We used positron emission tomography/computed tomography (PET/CT) and [(18)F]-FDG to test the hypothesis that glucose uptake (GU) heterogeneity in skeletal muscles as a measure of heterogeneity in muscle activity is greater in old than young men when they perform isometric contractions. Six young (26 +/- 6 years) and six old (77 +/- 6 years) men performed two types of submaximal isometric contractions that required either force or position control. [(18)F]-FDG was injected during the task and PET/CT scans were performed immediately after the task. Within-muscle heterogeneity of knee muscles was determined by calculating the coefficient of variation (CV) of GU in PET image voxels within the muscles of interest. The average GU heterogeneity (mean +/- SD) for knee extensors and flexors was greater for the old (35.3 +/- 3.3%) than the young (28.6 +/- 2.4%) (P = 0.006). Muscle volume of the knee extensors were greater for the young compared to the old men (1016 +/- 163 vs. 598 +/- 70 cm(3), P = 0.004). In a multiple regression model, knee extensor muscle volume was a predictor (partial r = -0.87; P = 0.001) of GU heterogeneity for old men (R (2) = 0.78; P < 0.001), and MVC force predicted GU heterogeneity for young men (partial r = -0.95, P < 0.001). The findings demonstrate that GU is more spatially variable for old than young men and especially so for old men who exhibit greater muscle atrophy