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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/H181    most recent 00329.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Jagatheesan, G. Articles by Wieczorek, D. F. PubMed PubMed Citation Articles by Jagatheesan, G. Articles by Wieczorek, D. F.

An internal domain of β-tropomyosin increases myofilament Ca²⁺ sensitivity

¹Department of Molecular Genetics, Biochemistry, and Microbiology, ²Institute of Molecular Pharmacology and Biophysics, Department of Surgery, and ³Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; ⁴Department of Physiology and Biophysics, University of Illinois-Chicago College of Medicine, Chicago, Illinois; ⁵Department of Medicine, University of Maryland, Baltimore, Maryland; and ⁶Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio

Submitted 28 March 2008 ; accepted in final form 5 May 2009

Tropomyosin (TM) is involved in Ca²⁺-mediated muscle contraction and relaxation in the heart. Striated muscle -TM is the major isoform expressed in the heart. The expression of striated muscle β-TM in the murine myocardium results in a decreased rate of relaxation and increased myofilament Ca²⁺ sensitivity. Replacing the carboxyl terminus (amino acids 258–284) of -TM with β-TM (a troponin T-binding region) results in decreased rates of contraction and relaxation in the heart and decreased myofilament Ca²⁺ sensitivity. We hypothesized that the putative internal troponin T-binding domain (amino acids 175–190) of β-TM may be responsible for the increased myofilament Ca²⁺ sensitivity observed when the entire β-TM is expressed in the heart. To test this hypothesis, we generated transgenic mice that expressed chimeric TM containing β-TM amino acids 175–190 in the backbone of -TM (amino acids 1–174 and 191–284). These mice expressed 16–57% chimeric TM and did not develop cardiac hypertrophy or any other morphological changes. Physiological analysis showed that these hearts exhibited decreased rates of contraction and relaxation and a positive response to isoproterenol. Skinned fiber bundle analyses showed a significant increase in myofilament Ca²⁺ sensitivity. Biophysical experiments demonstrated that the exchanged amino acids did not influence the flexibility of the TM. This is the first study to demonstrate that a specific domain within TM can increase the Ca²⁺ sensitivity of the thin filament and affect sarcomeric performance. Furthermore, these results enhance the understanding of why TM mutations associated with familial hypertrophic cardiomyopathy demonstrate increased myofilament sensitivity to Ca²⁺.

calcium sensitivity; contractile function; genetically altered mice