Abstract
Tropomyosin (TM) plays a central role in calcium mediated striated muscle contraction. There are three muscle TM isoforms: α-TM, β-TM, and γ-TM. α-TM is the predominant cardiac and skeletal muscle isoform. β-TM is expressed in skeletal and embryonic cardiac muscle. γ-TM is expressed in slow-twitch musculature, but is not found in the heart. Our previous work established that muscle TM isoforms confer different physiological properties to the cardiac sarcomere. To determine whether one of these isoforms is dominant in dictating its functional properties, we generated single and double transgenic mice expressing β-TM and/or γ-TM in the heart, in addition to the endogenously expressed α-TM. Results show significant TM protein expression in the βγ-DTG hearts: α-TM: 36%, β-TM: 32%, and γ-TM: 32%. These βγ-DTG mice do not develop pathological abnormalities; however, they exhibit a hyper contractile phenotype with decreased myofilament calcium sensitivity, similar to γ-TM transgenic hearts. Biophysical studies indicate that γ-TM is more rigid than either α-TM or β-TM. This is the first report showing that with approximately equivalent levels of expression within the same tissue, there is a functional dominance of γ-TM over α-TM or β-TM in regulating physiological performance of the striated muscle sarcomere. In addition to the effect expression of γ-TM has on Ca2+ activation of the cardiac myofilaments, our data demonstrates an effect on cooperative activation of the thin filament by strongly bound rigor cross-bridges. This is significant in relation to current ideas on the control mechanism of the steep relation between Ca2+ and tension.
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Acknowledgments
We thank Jon Neumann for production of the transgenic mice and Maureen Bender for her care of the animals. This work was supported in part by National Institutes of Health Grants HL71952 and HL081680 awarded to DFW, HL22231 and HL 62426 awarded to RJS, K01 HL67709 awarded to GMA.
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Jagatheesan, G., Rajan, S., Ahmed, R.P.H. et al. Striated muscle tropomyosin isoforms differentially regulate cardiac performance and myofilament calcium sensitivity. J Muscle Res Cell Motil 31, 227–239 (2010). https://doi.org/10.1007/s10974-010-9228-3
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DOI: https://doi.org/10.1007/s10974-010-9228-3