Recent evidence suggests aerobic exercise may help preserve soleus muscle mass during unloading. The purpose of this investigation was to examine the muscle specific metabolic response to running as it relates to muscle growth. Mixed muscle protein synthesis (FSR) and gene expression (GE) were examined in the vastus lateralis (VL) and soleus (SOL) muscles from eight men (26±2 yr; VO₂max 63±2 ml•kg^-1•min^-1) before and after a 45-min level grade treadmill run at 77±1% intensity. Muscle glycogen utilization was similar between muscles. Resting FSR was similar between the VL (0.080±0.007 %•h^-1) and SOL (0.086±0.008 %•h^-1) and was higher (P<0.05) 24h post-exercise compared to rest for both muscles. The absolute change in FSR was not different between muscles (0.030±0.007 vs. 0.037±0.012 %•h^-1 for VL and SOL). At baseline, myostatin GE was ~2-fold higher (P<0.05) in SOL compared to VL while no other muscle specific differences in GE were present. After running, myostatin GE was suppressed (P<0.05) in both muscles at 4h and was higher (P<0.05) than baseline at 24h for VL only. MRF4 mRNA was elevated (P<0.05) at 4h in both SOL and VL, MyoD and PGC-1 were higher (P<0.05) at 4h and FOXO3A at 24h in SOL only while MuRF-1 was higher (P<0.05) at 4h in VL only. Myogenin and atrogin-1 GE were unaltered. The similar increases between muscles in FSR support running as part of the exercise countermeasure to preserve soleus mass during unloading. The subtle differences in GE suggest a potential mechanism for muscle specific adaptations to chronic run training.