Terminally differentiated muscle cells are defective in base excision DNA repair and hypersensitive to oxygen injury

Laura Narciso, Paola Fortini, Deborah Pajalunga, Annapaola Franchitto, Pingfang Liu, Paolo Degan, Mathilde Frechet, Bruce Demple, Marco Crescenzi, Eugenia Dogliotti

Research output: Contribution to journalArticle

Abstract

The differentiation of skeletal myoblasts is characterized by permanent withdrawal from the cell cycle and fusion into multinucleated myotubes. Muscle cell survival is critically dependent on the ability of cells to respond to oxidative stress. Base excision repair (BER) is the main repair mechanism of oxidative DNA damage. In this study, we compared the levels of endogenous oxidative DNA damage and BER capacity of mouse proliferating myoblasts and their differentiated counterpart, the myotubes. Changes in the expression of oxidative stress marker genes during differentiation, together with an increase in 8-hydroxyguanine DNA levels in terminally differentiated cells, suggested that reactive oxygen species are produced during this process. The repair of 2-deoxyribonolactone, which is exclusively processed by longpatch BER, was impaired in cell extracts from myotubes. The repair of a natural abasic site (a preferred substrate for short-patch BER) also was delayed. The defect in BER of terminally differentiated muscle cells was ascribed to the nearly complete lack of DNA ligase I and to the strong down-regulation of XRCC1 with subsequent destabilization of DNA ligase IIIα. The attenuation of BER in myotubes was associated with significant accumulation of DNA damage as detected by increased DNA single-strand breaks and phosphorylated H2AX nuclear foci upon exposure to hydrogen peroxide. We propose that in skeletal muscle exacerbated by free radical injury, the accumulation of DNA repair intermediates, due to attenuated BER, might contribute to myofiber degeneration as seen in sarcopenia and many muscle disorders.

Original languageEnglish
Pages (from-to)17010-17015
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number43
DOIs
Publication statusPublished - Oct 23 2007

Keywords

  • 8-oxoguanine
  • DNA ligases
  • DNA single-strand breaks
  • Oxidative stress
  • XRCC1

ASJC Scopus subject areas

  • Genetics
  • General

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