Abstract
Tropomyosin (TM) is involved in Ca2+-mediated muscle contraction and relaxation in the heart. Striated muscle α-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 α-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 α-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+.
Original language | English (US) |
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Pages (from-to) | H181-H190 |
Journal | American Journal of Physiology - Heart and Circulatory Physiology |
Volume | 297 |
Issue number | 1 |
DOIs | |
State | Published - Jul 2009 |
Keywords
- Calcium sensitivity
- Contractile function
- Genetically altered mice
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine
- Physiology (medical)