Molecular and Cellular Biochemistry

, Volume 313, Issue 1–2, pp 11–18 | Cite as

Telomerase reconstitution contributes to resetting of circadian rhythm in fibroblasts

  • Yi Qu
  • Meng Mao
  • Xihong Li
  • Yanyou Liu
  • Jianmin Ding
  • Zhou Jiang
  • Chaomin Wan
  • Lin Zhang
  • Zhengrong WangEmail author
  • Dezhi MuEmail author


The synchronization of the circadian signals to external or suprachiasmatic nucleus stimulation in the peripheral clocks is essential for maintaining the usual function of human body. However, aging will disrupt the synchronization of peripheral circadian rhythms, thus leading to some age-associated diseases. Up to now, little is known about the modification of the oscillatory rhythms in aged cells. A recent report showed that cell senescence in vascular human smooth muscle cells (HSMCs) altered circadian rhythms by a dysregulation of rhythmic gene expression. Furthermore, this alteration could be reversed by telomerase reconstitution. To test whether telomerase reconstitution can restore disrupted circadian rhythm in other types of senescent cells, we used fibroblasts as cell models to profoundly investigate the relationship between cell senescence and circadian rhythm modulation. We found that the response of rhythmic gene expression to serum stimulation was markedly attenuated in senescent fibroblasts, telomerase-reconstituted fibroblasts reset the circadian oscillation of rhythmic gene expression, and the activation of pERK-CREB and p38-CREB pathways might be involved in the circadian rhythm resetting. These findings suggested that telomerase reconstitution might be a good way to reset synchronization of peripheral circadian rhythms disrupted in senescent tissues.


Telomerase Fibroblasts Circadian rhythm Rhythmic gene 



This work was supported by the National Natural Science Foundation of China (No. 30570902 to Zhengrong Wang, Nos. 30570623 and 30770748 to Dezhi Mu) and Doctoral Program of Ministry of Education of China (No. 20050610094 to Yi Qu and No. 20070610092 to Dezhi Mu).


  1. 1.
    Halberg F (1983) Quo vadis basic and clinical chronobiology: promise for health maintenance. Am J Anat 168:543–594PubMedCrossRefGoogle Scholar
  2. 2.
    Monk TH (2005) Aging human circadian rhythms: conventional wisdom may not always be right. J Biol Rhythms 20:366–374PubMedCrossRefGoogle Scholar
  3. 3.
    Hofman MA (2000) The human circadian clock and aging. Chronobiol Int 17:245–259PubMedCrossRefGoogle Scholar
  4. 4.
    Hofman MA, Swaab DF (2006) Living by the clock: the circadian pacemaker in older people. Ageing Res Rev 5:33–51PubMedCrossRefGoogle Scholar
  5. 5.
    Yamazaki S, Straume M, Tei H et al (2002) Effects of aging on central and peripheral mammalian clocks. Proc Natl Acad Sci USA 99:10801–10806PubMedCrossRefGoogle Scholar
  6. 6.
    Kolker DE, Fukuyama H, Huang DS et al (2003) Aging alters circadian and light-induced expression of clock genes in golden hamsters. J Biol Rhythms 18:159–169PubMedCrossRefGoogle Scholar
  7. 7.
    Kunieda T, Minamino T, Katsuno T et al (2006) Cellular senescence impairs circadian expression of rhythmic genes in vitro and in vivo. Circ Res 98:532–539PubMedCrossRefGoogle Scholar
  8. 8.
    Xie HQ, Yang ZM, Qu Y (2002) Culture of human fibroblasts transfected by human telomerase reverse transcriptase eukaryotic expression plasmid pGRN145 and their biological characteristics in vitro. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 16:195–199PubMedGoogle Scholar
  9. 9.
    Maier AB, Westendorp RJ, Heemst DV (2007) β-Galactosidase activity as a biomarker of replicative senescence during the course of human fibroblast cultures. Ann N Y Acad Sci 1100:323–332PubMedCrossRefGoogle Scholar
  10. 10.
    Balsalobre A, Damiola F, Schibler U (1998) A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93:929–937PubMedCrossRefGoogle Scholar
  11. 11.
    Obrietan K, Impey S, Smith D et al (1999) Circadian regulation of cAMP response element-mediated gene expression in the suprachiasmatic nuclei. J Biol Chem 274:17748–17756PubMedCrossRefGoogle Scholar
  12. 12.
    Travnickova BZ, Cermakian N, Reppert SM et al (2002) Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity. Proc Natl Acad Sci USA 99:7728–7733CrossRefGoogle Scholar
  13. 13.
    Fukada Y, Okano T (2002) Circadian clock system in the pineal gland. Mol Neurobiol 25:19–30PubMedCrossRefGoogle Scholar
  14. 14.
    Halberg F (1980) Chronobiology: methodological problems. Acta Med Romana 18:399–440Google Scholar
  15. 15.
    McNamara P, Seo SP, Rudic RD et al (2001) Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock. Cell 105:877–889PubMedCrossRefGoogle Scholar
  16. 16.
    Nagoshi E, Saini C, Bauer C et al (2004) Circadian gene expression in individual fibroblasts: cell-autonomous and self-sustained oscillators pass time to daughter cells. Cell 19:693–705CrossRefGoogle Scholar
  17. 17.
    Welsh DK, Yoo SH, Liu AC et al (2004) Bioluminescence imaging of individual fibroblasts reveals persistent, independently phased circadian rhythms of clock gene expression. Curr Biol 14:2289–2295PubMedCrossRefGoogle Scholar
  18. 18.
    Akashi M, Nishida E (2000) Involvement of the MAP kinase cascade in resetting of the mammalian circadian clock. Genes Dev 14:645–649PubMedGoogle Scholar
  19. 19.
    Dunlap JC (1999) Molecular bases for circadian clocks. Cell 96:271–290PubMedCrossRefGoogle Scholar
  20. 20.
    King DP, Takahashi JS (2000) Molecular genetics of the circadian rhythms in mammals. Annu Rev Neurosci 23:712–742CrossRefGoogle Scholar
  21. 21.
    Preitner N, Damiola F, Lopez-Molina L et al (2002) The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110:251–260PubMedCrossRefGoogle Scholar
  22. 22.
    Allada R, Emery P, Takahashi JS et al (2001) Stopping time: the genetics of fly and mouse circadian clocks. Annu Rev Neurosci 24:1091–1119PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Yi Qu
    • 1
  • Meng Mao
    • 1
  • Xihong Li
    • 1
  • Yanyou Liu
    • 2
  • Jianmin Ding
    • 3
  • Zhou Jiang
    • 2
  • Chaomin Wan
    • 1
  • Lin Zhang
    • 1
  • Zhengrong Wang
    • 2
    Email author
  • Dezhi Mu
    • 1
    Email author
  1. 1.Department of Pediatrics, West China Second University HospitalSichuan UniversityChengduChina
  2. 2.Health Ministry Key Lab of Chronobiology, West China Medical CenterSichuan UniversityChengduChina
  3. 3.Department of Physiology, Brody School of MedicineEast Carolina UniversityGreenvilleUSA

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