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-tropomyosin alter 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, USA2 Department of Biophysics and Biochemistry, Texas A & M University, College Station, TX 77843, USA3 Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital, Cincinnati, OH 45229-3039, USA
Striated muscle tropomyosin (TM) is an essential thin filament protein that is sterically and allosterically involved in calcium-mediated cardiac contraction. We have previously shown that overexpressing the ß-TM isoform in mouse hearts leads to physiological changes in myocardial relaxation and Ca2+ handling of myofilaments. Two important charge differences in ß-TM compared to 
-TM are the exchange of serine and histidine at positions 229 and 276 with glutamic acid and asparagine, respectively, imparting a more negative charge to ß-TM relative to -TM. Our hypothesis is that the net charge at specific sites on TM might be a major determinant of its role in modulating cardiac muscle performance and in regulating Ca2+ sensitivity of the myofilaments. To address this, we generated transgenic (TG) double mutation mouse lines (-TM DM) expressing mutated -TM at the two residues that differ between - and ß-TM (Ser229Glu + His276Asn). Molecular analyses show 60–88% of the native TM is replaced with -TM DM in the different TG lines. Work-performing heart analyses show that -TM DM mouse hearts exhibit decreased rates of pressure development and relaxation (+dP/dt and –dP/dt). Skinned myofibre preparations from the TG hearts indicate a decrease in calcium sensitivity of steady state force. Protein modelling studies show that these two charge alterations in -TM cause a change in the surface charges of the molecule. Our results provide the first evidence that charge changes at the carboxy-terminal of -TM alter the functional characteristics of the heart at both the whole organ and myofilament levels.
(Received 24 November 2003;
accepted after revision 2 February 2004;
first published online 6 February 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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