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Am J Physiol Heart Circ Physiol. 2009 Jul;297(1):H181-90. doi: 10.1152/ajpheart.00329.2008. Epub 2009 May 8.

An internal domain of beta-tropomyosin increases myofilament Ca(2+) sensitivity.

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1
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0524, USA.

Abstract

Tropomyosin (TM) is involved in Ca(2+)-mediated muscle contraction and relaxation in the heart. Striated muscle alpha-TM is the major isoform expressed in the heart. The expression of striated muscle beta-TM in the murine myocardium results in a decreased rate of relaxation and increased myofilament Ca(2+) sensitivity. Replacing the carboxyl terminus (amino acids 258-284) of alpha-TM with beta-TM (a troponin T-binding region) results in decreased rates of contraction and relaxation in the heart and decreased myofilament Ca(2+) sensitivity. We hypothesized that the putative internal troponin T-binding domain (amino acids 175-190) of beta-TM may be responsible for the increased myofilament Ca(2+) sensitivity observed when the entire beta-TM is expressed in the heart. To test this hypothesis, we generated transgenic mice that expressed chimeric TM containing beta-TM amino acids 175-190 in the backbone of alpha-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 Ca(2+) 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 Ca(2+) 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 Ca(2+).

PMID:
19429821
PMCID:
PMC2711731
DOI:
10.1152/ajpheart.00329.2008
[Indexed for MEDLINE]
Free PMC Article
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