An internal domain of β-tropomyosin increases myofilament Ca 2+ sensitivity

Ganapathy Jagatheesan, Sudarsan Rajan, Emily M. Schulz, Rafeeq P H Ahmed, Natalia Petrashevskaya, Arnold Schwartz, Greg P. Boivin, Grace M. Arteaga, Tao Wang, Yi Gang Wang, Muhammad Ashraf, Stephen B. Liggett, John Lorenz, R. John Solaro, David F. Wieczorek

Research output: Contribution to journalArticle

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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 languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume297
Issue number1
DOIs
StatePublished - Jul 2009

Fingerprint

Tropomyosin
Myofibrils
Amino Acids
Troponin T
Striated Muscle
Familial Hypertrophic Cardiomyopathy
Muscle Relaxation
Cardiomegaly
Muscle Contraction
Isoproterenol
Transgenic Mice

Keywords

  • Calcium sensitivity
  • Contractile function
  • Genetically altered mice

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Jagatheesan, G., Rajan, S., Schulz, E. M., Ahmed, R. P. H., Petrashevskaya, N., Schwartz, A., ... Wieczorek, D. F. (2009). An internal domain of β-tropomyosin increases myofilament Ca 2+ sensitivity. American Journal of Physiology - Heart and Circulatory Physiology, 297(1). https://doi.org/10.1152/ajpheart.00329.2008

An internal domain of β-tropomyosin increases myofilament Ca 2+ 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.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 297, No. 1, 07.2009.

Research output: Contribution to journalArticle

Jagatheesan, G, Rajan, S, Schulz, EM, Ahmed, RPH, Petrashevskaya, N, Schwartz, A, Boivin, GP, Arteaga, GM, Wang, T, Wang, YG, Ashraf, M, Liggett, SB, Lorenz, J, Solaro, RJ & Wieczorek, DF 2009, 'An internal domain of β-tropomyosin increases myofilament Ca 2+ sensitivity', American Journal of Physiology - Heart and Circulatory Physiology, vol. 297, no. 1. https://doi.org/10.1152/ajpheart.00329.2008
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. / An internal domain of β-tropomyosin increases myofilament Ca 2+ sensitivity. In: American Journal of Physiology - Heart and Circulatory Physiology. 2009 ; Vol. 297, No. 1.
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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+.",
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AU - Boivin, Greg P.

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AU - Wang, Yi Gang

AU - Ashraf, Muhammad

AU - Liggett, Stephen B.

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AU - Solaro, R. John

AU - Wieczorek, David F.

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