New Findings: What is the central question of this study? The purpose of this study was to determine if the nucleotides in a nucleoprotein diet could ameliorate the unloading-associated decrease in soleus muscle mass and fiber size. What is the main finding and its importance? The results indicate that the nucleotides in the nucleoprotein-enriched diet could ameliorate the unloading-associated decrease in type I fiber size and muscle mass most likely due to the activation of protein synthesis pathways and satellite cell proliferation and differentiation via ERK1/2 phosphorylation. Thus nucleotide supplementation appears to be an effective countermeasure for muscle atrophy.