Differential thiol oxidation of the signaling proteins Akt, PTEN or PP2A determines whether Akt phosphorylation is enhanced or inhibited by oxidative stress in C2C12 myotubes derived from skeletal muscle.
Oxidative stress, caused by excess reactive oxygen species (ROS), has been hypothesized to cause or exacerbate skeletal muscle wasting in a number of diseases and chronic conditions. ROS, such as hydrogen peroxide, have the potential to affect signal transduction pathways such as the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3 K)/Akt pathway that regulates protein synthesis. Previous studies have found contradictory outcomes for the effect of ROS on the PI3K/Akt signaling pathway, where oxidative stress can either enhance or inhibit Akt phosphorylation. The apparent contradictions could reflect differences in experimental cell types or types of ROS treatments. We replicate both effects in myotubes of cultured skeletal muscle C2C12 cells, and show that increased oxidative stress can either inhibit or enhance Akt phosphorylation. This differential response could be explained: thiol oxidation of Akt, but not the phosphatases PTEN or PP2A, caused a decline in Akt phosphorylation; whereas the thiol oxidation of Akt, PTEN and PP2A increased Akt phosphorylation. These observations indicate that a more complete understanding of the effects of oxidative stress on a signal transduction pathway comes not only from identifying the proteins susceptible to thiol oxidation, but also their relative sensitivity to ROS.
School of Anatomy, Physiology and Human Biology, The University of Western Australia, Western Australia, Australia; School of Chemistry and Biochemistry, The University of Western Australia, Western Australia, Australia.
Pearl Lin
PL
Tan
School of Anatomy, Physiology and Human Biology, The University of Western Australia, Western Australia, Australia.
Tea
T
Shavlakadze
School of Anatomy, Physiology and Human Biology, The University of Western Australia, Western Australia, Australia.
Miranda D
MD
Grounds
School of Chemistry and Biochemistry, The University of Western Australia, Western Australia, Australia. Electronic address: peter.arthur@uwa.edu.au.
Peter G
PG
Arthur
D000818:Animals; D002460:Cell Line; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000378:metabolism*
D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D006861:Hydrogen Peroxide; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2; D051059:PTEN Phosphohydrolase
Akt; Hydrogen peroxide; Oxidative stress; Protein thiol oxidation; Reactive oxygen species