Deficiency in Repair of the Mitochondrial Genome Sensitizes Proliferating Myoblasts to Oxidative Damage

Bartosz Szczesny, Gabor Olah, Dillon K. Walker, Elena Volpi, Blake Rasmussen, Csaba Szabo, Sankar Mitra

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Reactive oxygen species (ROS), generated as a by-product of mitochondrial oxidative phosphorylation, are particularly damaging to the genome of skeletal muscle because of their high oxygen consumption. Proliferating myoblasts play a key role during muscle regeneration by undergoing myogenic differentiation to fuse and restore damaged muscle. This process is severely impaired during aging and in muscular dystrophies. In this study, we investigated the role of oxidatively damaged DNA and its repair in the mitochondrial genome of proliferating skeletal muscle progenitor myoblasts cells and their terminally differentiated product, myotubes. Using the C2C12 cell line as a well-established model for skeletal muscle differentiation, we show that myoblasts are highly sensitive to ROS-mediated DNA damage, particularly in the mitochondrial genome, due to deficiency in 5' end processing at the DNA strand breaks. Ectopic expression of the mitochondrial-specific 5' exonuclease, EXOG, a key DNA base excision/single strand break repair (BER/SSBR) enzyme, in myoblasts but not in myotubes, improves the cell's resistance to oxidative challenge. We linked loss of myoblast viability by activation of apoptosis with deficiency in the repair of the mitochondrial genome. Moreover, the process of myoblast differentiation increases mitochondrial biogenesis and the level of total glutathione. We speculate that our data may provide a mechanistic explanation for depletion of proliferating muscle precursor cells during the development of sarcopenia, and skeletal muscle dystrophies.

Original languageEnglish (US)
Article numbere75201
JournalPLoS One
Volume8
Issue number9
DOIs
StatePublished - Sep 16 2013

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myoblasts
Mitochondrial Genome
Myoblasts
Muscle
Repair
Genes
skeletal muscle
Skeletal Muscle
DNA
Skeletal Muscle Fibers
reactive oxygen species
Reactive Oxygen Species
sarcopenia
Phosphodiesterase I
muscles
muscular dystrophy
Sarcopenia
oxidative phosphorylation
muscle development
Muscles

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Deficiency in Repair of the Mitochondrial Genome Sensitizes Proliferating Myoblasts to Oxidative Damage. / Szczesny, Bartosz; Olah, Gabor; Walker, Dillon K.; Volpi, Elena; Rasmussen, Blake; Szabo, Csaba; Mitra, Sankar.

In: PLoS One, Vol. 8, No. 9, e75201, 16.09.2013.

Research output: Contribution to journalArticle

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