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-tropomyosin differentially affect mouse cardiac muscle contractility
1 336 Reynolds Medical Building, Cardiovascular Research Institute and Department of Medical Physiology, College of Medicine, Texas A & M University System Health Science Center, College Station, TX 77843-1114, USA
2 Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital, Cincinnati, OH 45229-3039, USA
Two important charge differences between the 
- and ß-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 -TM to their ß-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 -TM modulate cardiac function differentially. To test this hypothesis we generated two TG lines: -TMSer229Glu and -TMHis276Asn. Molecular analyses show that 98% of native -TM is replaced by mutated protein in -TM229 hearts whereas -TM276 hearts show 82% replacement with the mutated protein. Isolated working heart data show that -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 -TM229 hearts. -TM276 hearts show a decrease only in –dP/dt (14%) and TPP is increased. pCa2+–tension relationships in skinned fibre preparations indicate decreased calcium sensitivity in -TM229 but no change in -TM276 preparations. Force–[Ca2+]IC measurements from intact papillary fibres indicate that -TM276 fibres produce more force per given [Ca2+]IC when compared to NTG fibres, while -TM229 fibres produce less force per given [Ca2+]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.
(Received 24 June 2004;
accepted after revision 13 October 2004;
first published online 14 October 2004)
Corresponding author M. Muthuchamy: 336 Reynolds Medical Building, Cardiovascular Research Institute and Department of Medical Physiology, College of Medicine, Texas A & M University System Health Science Center, College Station, TX 77843-1114, USA. Email: marim{at}tamu.edu
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