the inner-core domain or the carboxyl end of TM alters sarcomeric performance differently, suggesting that the function of TM is compartmentalized along its length.

published proceedings

  • J Physiol

author list (cited authors)

  • Gaffin, R. D., Tong, C. W., Zawieja, D. C., Hewett, T. E., Klevitsky, R., Robbins, J., & Muthuchamy, M

citation count

  • 8

complete list of authors

  • Gaffin, Robert D||Tong, Carl W||Zawieja, David C||Hewett, Timothy E||Klevitsky, Raisa||Robbins, Jeffrey||Muthuchamy, Mariappan

publication date

  • December 2004