title: A dominantly negative mutation in cardiac troponin I at the interface with troponin T causes early remodeling in ventricular cardiomyocytes.
abstract: We previously reported a point mutation substituting Cys for Arg(111) in the highly conserved troponin T (TnT)-contacting helix of cardiac troponin I (cTnI) in wild turkey hearts (Biesiadecki et al. J Biol Chem 279: 13825-13832, 2004). This dominantly negative TnI-TnT interface mutation decreases the binding affinity of cTnI for TnT, impairs diastolic function, and blunts the β-adrenergic response of cardiac muscle (Wei et al. J Biol Chem 285: 27806-27816, 2010). Here we further investigate cellular phenotypes of transgenic mouse cardiomyocytes expressing the equivalent mutation cTnI-K118C. Functional studies were performed on single adult cardiomyocytes after recovery in short-term culture from isolation stress. The amplitude of contraction and the velocities of shortening and relengthening were lower in cTnI-K118C cardiomyocytes than wild-type controls. The intracellular Ca(2+) transient was slower in cTnI-K118C cardiomyocytes than wild-type cells. cTnI-K118C cardiomyocytes also showed a weaker β-adrenergic response. The resting length of cTnI-K118C cardiomyocytes was significantly greater than that of age-matched wild-type cells, with no difference in cell width. The resting sarcomere was not longer, but slightly shorter, in cTnI-K118C cardiomyocytes than wild-type cells, indicating longitudinal addition of sarcomeres. More tri- and quadrinuclei cardiomyocytes were found in TnI-K118C than wild-type hearts, suggesting increased nuclear divisions. Whole-genome mRNA array and Western blots detected an increased expression of leukemia inhibitory factor receptor-β in the hearts of 2-mo-old cTnI-K118C mice, suggesting a signaling pathway responsible for the potent effect of cTnI-K118C mutation on early remodeling in cardiomyocytes.
authors.affiliation: Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Hongguang
authors.initials: H
authors.lastname: Wei
authors.affiliation: Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan jjin@med.wayne.edu.
authors.forename: J-P
authors.initials: JP
authors.lastname: Jin
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling; D048429:Cell Size; D002478:Cells, Cultured; D005838:Genotype; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism*; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism; D013997:Time Factors; D019210:Troponin I / Q000235:genetics / Q000378:metabolism*; D020107:Troponin T / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000318:Adrenergic beta-Agonists; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507841:Lifr protein, mouse; D012333:RNA, Messenger; D019210:Troponin I; D020107:Troponin T
keywords: cardiac troponin I; culture of adult cardiomyocyte; myocardial remodeling; prolongation of cardiomyocytes