Abstract Tropomyosin (TM) is involved in Ca 2+ -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 Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 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+ .
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An internal domain of β-tropomyosin increases myofilament Ca2+ sensitivity
Jagatheesan, Ganapathy; Rajan, Sudarsan; Schulz, Emily M.; Ahmed, Rafeeq P. H.; Petrashevskaya, Natalia; Schwartz, Arnold; Boivin, Greg P.; Arteaga, Grace M.; Wang, Tao; Wang, Yi-Gang; Ashraf, Muhammad; Liggett, Stephen B.; Lorenz, John; Solaro, R. John; Wieczorek, David F.
Follow AJP - Heart and Circulatory Physiology
, Volume 297 (1): H181
The American Physiological Society – Jul 1, 2009
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