Age-dependent changes in 8-oxoguanine-DNA glycosylase activity are modulated by adaptive responses to physical exercise in human skeletal muscle

Abstract

8-Oxo-7,8 dihydroguanine (8-oxoG) accumulates in the genome over time and is believed to contribute to the development of aging characteristics of skeletal muscle and various aging-related diseases. Here, we show a significantly increased level of intrahelical 8-oxoG and 8-oxoguanine DNA glycosylase (OGG1) expression in aged human skeletal muscle compared to that of young individuals. In response to exercise, the 8-oxoG level was found to be lastingly elevated in sedentary young and old subjects, but returned rapidly to pre-exercise levels in the DNA of physically active individuals independent of age. 8-OxoG levels in DNA were inversely correlated with the abundance of acetylated OGG1 (Ac-OGG1), but not with total OGG1, apurinic/apyrimidinic endonuclease (AP)-1 or Ac-APE1. The actual Ac-OGG1 level was linked to exercise-induced oxidative stress, as shown by changes in lipid peroxide levels and expression of Cu,Zn-SOD, Mn-SOD and SIRT3, as well as the balance between acetyl transferase p300/CBP and the deacetylase SIRT1, but not SIRT6 expression. Together these data suggest that that acetylated form of OGG1, and not OGGl itself, correlates inversely with the 8-oxoG level in the DNA of human skeletal muscle, and the Ac-OGG1 level is dependent on adaptive cellular responses to physical activity, but is age independent.

Exogenous nicotinamide supplementation and moderate physical exercise can attenuate the aging process in skeletal muscle of rats

“…We and others have shown that exercise increases the activity and content of SIRT1 (Hart et al 2014;Kang et al 2013;Koltai et al 2011;Marton et al 2015;Radak et al 2011;Suwa et al 2008), while aging decreases NAD levels and NAMPT concentration (Koltai et al 2010). Moreover, it has also been reported that exercise training can attenuate the age associated decline in NAD and NAMT levels in skeletal muscle of rats (Koltai et al 2012).…”

Combined Exercise and Insulin-Like Growth Factor-1 Supplementation Induces Neurogenesis in Old Rats, but Do Not Attenuate Age-Associated DNA Damage

“…This was also confirmed in our recent finding from aged human skeletal muscle (Radak et al, 2011). 85 Acetylation of OGG1 is a posttranslational activation of the incision activity of this enzyme. 14,29 Thus, it cannot be excluded that the age-associated increase in 8-oxoG levels could be due to the large decrease in acetylation of OGG1.…”

Redox-regulating sirtuins in aging, caloric restriction, and exercise

“…OGG1 has been shown to be acetylated by p300/CBP at lysines 338 and 341, which results in a significant increase in its activity [81]. We have recently demonstrated that Ac-OGG1 is present in human skeletal muscle and rat tissues, and the level of acetylation decreases with aging, whereas a parallel pattern was found for SIRT1 activity [82,83]. Moreover, we have shown that resveratrol administration decreases the acetylation level of OGG1 and ablation of SIRT1 by siRNA-increased levels of Ac-OGG1.…”