Abstract
Troponin-based Ca2+ regulation of striated muscle contraction emerged approximately 700 million years ago with largely conserved functions during evolution. Troponin I (TnI) is the inhibitory subunit of troponin and has evolved into three muscle type-specific isoforms in vertebrates. Cardiac TnI is specifically expressed in the adult heart and has a unique N-terminal extension implicating a specific value during natural selection. The N-terminal extension of cardiac TnI in higher vertebrates contains β-adrenergic-regulated protein kinase A (PKA) phosphorylation sites as a mechanism to enhance cardiac muscle relaxation and facilitate ventricular filling. Phylogenic studies showed that the N-terminal extension of cardiac TnI first emerged in the genomes of early tetrapods as well as primordial lobe-finned fishes such as the coelacanth whereas it is absent in ray-finned fish. This apparently rapid evolution of β-adrenergic regulation of cardiac function suggests a high selection value for the heart of vertebrate animals on land to work under higher metabolic demands. Sequencing and PKA phosphorylation data showed that lungfish cardiac TnI has evolved with an amphibian-like N-terminal extension with prototype PKA phosphorylation sites while its overall structure remained fish like. The data demonstrate that the submolecular structure of TnI may evolve ahead of the whole protein for cardiac muscle contractility to adapt to new environmental conditions. Understanding the evolution of the β-adrenergic regulation of TnI and cardiac adaptation to the increased energetic demands of life on land adds knowledge for the treatment of human heart diseases and failure.
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Data Availability
All data required to evaluate the conclusions of the paper are presented within the paper or supplementary materials, and all genome sequences are publicly available on NCBI GenBank. Any additional data may be requested from the authors.
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Acknowledgements
We thank Dr. Irene Salinas and Dr. Ottavia Benedicenti for providing lungfish hearts.
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This research was supported by grants from the National Institutes of Health, HL127691, JianPing Jin, HL138007, JianPing Jin
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MR: performed experiments, analyzed data, drafted, and edited manuscript, approved final version for submission; HZF: performed experiments, analyzed data, drafted manuscript, approved final version for submission; JPJ: conceived the research project, drafted and edited manuscript, approved final version for submission.
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Communicated by Belinda Chang.
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Rasmussen, M., Feng, HZ. & Jin, JP. Evolution of the N-Terminal Regulation of Cardiac Troponin I for Heart Function of Tetrapods: Lungfish Presents an Example of the Emergence of Novel Submolecular Structure to Lead the Capacity of Adaptation. J Mol Evol 90, 30–43 (2022). https://doi.org/10.1007/s00239-021-10039-9
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DOI: https://doi.org/10.1007/s00239-021-10039-9