Cardiac troponin i Pro82Ser variant induces diastolic dysfunction, blunts β-adrenergic response, and impairs myofilament cooperativity

Genaro A. Ramirez-Correa, Aisha H. Frazier, Guangshuo Zhu, Pingbo Zhang, Thomas Rappold, Viola Kooij, Djahida Bedja, Greg A. Snyder, Nahyr S. Lugo-Fagundo, Raena Hariharan, Yuejin Li, Xiaoxu Shen, Wei Dong Gao, Oscar H. Cingolani, Eiki Takimoto, D. Brian Foster, Anne M. Murphy

Research output: Contribution to journalArticle

Abstract

Troponin I (TnI) variant Pro82Ser (cTnIP82S) was initially considered a diseasecausing mutation; however, later studies suggested the contrary. We tested the hypothesis of whether a causal link exists between cTnIP82S and cardiac structural and functional remodeling, such as during aging or chronic pressure overload. A cardiac-specific transgenic (Tg) mouse model of cTnIP82S was created to test this hypothesis. During aging, Tg cTnIP82S displayed diastolic dysfunction, characterized by longer isovolumetric relaxation time, and impaired ejection and relaxation time. In young, Tg mice in vivo pressurevolume loops and intact trabecular preparations revealed normal cardiac contractility at baseline. However, upon β-adrenergic stimulation, a blunted contractile reserve and no hastening in left ventricle relaxation were evident in vivo, whereas, in isolated muscles, Ca2+ transient amplitude isoproterenol dose-response was blunted. In addition, when exposed to chronic pressure overload, Tg mice show exacerbated hypertrophy and decreased contractility compared with age-matched non-Tg littermates. At the molecular level, this mutation significantly impairs myofilament cooperative activation. Importantly, this occurs in the absence of alterations in TnI or myosin-binding protein C phosphorylation. The cTnIP82S variant occurs near a region of interactions with troponin T; therefore, structural changes in this region could explain its meaningful effects on myofilament cooperativity. Our data indicate that cTnIP82S mutation modifies age-dependent diastolic dysfunction and impairs overall contractility after β-adrenergic stimulation or chronic pressure overload. Thus cTnIP82S variant should be regarded as a disease-modifying factor for dysfunction and adverse remodeling with aging and chronic pressure overload.

Original languageEnglish (US)
Pages (from-to)212-223
Number of pages12
JournalJournal of applied physiology
Volume118
Issue number2
DOIs
StatePublished - Jan 15 2015

Keywords

  • Cardiac troponin I mutation
  • Diastolic dysfunction
  • Hypertrophy
  • Transgenic mouse

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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    Ramirez-Correa, G. A., Frazier, A. H., Zhu, G., Zhang, P., Rappold, T., Kooij, V., Bedja, D., Snyder, G. A., Lugo-Fagundo, N. S., Hariharan, R., Li, Y., Shen, X., Gao, W. D., Cingolani, O. H., Takimoto, E., Foster, D. B., & Murphy, A. M. (2015). Cardiac troponin i Pro82Ser variant induces diastolic dysfunction, blunts β-adrenergic response, and impairs myofilament cooperativity. Journal of applied physiology, 118(2), 212-223. https://doi.org/10.1152/japplphysiol.00463.2014