title: Cardiac troponin I Pro82Ser variant induces diastolic dysfunction, blunts β-adrenergic response, and impairs myofilament cooperativity.
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.
authors.affiliation: Department of Pediatrics and Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Genaro A
authors.initials: GA
authors.lastname: Ramirez-Correa
authors.affiliation: Department of Pediatrics and Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Aisha H
authors.initials: AH
authors.lastname: Frazier
authors.affiliation: Department of Medicine and Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Guangshuo
authors.initials: G
authors.lastname: Zhu
authors.affiliation: The Hopkins Bayview Proteomics Center, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Pingbo
authors.initials: P
authors.lastname: Zhang
authors.affiliation: The Hopkins Bayview Proteomics Center, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Thomas
authors.initials: T
authors.lastname: Rappold
authors.affiliation: The Hopkins Bayview Proteomics Center, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Viola
authors.initials: V
authors.lastname: Kooij
authors.affiliation: Department of Comparative Medicine and Comparative Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.affiliation: Institute of Human Virology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Snyder
authors.affiliation: Department of Pediatrics and Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Nahyr S
authors.initials: NS
authors.lastname: Lugo-Fagundo
authors.affiliation: Department of Pediatrics and Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Raena
authors.initials: R
authors.lastname: Hariharan
authors.affiliation: Department of Pediatrics and Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Wei Dong
authors.initials: WD
authors.lastname: Gao
authors.affiliation: Department of Medicine and Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Cingolani
authors.affiliation: Department of Medicine and Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Eiki
authors.initials: E
authors.lastname: Takimoto
authors.affiliation: Department of Medicine and Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: D Brian
authors.initials: DB
authors.lastname: Foster
authors.affiliation: Department of Pediatrics and Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland; murphy@jhmi.edu.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Murphy
mesh_terms: D000375:Aging / Q000502:physiology*; D019943:Amino Acid Substitution; D000818:Animals; D003971:Diastole; D005260:Female; D006321:Heart / Q000502:physiology*; D006331:Heart Diseases / Q000235:genetics* / Q000378:metabolism; D006984:Hypertrophy; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013312:Stress, Physiological; D019210:Troponin I / Q000235:genetics*
chemical_list: D011943:Receptors, Adrenergic, beta; D019210:Troponin I
keywords: cardiac troponin I mutation; diastolic dysfunction; hypertrophy; transgenic mouse