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J Appl Physiol (1985). 2015 Jan 15;118(2):212-23. doi: 10.1152/japplphysiol.00463.2014. Epub 2014 Oct 16.

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

Author information

1
Department of Pediatrics and Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
2
Department of Medicine and Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
3
The Hopkins Bayview Proteomics Center, Johns Hopkins University School of Medicine, Baltimore, Maryland;
4
Department of Comparative Medicine and Comparative Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
5
Institute of Human Virology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
6
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
7
Department of Pediatrics and Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland; murphy@jhmi.edu.

Abstract

Troponin I (TnI) variant Pro82Ser (cTnIP82S) was initially considered a disease-causing 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 pressure-volume 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, Ca(2+) 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.

KEYWORDS:

cardiac troponin I mutation; diastolic dysfunction; hypertrophy; transgenic mouse

PMID:
25324519
PMCID:
PMC4297775
DOI:
10.1152/japplphysiol.00463.2014
[Indexed for MEDLINE]
Free PMC Article

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