Differentiation-Associated Downregulation of Poly(ADP-Ribose) Polymerase-1 Expression in Myoblasts Serves to Increase Their Resistance to Oxidative Stress

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...

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Bibliographic Details
Published in:PloS one 2015-07, Vol.10 (7), p.e0134227-e0134227
Main Authors: Oláh, Gábor, Szczesny, Bartosz, Brunyánszki, Attila, López-García, Isabel A, Gerö, Domokos, Radák, Zsolt, Szabo, Csaba
Format: Article
Language:English
Subjects:
Adenosine diphosphate
Anesthesiology
Animals
Apoptosis
ATP
Cancer
Catalysis
Catalytic activity
Cell cycle
Cell death
Cell Differentiation
Cells, Cultured
Cellular signal transduction
Deoxyribonucleic acid
Diabetes mellitus
Differentiation
DNA
DNA repair
Down-Regulation
Electron transport
Energy Metabolism
Enzymes
Exercise
Injury prevention
Membrane potential
Membrane Potential, Mitochondrial
Metabolism
Mice
Microscopy, Fluorescence
Mitochondria
Mitochondria - enzymology
Mitochondria - pathology
Mitochondrial DNA
Muscle Fibers, Skeletal - enzymology
Muscle Fibers, Skeletal - pathology
Muscles
Musculoskeletal system
Myoblasts
Myoblasts - enzymology
Myoblasts - pathology
Myotubes
NAD
Oxidation resistance
Oxidative Stress
Poly Adenosine Diphosphate Ribose
Poly(ADP-ribose)
Poly(ADP-ribose) polymerase
Poly(ADP-ribose) Polymerases - chemistry
Poly(ADP-ribose) Polymerases - metabolism
Proteins
Rats
Ribose
Rodents
Sepsis
Skeletal muscle
Substrates
Transduction
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0134227