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Gene Review

Tnni3  -  troponin I, cardiac 3

Mus musculus

Synonyms: Cardiac troponin I, Tn1, Troponin I, cardiac muscle, cTnI, cardiac troponin I
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Disease relevance of Tnni3

  • To confirm the role of p90RSK in cTnI phosphorylation in vivo, we generated adenovirus containing a dominant negative form of p90RSK (Ad-DN-p90RSK) [1].
  • Gene mutations in cardiac troponin I (cTnI) account for up to 5% of genotyped families with familial hypertrophic cardiomyopathy (FHC) [2].
  • These data indicate that individual genetic conditions and environmental factors participate together in the development of the cTnI mutation based-cardiac muscle disorders [3].
  • Cardiac troponin I (cTnI) mutations have been linked to the development of restrictive cardiomyopathy (RCM) in human patients [3].
  • To address this question, the following recombinant proteins were expressed in Escherichia coli and purified: mouse wild-type cTnI (WT cTnI; 211 residues), cTnI-(1-199) (missing 12 residues), cTnI-(1-188) (missing 23 residues), and cTnI-(1-151) (missing 60 residues) [4].

High impact information on Tnni3

  • Unexpectedly, in addition to loss of Tnnt2 expression in sih mutant hearts, we observed a significant reduction in Tpma and Tnni3, and consequently, severe sarcomere defects [5].
  • In this study, we purified the 30-kDa protein from heart extract and identified it as cardiac troponin I (cTnI), encoded by a gene in which mutations can cause familial hypertrophic cardiomyopathy (HCM) [6].
  • Furthermore, this fragment is able to repress cardiac troponin I (cTnI) promoter activity selectively in the embryonic myocardium of the atrioventricular canal (AVC) [7].
  • Importantly, elevations of cTnI in patients with myocarditis were significantly correlated with < or = 1 month duration of heart failure symptoms (P = .02), suggesting that the majority of myocyte necrosis occurs early, and thus the window for diagnosis and treatment may be relatively brief [8].
  • Because the histological diagnosis of myocarditis requires the presence of myocyte injury, we sought to determine whether measurement of cardiac troponin I (cTnI), which is a serum marker with high sensitivity and specificity for cardiac myocyte injury, could aid in the diagnosis of myocarditis [8].

Chemical compound and disease context of Tnni3

  • Histopathological and pathophysiological cardiac changes in dogs, rats and mice correlated with increased serum cTnI with various cardiac inotropic agents, and cardiotoxic drugs and with cardiac arrhythmias, tachycardia, cardiac effusion with dyspnoea, and ageing [9].

Biological context of Tnni3

  • The cardiac troponin I locus (Tnni3) also mapped to Chr 7, approximately 5-10 cM from the centromere and unlinked to the fast skeletal muscle troponin I locus [10].
  • No differences in isoform expression of tropomyosin, myosin heavy chain, essential and regulatory myosin light chains (MLC), TnI, or in posttranslational modifications of mouse cTnT, cTnI, or regulatory MLC were observed [11].
  • Protein kinase C (PKC)-induced phosphorylation of cardiac troponin I (cTnI) depresses the acto-myosin interaction and may be important during the progression of heart failure [1].
  • The observed Ca(2+)-induced conformational change may be a switch mechanism by which movement of the regulatory region of cTnI to the exposed hydrophobic patch of the open regulatory N-domain of cTnC pulls the inhibitory region away from actin upon Ca(2+) activation in cardiac muscle [12].
  • To approach this question we have used molecular cloning, mutagenesis, and bacterial synthesis of a full-length cTnI and a truncated mutant (cTnI/NH2) missing the 32 amino acids [13].

Anatomical context of Tnni3

  • Although both PKCbetaII and PKCepsilon can phosphorylate cTnI, only PKCbeta expression and activity are elevated in failing human myocardium during end-stage heart failure [1].
  • Although the C terminus of troponin I is known to be important in myofilament Ca2+ regulation in skeletal muscle, the regulatory function of this region of cardiac troponin I (cTnI) has not been defined [4].
  • We also formed a complex of either WT cTnI or each of the mutants with cTnC, reconstituted the complex into the cTnT-treated myofibrils, and measured the Mg2+-ATPase activity as a function of pCa [4].
  • We studied intact and detergent-extracted papillary muscles from nontransgenic (NTG) and transgenic (TG) mouse hearts that express a mutant cTnI (Ser43Ala, Ser45Ala) that lacks specific PKC-dependent phosphorylation sites [14].
  • Here, we report that regulation of myocyte twitch kinetics by beta-stimulation and by endothelin-1 was altered in myocytes containing mutant cTnI [15].

Associations of Tnni3 with chemical compounds


Physical interactions of Tnni3

  • These data provide the first evidence of a significant function of a cTnT-binding domain on cTnI [20].

Regulatory relationships of Tnni3


Other interactions of Tnni3


Analytical, diagnostic and therapeutic context of Tnni3

  • Western blot analysis of human or mouse homogenized muscle specimens showed no evidence for cardiac TnT and cTnI expression, despite strong signals for skeletal muscle troponin isoforms [23].
  • Each cTnI C-terminal deletion mutant was able to bind to cTnC, as shown by urea-polyacrylamide gel-shift analysis and size exclusion chromatography [4].
  • Two of the five cTnI-specific monoclonal antibodies were utilized in an immunoassay [24].
  • However, during ISO perfusion, when cTnI was phosphorylated, the rate of relaxation was significantly slower in PLBKO/ssTnI compared to PLBKO/cTnI hearts [25].
  • We conclude that cTnI is a powerful candidate in mammals, a possible candidate in birds, but unlikely to be of use in fish as a sensitive and tissue-selective diagnostic test for cardiac injury [26].


  1. Role of p90 ribosomal S6 kinase (p90RSK) in reactive oxygen species and protein kinase C beta (PKC-beta)-mediated cardiac troponin I phosphorylation. Itoh, S., Ding, B., Bains, C.P., Wang, N., Takeishi, Y., Jalili, T., King, G.L., Walsh, R.A., Yan, C., Abe, J. J. Biol. Chem. (2005) [Pubmed]
  2. Molecular insights from a novel cardiac troponin I mouse model of familial hypertrophic cardiomyopathy. Tsoutsman, T., Chung, J., Doolan, A., Nguyen, L., Williams, I.A., Tu, E., Lam, L., Bailey, C.G., Rasko, J.E., Allen, D.G., Semsarian, C. J. Mol. Cell. Cardiol. (2006) [Pubmed]
  3. A point mutation (R192H) in the C-terminus of human cardiac troponin I causes diastolic dysfunction in transgenic mice. Du, J., Zhang, C., Liu, J., Sidky, C., Huang, X.P. Arch. Biochem. Biophys. (2006) [Pubmed]
  4. The C terminus of cardiac troponin I is essential for full inhibitory activity and Ca2+ sensitivity of rat myofibrils. Rarick, H.M., Tu, X.H., Solaro, R.J., Martin, A.F. J. Biol. Chem. (1997) [Pubmed]
  5. Cardiac troponin T is essential in sarcomere assembly and cardiac contractility. Sehnert, A.J., Huq, A., Weinstein, B.M., Walker, C., Fishman, M., Stainier, D.Y. Nat. Genet. (2002) [Pubmed]
  6. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Okazaki, T., Tanaka, Y., Nishio, R., Mitsuiye, T., Mizoguchi, A., Wang, J., Ishida, M., Hiai, H., Matsumori, A., Minato, N., Honjo, T. Nat. Med. (2003) [Pubmed]
  7. Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation. Habets, P.E., Moorman, A.F., Clout, D.E., van Roon, M.A., Lingbeek, M., van Lohuizen, M., Campione, M., Christoffels, V.M. Genes Dev. (2002) [Pubmed]
  8. Elevations of cardiac troponin I associated with myocarditis. Experimental and clinical correlates. Smith, S.C., Ladenson, J.H., Mason, J.W., Jaffe, A.S. Circulation (1997) [Pubmed]
  9. Cardiac troponin I is a sensitive, specific biomarker of cardiac injury in laboratory animals. O'Brien, P.J., Smith, D.E., Knechtel, T.J., Marchak, M.A., Pruimboom-Brees, I., Brees, D.J., Spratt, D.P., Archer, F.J., Butler, P., Potter, A.N., Provost, J.P., Richard, J., Snyder, P.A., Reagan, W.J. Lab. Anim. (2006) [Pubmed]
  10. Cardiac and skeletal muscle troponin I isoforms are encoded by a dispersed gene family on mouse chromosomes 1 and 7. Guenet, J.L., Simon-Chazottes, D., Gravel, M., Hastings, K.E., Schiaffino, S. Mamm. Genome (1996) [Pubmed]
  11. cTnT1, a cardiac troponin T isoform, decreases myofilament tension and affects the left ventricular pressure waveform. Nassar, R., Malouf, N.N., Mao, L., Rockman, H.A., Oakeley, A.E., Frye, J.R., Herlong, J.R., Sanders, S.P., Anderson, P.A. Am. J. Physiol. Heart Circ. Physiol. (2005) [Pubmed]
  12. Ca(2+) induces an extended conformation of the inhibitory region of troponin I in cardiac muscle troponin. Dong, W.J., Xing, J., Robinson, J.M., Cheung, H.C. J. Mol. Biol. (2001) [Pubmed]
  13. Mutagenesis of cardiac troponin I. Role of the unique NH2-terminal peptide in myofilament activation. Guo, X., Wattanapermpool, J., Palmiter, K.A., Murphy, A.M., Solaro, R.J. J. Biol. Chem. (1994) [Pubmed]
  14. alpha-Adrenergic response and myofilament activity in mouse hearts lacking PKC phosphorylation sites on cardiac TnI. Montgomery, D.E., Wolska, B.M., Pyle, W.G., Roman, B.B., Dowell, J.C., Buttrick, P.M., Koretsky, A.P., Del Nido, P., Solaro, R.J. Am. J. Physiol. Heart Circ. Physiol. (2002) [Pubmed]
  15. Phosphorylation of troponin I controls cardiac twitch dynamics: evidence from phosphorylation site mutants expressed on a troponin I-null background in mice. Pi, Y., Kemnitz, K.R., Zhang, D., Kranias, E.G., Walker, J.W. Circ. Res. (2002) [Pubmed]
  16. Functional effects of rho-kinase-dependent phosphorylation of specific sites on cardiac troponin. Vahebi, S., Kobayashi, T., Warren, C.M., de Tombe, P.P., Solaro, R.J. Circ. Res. (2005) [Pubmed]
  17. In vivo and in vitro analysis of cardiac troponin I phosphorylation. Sakthivel, S., Finley, N.L., Rosevear, P.R., Lorenz, J.N., Gulick, J., Kim, S., VanBuren, P., Martin, L.A., Robbins, J. J. Biol. Chem. (2005) [Pubmed]
  18. Essential role of troponin I in the positive inotropic response to isoprenaline in mouse hearts contracting auxotonically. Layland, J., Grieve, D.J., Cave, A.C., Sparks, E., Solaro, R.J., Shah, A.M. J. Physiol. (Lond.) (2004) [Pubmed]
  19. Protein kinase C and A sites on troponin I regulate myofilament Ca2+ sensitivity and ATPase activity in the mouse myocardium. Pi, Y., Zhang, D., Kemnitz, K.R., Wang, H., Walker, J.W. J. Physiol. (Lond.) (2003) [Pubmed]
  20. Interactions at the NH2-terminal interface of cardiac troponin I modulate myofilament activation. Rarick, H.M., Tang, H.P., Guo, X.D., Martin, A.F., Solaro, R.J. J. Mol. Cell. Cardiol. (1999) [Pubmed]
  21. Effects of oxytocin on cardiomyocyte differentiation from mouse embryonic stem cells. Hatami, L., Valojerdi, M.R., Mowla, S.J. Int. J. Cardiol. (2007) [Pubmed]
  22. Proteolytic N-terminal truncation of cardiac troponin I enhances ventricular diastolic function. Barbato, J.C., Huang, Q.Q., Hossain, M.M., Bond, M., Jin, J.P. J. Biol. Chem. (2005) [Pubmed]
  23. Clinical and experimental results on cardiac troponin expression in Duchenne muscular dystrophy. Hammerer-Lercher, A., Erlacher, P., Bittner, R., Korinthenberg, R., Skladal, D., Sorichter, S., Sperl, W., Puschendorf, B., Mair, J. Clin. Chem. (2001) [Pubmed]
  24. Development of monoclonal antibodies for an assay of cardiac troponin-I and preliminary results in suspected cases of myocardial infarction. Bodor, G.S., Porter, S., Landt, Y., Ladenson, J.H. Clin. Chem. (1992) [Pubmed]
  25. Troponin I phosphorylation plays an important role in the relaxant effect of beta-adrenergic stimulation in mouse hearts. Peña, J.R., Wolska, B.M. Cardiovasc. Res. (2004) [Pubmed]
  26. Differential reactivity of cardiac and skeletal muscle from various species in a cardiac troponin I immunoassay. O'Brien, P.J., Landt, Y., Ladenson, J.H. Clin. Chem. (1997) [Pubmed]
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