Enhanced N-terminal degradation of troponin I blunts cardiac function responsiveness to isoproterenol in 4-week tail-suspended rats

Zhang,Lin; Song,Zhen; Chang,Hui; Wang,Yun-Ying; Yu,Zhi-Bin

doi:10.3892/mmr.2012.1119

Enhanced N-terminal degradation of troponin I blunts cardiac function responsiveness to isoproterenol in 4-week tail-suspended rats

Authors:
- Lin Zhang
- Zhen Song
- Hui Chang
- Yun-Ying Wang
- Zhi-Bin Yu
View Affiliations

Affiliations: Department of Aerospace Physiology, Fourth Military Medical University, Xi'an 710032, P.R. China
Published online on: October 8, 2012 https://doi.org/10.3892/mmr.2012.1119
Pages: 271-279

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The N-terminal extension of cardiac troponin I (cTnI) is important in regulating cardiac function. Although the normal rat myocardium shows some cTnI N-terminal degradation (cTnI-ND), exposure to 4 weeks of tail-suspension markedly increased cTnI-ND. We hypothesized that the increased cTnI-ND in tail-suspended rats may affect cardiac function, particularly during β-adrenergic (β-A) stimulation. The increase in cardiac output with isoproterenol (ISO) treatment was smaller in tail-suspended rats compared with controls. Left ventricular end-diastolic pressure was elevated and increases in maximal rates of left ventricular pressure development and relaxation were lower during ISO treatment in tail-suspended rats. Response to ISO, forskolin, DB-cAMP and IBMX was also lower in cardiomyocytes from tail-suspended rats. The increase in shortening and re-lengthening the rates of cardiomyocytes at a maximal dose of ISO, forskolin, DB-cAMP and IBMX treatment was limited in tail-suspended rats. There was no difference in Ca2+ sensitivity of the isometric force between tail-suspended and control rats, although Ca2+ sensitivity was decreased less in tail-suspended rats versus control rats during PKA phosphorylation. There was no difference in PKA protein expression and activation during ISO stimulation between the two groups. Due to the increase in cTnI-ND, ISO-induced phosphorylation of cTnI was reduced in tail-suspended rats. The total phospholamban expression and phosphorylation by ISO was unaltered in tail-suspended rat hearts. These data suggest that enhanced cTnI-ND following 4-week tail-suspension is a major component of the β-A receptor signaling pathway, depressing cardiac function under ISO stimulation.

View Figures

View References

1	Layland J, Solaro RJ and Shah AM: Regulation of cardiac contractile function by troponin I phosphorylation. Cardiovasc Res. 66:12–21. 2005. View Article : Google Scholar : PubMed/NCBI
2	Marston SB and Redwood CS: Modulation of thin filament activation by breakdown or isoform switching of thin filament proteins: physiological and pathological implications. Circ Res. 93:1170–1178. 2003. View Article : Google Scholar : PubMed/NCBI
3	Solaro RJ, Rosevear P and Kobayashi T: The unique functions of cardiac troponin I in the control of cardiac muscle contraction and relaxation. Biochem Biophys Res Commun. 369:82–87. 2008. View Article : Google Scholar : PubMed/NCBI
4	Fentzke RC, Buck SH, Patel JR, Lin H, Wolska BM, Stojanovic MO, Martin AF, Solaro RJ, Moss RL and Leiden JM: Impaired cardiomyocyte relaxation and diastolic function in transgenic mice expressing slow skeletal troponin I in the heart. J Physiol. 517:143–157. 1999. View Article : Google Scholar : PubMed/NCBI
5	Arteaga GM, Warren CM, Milutinovic S, Martin AF and Solaro RJ: Specific enhancement of sarcomeric response to Ca²⁺ protects murine myocardium against ischemia-reperfusion dysfunction. Am J Physiol Heart Circ Physiol. 289:H2183–H2192. 2005. View Article : Google Scholar : PubMed/NCBI
6	Barbato JC, Huang QQ, Hossain MM, Bond M and Jin JP: Proteolytic N-terminal truncation of cardiac troponin I enhances ventricular diastolic function. J Biol Chem. 280:6602–6609. 2005. View Article : Google Scholar : PubMed/NCBI
7	Takimoto E, Soergel DG, Janssen PM, Stull LB, Kass DA and Murphy AM: Frequency- and afterload-dependent cardiac modulation in vivo by troponin I with constitutively active protein kinase A phosphorylation sites. Circ Res. 94:496–504. 2004. View Article : Google Scholar : PubMed/NCBI
8	Dong WJ, An J, Xing J and Cheung HC: Structural transition of the inhibitory region of troponin I within the regulated cardiac thin filament. Arch Biochem Biophys. 456:135–142. 2006. View Article : Google Scholar : PubMed/NCBI
9	Sadayappan S, Finley N, Howarth JW, Osinska H, Klevitsky R, Lorenz JN, Rosevear PR and Robbins J: Role of the acidic N’ region of cardiac troponin I in regulating myocardial function. FASEB J. 22:1246–1257. 2008.
10	Yu ZB, Zhang LF and Jin JP: A proteolytic NH₂-terminal truncation of cardiac troponin I that is up-regulated in simulated microgravity. J Biol Chem. 276:15753–15760. 2001.PubMed/NCBI
11	Zhang L, Wang YY and Yu ZB: Depressed responsiveness of cardiomyocytes to isoproterenol in simulated weightlessness rats. Sheng Li Xue Bao. 59:845–850. 2007.(In Chinese).
12	Yin W, Liu JC, Fan R, Sun XQ, Ma J, Feng N, Zhang QY, Yin Z, Zhang SM, Guo HT, Bi H, Wang YM, Sun X, Cheng L, Cui Q, Yu SQ, Yi DH and Pei JM: Modulation of {beta}-adrenoceptor signaling in the hearts of 4-wk simulated weightlessness rats. J Appl Physiol. 105:569–574. 2008.
13	Morey-Holton ER and Globus RK: Hindlimb unloading rodent model: technical aspects. J Appl Physiol. 92:1367–1377. 2002. View Article : Google Scholar : PubMed/NCBI
14	Nagata K, Liao R, Eberli FR, Satoh N, Chevalier B, Apstein CS and Suter TM: Early changes in excitation-contraction coupling: transition from compensated hypertrophy to failure in Dahl salt-sensitive rat myocytes. Cardiovasc Res. 37:467–477. 1998. View Article : Google Scholar : PubMed/NCBI
15	Fabiato A and Fabiato F: Effects of magnesium on contractile activation of skinned cardiac cells. J Physiol. 249:497–517. 1975. View Article : Google Scholar : PubMed/NCBI
16	MacDonnell SM, García-Rivas G, Scherman JA, Kubo H, Chen X, Valdivia H and Houser SR: Adrenergic regulation of cardiac contractility does not involve phosphorylation of the cardiac ryanodine receptor at serine 2808. Circ Res. 102:e65–e72. 2008. View Article : Google Scholar : PubMed/NCBI
17	Stelzer JE, Patel JR, Walker JW and Moss RL: Differential roles of cardiac myosin-binding protein C and cardiac troponin I in the myofibrillar force responses to protein kinase A phosphorylation. Circ Res. 101:503–511. 2007. View Article : Google Scholar : PubMed/NCBI
18	Sadayappan S, Gulick J, Klevitsky R, Lorenz JN, Sargent M, Molkentin JD and Robbins J: Cardiac myosin binding protein-C phosphorylation in a {beta}-myosin heavy chain background. Circulation. 119:1253–1262. 2009.PubMed/NCBI
19	Sadayappan S, Osinska H, Klevitsky R, Lorenz JN, Sargent M, Molkentin JD, Seidman CE, Seidman JG and Robbins J: Cardiac myosin binding protein C phosphorylation is cardioprotective. Proc Natl Acad Sci USA. 103:16918–16923. 2006. View Article : Google Scholar : PubMed/NCBI
20	Li L, Desantiago J, Chu G, Kranias EG and Bers DM: Phosphorylation of phospholamban and troponin I in beta-adrenergic-induced acceleration of cardiac relaxation. Am J Physiol Heart Circ Physiol. 278:H769–H779. 2000.PubMed/NCBI
21	Saucerman JJ and McCulloch AD: Mechanistic systems models of cell signaling networks: a case study of myocyte adrenergic regulation. Prog Biophys Mol Biol. 85:261–278. 2004. View Article : Google Scholar : PubMed/NCBI
22	Zhang R, Zhao J, Mandveno A and Potter JD: Cardiac troponin I phosphorylation increases the rate of cardiac muscle relaxation. Circ Res. 76:1028–1035. 1995. View Article : Google Scholar : PubMed/NCBI