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. 2009 Jan 15;46(2):238-43.
doi: 10.1016/j.freeradbiomed.2008.10.022. Epub 2008 Oct 18.

Exercise improves import of 8-oxoguanine DNA glycosylase into the mitochondrial matrix of skeletal muscle and enhances the relative activity

Zsolt Radak  1 , Mustafa Atalay, Judit Jakus, István Boldogh, Kelvin Davies, Sataro Goto
Affiliations

Exercise improves import of 8-oxoguanine DNA glycosylase into the mitochondrial matrix of skeletal muscle and enhances the relative activity

Zsolt Radak et al. Free Radic Biol Med. .

Abstract (V体育ios版)

Exercise has been shown to modify the level/activity of the DNA damage repair enzyme 8-oxoguanine-DNA glycosylase (OGG1) in skeletal muscle. We have studied the impact of regular physical training (8 weeks of swimming) and detraining (8 weeks of rest after an 8-week training session) on the activity of OGG1 in the nucleus and mitochondria as well as its targeting to the mitochondrial matrix in skeletal muscle. Neither exercise training nor detraining altered the overall levels of reactive species; however, mitochondrial levels of carbonylated proteins were decreased in the trained group as assessed by electron spin resonance and biochemical approaches. Importantly, nuclear OGG1 activity was increased by daily exercise training, whereas detraining reversed the up-regulating effect of training. Interestingly, training decreased the outer-membrane-associated mitochondrial OGG1 levels, whereas detraining reversed this effect. These results suggest that exercise training improves OGG1 import into the mitochondrial matrix, thereby increasing OGG1-mediated repair of oxidized guanine bases VSports手机版. Taken together, our data suggest that physical inactivity could impair the mitochondrial targeting of OGG1; however, exercise training increases OGG1 levels/activity in the nucleus and specific activity of OGG1 in mitochondrial compartments, thereby augmenting the repair of oxidized nuclear and mitochondrial DNA bases. .

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Figures

Fig. 1
Fig. 1
Free radical levels in skeletal muscle. (A) A typical ESR spectrum taken ex vivo at 77 K showing steady-state basal ROS levels in the red muscle tissue of rats. Spectrum contains two Mn/MnO signals as internal standards, indicated by arrows. The signal observed between the two signals of standards was double integrated for evaluation. (B) Graphical illustration of ESR data shows no change in overall ROS levels in the skeletal muscle of experimental animals after adaptation to physical exercise. Values are means±SD for six animals per group. *p<0.05 vs control.
Fig. 2
Fig. 2
(A) Overall levels of lipid peroxides and (B) GSSG:GSG ratios are unaltered in muscle. Malondialdehyde levels and GSSG:GSH ratios were assessed in muscle tissue lysates from trained (T), detrained (DT), and control (C) groups of animals as described under Materials and methods. Data are expressed as the means±SD for six animals per group.
Fig. 3
Fig. 3
(B) The levels of lipid peroxidation and (C) GSSG:GSH ratios are not changed in the mitochondrial lysates of skeletal muscle. (A) The purity of mitochondrial and nuclear extracts was evaluated by the concentration of the nuclear envelope marker lamin A (Abcam 133A2, Cambridge, UK). Malondialdehyde levels and GSSG:GSH ratios were assessed from mitochondrial lysates from trained (T), detrained (DT), and control (C) groups of animals as described under Materials and methods. Data are expressed as the means±SD for six animals per group.
Fig. 4
Fig. 4
Decreases in mitochondrial protein carbonyl levels in animals adapted to exercise. (A) A representative image showing the abundance of protein carbonyls in individual control (C), trained (T), and detrained (DT) animals. (B) Graphical illustration of changes in protein carbonyl levels from densitometry of autoradiograms (N=6). The levels of protein carbonylation were similar in control and detrained animals. The trained group showed significantly less damage, especially in low-molecular-weight proteins. *p<0.05.
Fig. 5
Fig. 5
Exercise increases the activity of OGG1 in the nucleus. Two micrograms of nuclear extract was mixed with 20 pmol of 32P-labeled synthetic substrate containing 8-oxoG in 20 µl of reaction buffer and incubated at 30°C for 15 min. Incision products were separated by polyacrylamide (20%) with 7 M urea gel and the gels were analyzed using a STORM bioimaging analyzer (Materials and methods). The OGG1 8-oxoG-repair activity was determined and expressed as a percentage of the substrate cleaved [24,15]. (A) Image showing increased nOGG1 activity as a result of exercise training, whereas detraining did not alter the activity. Fpg, formamidopyrimidine DNA glycosylase. (B) Graphical illustration of densitometric data obtained from six animals for each group as described under Materials and methods. Assays were run three times and representative data for three animals from each group are shown in (A). S, substrate; P, product. *p<0.05 vs control.
Fig. 6
Fig. 6
Exercise decreases the activity of mitochondria-associated OGG1. The activities of OGG1β in mitochondrial lysates were determined as described for Fig. 4. (A) Image illustrating the changes in OGG1β activity in mitochondrial lysates of individual animals, trained (T), detrained (DT), and controls (C). Fpg, formamidopyrimidine DNA glycosylase. Assays were run three times and a representative gel is shown. (B) Graphical illustration of densitometric data obtained from six animals for each group as described under Materials and methods. S, substrate; P, product. *p<0.05 vs control, #p<0.05 vs trained.
Fig. 7
Fig. 7
OGG1β level and activity in mitochondrial lysates before and after trypsin digestion. (A) Purified mitochondrial suspensions from control (C), trained (T), and detrained (DT) groups of animals were subjected to mild trypsin digestion or mock treatment and OGG1β levels were assessed as described under Materials and methods. Trypsin treatment resulted in significantly decreased OGG1β levels in control and detrained groups, suggesting that OGG1β was attached to the outer membrane. (B) Mitochondria-associated OGG1β activity is decreased by trypsin digestion in C and DT groups compared to T animals. OGG1 activity was determined as for Fig. 4. *p<0.05 vs control, #p<0.05 vs detrained.
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