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. 2009 Aug 14;15(1):1. doi: 10.2478/s11658-009-0030-4

The age-dependent induction of apoptosis-inducing factor (AIF) in the human semitendinosus skeletal muscle

Soo Yeon Park 1,✉, Ha Young Kim 2, Jung Hwan Lee 1, Kyoung Ho Yoon 3, Mun Seog Chang 2, Seong Kyu Park 2,✉
PMCID: PMC6275598  PMID: 19685011

Abstract

To assess the dependence on age of the expression of apoptosis regulatory proteins in the human semitendinosus muscle, we measured the expression levels of several apoptosis-related genes, including apoptosis-inducing factor (AIF), Bax, Bcl-2, caspase-3 and heat shock protein 70 (HSP70), using RT-PCR, immunohistochemistry and TUNEL assays. We found that the DNA fragmentation was proportional to the age of the tissues sample donors. The expression levels of AIF were significantly elevated (by 10 to 25%) in semitendinosus tissue samples from older individuals, but the Bax, Bcl-2, caspase-3 and HSP 70 levels remained almost constant. This data suggests that the morphological and functional changes observed in aged human semitendinosus muscle correlates with the apoptosis of muscle cells through the induction of AIF.

Key words: Human skeletal muscle, Semitendinosus, Apoptosis, Aging, Apoptosis-inducing factor

Full Text

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Abbreviations used

AIF

apoptosis inducing factor

Bcl-2

B-cell leukemia/lymphoma 2

caspase-3

cysteine-aspartic acid protease-3

HSP70

heat shock protein 70

References

  • 1.Dirks A., Leeuwenburgh C. Apoptosis in skeletal muscle with aging. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2002;282:R519–R527. doi: 10.1152/ajpregu.00458.2001. [DOI] [PubMed] [Google Scholar]
  • 2.Welle S., Brools A.L., Delehanty J.M., Needler N., Thornton C.A. Gene expression profile of aging in human muscle. Physiol. Genomics. 2003;14:149–159. doi: 10.1152/physiolgenomics.00049.2003. [DOI] [PubMed] [Google Scholar]
  • 3.Faulkner J.A., Davis C.S., Mendias C.L., Brooks S.V. The aging of elite male athletes: age-related changes in performance and skeletal muscle structure and function. Clin. J. Sport Med. 2008;18:501–507. doi: 10.1097/JSM.0b013e3181845f1c. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Lavendera A.P., Nosakab K. Changes in markers of muscle damage of middle-aged and young men following eccentric exercise of the elbow flexors. J. Sci. Med. Sport. 2008;11:124–131. doi: 10.1016/j.jsams.2006.11.004. [DOI] [PubMed] [Google Scholar]
  • 5.Marzetti E., Groban L., Wohlgemuth S.E., Lees H.A., Lin M., Jobe H., Giovannini S., Leeuwenburgh C., Carter C.S. Effects of short-term GH supplementation and treadmill exercise training on physical performance and skeletal muscle apoptosis in old rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2008;294:R558–567. doi: 10.1152/ajpregu.00620.2007. [DOI] [PubMed] [Google Scholar]
  • 6.Nikolić M., Bajek S., Bobinac D., Vranić T.S., Jerković R. Aging of human skeletal muscles. Coll. Antropol. 2005;29:67–70. [PubMed] [Google Scholar]
  • 7.Zerba E., Lomorowski T.E., Faulkner J.A. Free radical injury to skeletal muscles of young, adult, and old mice. Am. J. Physiol. 1990;258:C429–435. doi: 10.1152/ajpcell.1990.258.3.C429. [DOI] [PubMed] [Google Scholar]
  • 8.Lexell J., Taylor C.C., Sjöström M. What is the cause of the ageing atrophy? Total number, size and proportion of different fiber types studied in whole vastus lateralis muscle from 15- to 83-year-old men. J. Neurol. Sci. 1998;84:275–294. doi: 10.1016/0022-510X(88)90132-3. [DOI] [PubMed] [Google Scholar]
  • 9.Mcardle A., Jacson M.J. Exercise, oxidative stress and ageing. J. Anat. 2000;197:539–542. doi: 10.1046/j.1469-7580.2000.19740539.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Dupont-Versteegden E.E. Apoptosis in skeletal muscle and its relevance to atrophy. World J. Gastroenterol. 2006;12:7463–7466. doi: 10.3748/wjg.v12.i46.7463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Marzetti E., Leeuwenburh C. Skeletal muscle apoptosis, sarcopenia and frailty at old age. Exp. Gerontol. 2006;41:1234–1238. doi: 10.1016/j.exger.2006.08.011. [DOI] [PubMed] [Google Scholar]
  • 12.Meglara A., Jackson M.J., Meardle A. Programmed cell death in skeletal muscle. Biochem. Soc. Trans. 1998;26:S259. doi: 10.1042/bst026s259. [DOI] [PubMed] [Google Scholar]
  • 13.Higami Y., Shimokawa I. Apoptosis in the aging process. Cell Tissue Res. 2000;301:125–132. doi: 10.1007/s004419900156. [DOI] [PubMed] [Google Scholar]
  • 14.Green D.R., Reed J.C. Mitochondria and apoptosis. Science. 1998;281:1309–1312. doi: 10.1126/science.281.5381.1309. [DOI] [PubMed] [Google Scholar]
  • 15.Jiang X., Wang X. Cytochrome c-mediated apoptosis. Annu. Rev. Biochem. 2004;73:87–106. doi: 10.1146/annurev.biochem.73.011303.073706. [DOI] [PubMed] [Google Scholar]
  • 16.Cohen G.M. Caspases: the executioners of apoptosis. Biochem. J. 1997;15:1–16. doi: 10.1042/bj3260001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Kumar S. Mechanisms mediating caspase activation in cell death. Cell Death Diff. 1999;6:1060–1066. doi: 10.1038/sj.cdd.4400600. [DOI] [PubMed] [Google Scholar]
  • 18.Zhang Y., Chong E., Herman B. Age-associated increases in the activity of multiple caspases in Fisher 344 rat organs. Exp. Gerontol. 2002;37:777–789. doi: 10.1016/S0531-5565(02)00013-X. [DOI] [PubMed] [Google Scholar]
  • 19.Zhang J.H., Zhang Y., Herman B. Caspases, apoptosis and aging. Ageing Res. Rev. 2003;2:357–366. doi: 10.1016/S1568-1637(03)00026-6. [DOI] [PubMed] [Google Scholar]
  • 20.Adhihetty P.J., Hood D.A. Mechanisms of apoptosis in skeletal muscle. Basic Appl. Myol. 2003;13:171–179. [Google Scholar]
  • 21.Susin S.A., Lorenzo H.K., Zamzami N., Marzo I., Snow B.E., Brothers G.M., Mangion J., Jacotot E., Costantini P., Loeffler M., Larochette N., Goodlett D.R., Aebersold R., Siderovski D.P., Penninger J.M., Kroemer G. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature. 1999;397:441–446. doi: 10.1038/17135. [DOI] [PubMed] [Google Scholar]
  • 22.Li L.Y., Luo X., Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature. 2001;421:95–99. doi: 10.1038/35083620. [DOI] [PubMed] [Google Scholar]
  • 23.Candé C., Cohen I., Daugas E., Candé C., Cohen I., Daugas E., Ravagnan L., Larochette N., Zamzami N., Kroemer G. Apoptosisinducing factor (AIF): a novel caspase independent death effector released from mitochondria. Biochimie. 2002;84:215–222. doi: 10.1016/S0300-9084(02)01374-3. [DOI] [PubMed] [Google Scholar]
  • 24.Candé C., Vahsen N., Garrido C., Kroemer G. Apoptosis- inducing factor (AIF): caspase-independent after all. Cell Death Differ. 2004;11:591–595. doi: 10.1038/sj.cdd.4401400. [DOI] [PubMed] [Google Scholar]
  • 25.Daugas E., Susin S.A., Zamzami N., Ferri K.F., Irinopoulou T., Larochette N., Prévost M.C., Leber B., Andrews D., Penninger J., Kroemer G. Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J. 2000;14:729–739. [PubMed] [Google Scholar]
  • 26.Cory S., Adams J.M. The Bcl-2 family: regulators of the cellular life-or death switch. Nat. Rev. Cancer. 2002;2:647–656. doi: 10.1038/nrc883. [DOI] [PubMed] [Google Scholar]
  • 27.Daugas E., Nochy D., Ravagnan L., Loeffler M., Susin S.A., Zamzami N., Kroemer G. Apoptosis-inducing factor (AIF): a ubiquitous mitochondrial oxidoreductase involved in apoptosis. FEBS Lett. 2000;476:118–123. doi: 10.1016/S0014-5793(00)01731-2. [DOI] [PubMed] [Google Scholar]
  • 28.Marzetti E., Wohlgemuth S.E., Lees H.A., Chung H.Y., Giovannini S., Leeuwenburgh C. Age-related activation of mitochondrial caspaseindependent apoptotic signaling in rat gastrocnemius muscle. Mech. Ageing Dev. 2008;129:542–549. doi: 10.1016/j.mad.2008.05.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Gurbuxani S., Schmitt E., Cande C., Parcellier A., Hammann A., Daugas E., Kouranti I., Spahr C., Pance A., Kroemer G., Garrido C. Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor. Oncogene. 2003;22:6669–6678. doi: 10.1038/sj.onc.1206794. [DOI] [PubMed] [Google Scholar]
  • 30.Thornberry N.A., Lazebnik Y. Caspases: enemies within. Science. 1998;281:1312–1316. doi: 10.1126/science.281.5381.1312. [DOI] [PubMed] [Google Scholar]
  • 31.Fuentes-Prior P., Salvesen G.S. The protein structures that shape caspase activity, specificity, activation and inhibition. Biochem. J. 2004;384:201–232. doi: 10.1042/BJ20041142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Hewitson T.D., Bisucci T., Darby I.A. Histochemistry localization of apoptosis with in situ labeling of fragmented DNA. Methods Mol. Biol. 2006;326:27–34. doi: 10.1385/1-59745-007-3:227. [DOI] [PubMed] [Google Scholar]
  • 33.Strasser H., Tiefenthaler M., Steinlechner M., Eder I., Bartsch G., Konwalinka G. Age dependent apoptosis and loss of rhabdosphincter cells. J. Urol. 2000;164:1781–1785. doi: 10.1016/S0022-5347(05)67106-6. [DOI] [PubMed] [Google Scholar]
  • 34.Whitman S.A., Wacker M.J., Richmond S.R., Godard M.P. Contributions of the ubiquitin-proteasome pathway and apoptosis to human skeletal muscle wasting with age. Pflugers Arch. 2005;450:437–446. doi: 10.1007/s00424-005-1473-8. [DOI] [PubMed] [Google Scholar]
  • 35.Siu P.M., Pistilli E.E., Always S.E. Apoptotic responses to hindlimb suspension in gastrocnemius muscles from young adult and aged rats. Am. J. Physiol. Integr. Comp. Physiol. 2005;289:R1015–1026. doi: 10.1152/ajpregu.00198.2005. [DOI] [PubMed] [Google Scholar]
  • 36.Parsell D.A., Lindquist S. The function of heat-shock proteins in stress tolerance: degradation and reactivation of damaged proteins. Annu. Rev. Genet. 1993;27:437–496. doi: 10.1146/annurev.ge.27.120193.002253. [DOI] [PubMed] [Google Scholar]
  • 37.Nollen E.A., Morimoto R.I. Chaperoning signaling pathways: molecular chaperones as stress-sensing ‘heat shock’ proteins. J. Cell Sci. 2002;115:2809–2816. doi: 10.1242/jcs.115.14.2809. [DOI] [PubMed] [Google Scholar]
  • 38.Garrido C., Gurbuxani S., Ravagnan L., Kroemer G. Heat shock proteins: endogenous modulators of apoptotic cell death. Biochem. Biophys. Res. Commun. 2001;286:433–442. doi: 10.1006/bbrc.2001.5427. [DOI] [PubMed] [Google Scholar]
  • 39.Vasilaki A., Jackson M. J., McArdle A. Attenuated HSP70 response in skeletal muscle of aged rats following contractile activity. Muscle Nerve. 2002;25:902–905. doi: 10.1002/mus.10094. [DOI] [PubMed] [Google Scholar]

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