Lower oxidative DNA damage despite greater ROS production in muscles from rats selectively bred for high running capacity

Tweedie C, Romestaing C, Burelle Y, Safdar A, Tarnopolsky MA, Seadon S, Britton SL, Koch LG, Hepple RT. Lower oxidative DNA damage despite greater ROS production in muscles from rats selectively bred for high running capacity. Am J Physiol Regul Integr Comp Physiol 300: R544-R553, 2011. First published December 15, 2010; doi: 10.1152/ajpregu.00250.2010.-Artificial selection in rat has yielded high-capacity runners (HCR) and low-capacity runners (LCR) that differ in intrinsic (untrained) aerobic exercise ability and metabolic disease risk. To gain insight into how oxygen metabolism may have been affected by selection, we compared mitochondrial function, oxidative DNA damage (8-dihydroxy-guanosine; 8dOHG), and antioxidant enzyme activities in soleus muscle (Sol) and gastrocnemius muscle (Gas) of adult and aged LCR vs. HCR rats. In Sol of adult HCR rats, maximal ADP-stimulated respiration was 37% greater, whereas in Gas of adult HCR rats, there was a 23% greater complex IV-driven respiratory capacity and 54% greater leak as a fraction of electron transport capacity (suggesting looser mitochondrial coupling) vs. LCR rats. H2O2 emission per gram of muscle was 24-26% greater for both muscles in adult HCR rats vs. LCR, although H2O2 emission in Gas was 17% lower in HCR, after normalizing for citrate synthase activity (marker of mitochondrial content). Despite greater H2O2 emission, 8dOHG levels were 62-78% lower in HCR rats due to 62-96% higher superoxide dismutase activity in both muscles and 47% higher catalase activity in Sol muscle in adult HCR rats, with no evidence for higher 8 oxoguanine glycosylase (OGG1; DNA repair enzyme) protein expression. We conclude that genetic segregation for high running capacity has generated a molecular network of cellular adaptations, facilitating a superior response to oxidative stress.