Increased iron content and RNA oxidative damage in skeletal muscle with aging and disuse atrophy

Tim Hofer, Emanuele Marzetti, Jinze Xu, Arnold Y. Seo, Sukru Gulec, Mitchell D. Knutson, Christiaan Leeuwenburgh, Esther E. Dupont-Versteegden

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

Abstract

Muscle atrophy with aging or disuse is associated with deregulated iron homeostasis and increased oxidative stress likely inflicting damage to nucleic acids. Therefore, we investigated RNA and DNA oxidation, and iron homeostasis in gastrocnemius muscles. Disuse atrophy was induced in 6- and 32-month old male Fischer 344/Brown Norway rats by 14 days of hind limb suspension (HS). We show that RNA, but not DNA, oxidative damage increased 85% with age and 36% with HS in aged muscle. Additionally, non-heme iron levels increased 233% with aging and 83% with HS at old age, while staining for free iron was strongest in the smallest fibers. Simultaneously, the mRNA abundance of transferrin receptor-1 decreased by 80% with age and 48% with HS for young animals, while that of the hepcidin regulator hemojuvelin decreased 37% with age, but increased about 44% with disuse, indicating a dysregulation of iron homeostasis favoring increased intracellular free iron in atrophied muscles. RNA and DNA concentrations increased with age and were negatively correlated with muscle mass, whereas protein concentrations decreased with aging, indicating a preferential loss of protein compared to nucleic acids. Furthermore, xanthine oxidase activity increased with age, but not with HS, while mRNA abundance of the Y box-binding protein-1, which has been suggested to bind oxidized RNA, did not change with age or HS. These results suggest that RNA oxidation, possibly mediated by increased non-heme iron, might contribute to muscle atrophy due to disuse particularly in aged muscle.

Original languageEnglish
Pages (from-to)563-570
Number of pages8
JournalExperimental Gerontology
Volume43
Issue number6
DOIs
StatePublished - Jun 2008

Bibliographical note

Funding Information:
This research was supported by grants from the National Institute on Aging (AG17994 and AG21042 to C.L. and AG20407 and AG028925 to E.D.), an American Heart Postdoctoral Fellowship to T.H. (0525346B), and an American Heart Fellowship to A.Y.S. (0615256B). E.M. is supported by the Claude D. Pepper Older Americans Independence Center (OAIC) (1 P30 AG028740-01). We would like to thank Cathy Gurley for technical assistance.

Keywords

  • Gastrocnemius
  • Hemojuvelin (HJV)
  • RNA oxidation
  • Sarcopenia
  • Transferrin receptor-1 (TfR1)
  • Xanthine oxidase (XOD)
  • Y box-binding protein-1 (YB-1)

ASJC Scopus subject areas

  • Biochemistry
  • Aging
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Cell Biology

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