Low physical activity levels have been associated with a more glycolytic skeletal muscle phenotype and impaired endogenous antioxidant stores which can lead to increased oxidative stress and associated pathways which include but are not limited to impaired insulin signaling. PURPOSE: We utilized a unique polygenic model of rats bred for high or low voluntary wheel running (HVR and LVR, respectively) to identify differential oxidative stress and gene expression patterns between LVR and HVR rodents. METHODS: Four groups of 2-month old male Wistar rats were used: 1) low voluntary wheel running (LVR) rats housed without a running wheel (LVR SED; n=7); 2) LVR housed with a running wheel (LVR W/WHEEL; n=7); 3) LVR housed with a running wheel and exercised on the treadmill (5 days/week for 20 min/day at 15.0 m/min) (LVR W/WHEEL+TM; n=7); and 4) high voluntary wheel running (HVR) rats housed with a running wheel (HVR W/WHEEL; n=8). Animals were euthanized five weeks after the start of the experiment and the soleus muscles were excised and used for biochemical analyses. RESULTS: Soleus from LVR W/WHEEL+TM and HVR W/WHEEL had higher protein levels of manganese superoxide dismutase than LVR SED (p<0.05). Also, soleus muscles of HVR W/WHEEL had higher protein levels of catalase than LVR SED and LVR W/WHEEL+TM (p<0.05). Soleus from LVR W/WHEEL, LVR W/WHEEL+TM, and HVR W/WHEEL had significantly less 4HNE (marker of oxidative damage) than LVR SED (p<0.05). Soleus UCP3 mRNA levels were less in LVR W/WHEEL+TM compared to LVR SED and LVR W/WHEEL (p<0.05). No changes were detected in soleus GLUT4 or PGC1a (p>0.05). CONCLUSION: These data suggest that varying forms of physical activity have the capacity to modify soleus mRNA markers of oxidative stress differentially between HVR and LVR rats. Therefore, this distinctive polygenic animal model can be employed in future studies to dissect out differences in transcriptomics and proteomics between selectively bred LVR and HVR rodents.