Differentiation-associated downregulation of poly(ADP-Ribose) polymerase-1 expression in myoblasts serves to increase their resistance to oxidative stress

Gábor Oláh, Bartosz Szczesny, Attila Brunyánszki, Isabel A. Lopez-García, Domokos Gerö, Zsolt Radák, Csaba Szabo

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Poly(ADP-ribose) polymerase 1 (PARP-1), the major isoform of the poly (ADP-ribose) polymerase family, is a constitutive nuclear and mitochondrial protein with well-recognized roles in various essential cellular functions such as DNA repair, signal transduction, apoptosis, as well as in a variety of pathophysiological conditions including sepsis, diabetes and cancer. Activation of PARP-1 in response to oxidative stress catalyzes the covalent attachment of the poly (ADP-ribose) (PAR) groups on itself and other acceptor proteins, utilizing NAD+ as a substrate. Overactivation of PARP-1 depletes intracellular NAD+ influencing mitochondrial electron transport, cellular ATP generation and, if persistent, can result in necrotic cell death. Due to their high metabolic activity, skeletal muscle cells are particularly exposed to constant oxidative stress insults. In this study, we investigated the role of PARP-1 in a well-defined model of murine skeletal muscle differentiation (C2C12) and compare the responses to oxidative stress of undifferentiated myoblasts and differentiated myotubes. We observed a marked reduction of PARP-1 expression as myoblasts differentiated into myotubes. This alteration correlated with an increased resistance to oxidative stress of the myotubes, as measured by MTT and LDH assays. Mitochondrial function, assessed by measuring mitochondrial membrane potential, was preserved under oxidative stress in myotubes compared to myoblasts. Moreover, basal respiration, ATP synthesis, and the maximal respiratory capacity of mitochondria were higher in myotubes than in myoblasts. Inhibition of the catalytic activity of PARP-1 by PJ34 (a phenanthridinone PARP inhibitor) exerted greater protective effects in undifferentiated myoblasts than in differentiated myotubes. The above observations in C2C12 cells were also confirmed in a rat-derived skeletal muscle cell line (L6). Forced overexpression of PARP1 in C2C12 myotubes sensitized the cells to oxidant-induced injury. Taken together, our data indicate that the reduction of PARP-1 expression during the process of the skeletal muscle differentiation serves as a protective mechanism to maintain the cellular functions of skeletal muscle during oxidative stress.

Original languageEnglish (US)
Article numbere0134227
JournalPLoS One
Volume10
Issue number7
DOIs
StatePublished - Jul 28 2015

Fingerprint

NAD ADP-ribosyltransferase
myoblasts
Oxidative stress
Poly(ADP-ribose) Polymerases
Myoblasts
Skeletal Muscle Fibers
Oxidative Stress
oxidative stress
Down-Regulation
Skeletal Muscle
Muscle
skeletal muscle
NAD
Muscle Cells
myocytes
Adenosine Triphosphate
Poly Adenosine Diphosphate Ribose
Cells
Mitochondrial Membrane Potential
Mitochondrial Proteins

ASJC Scopus subject areas

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

Cite this

Differentiation-associated downregulation of poly(ADP-Ribose) polymerase-1 expression in myoblasts serves to increase their resistance to oxidative stress. / Oláh, Gábor; Szczesny, Bartosz; Brunyánszki, Attila; Lopez-García, Isabel A.; Gerö, Domokos; Radák, Zsolt; Szabo, Csaba.

In: PLoS One, Vol. 10, No. 7, e0134227, 28.07.2015.

Research output: Contribution to journalArticle

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