Glycogenolysis results in the selective catabolism of individual glycogen granules by glycogen phosphorylase. However, once the carbohydrate portion of the granule is metabolized, the fate of glycogenin, the protein primer of granule formation, is not known. To examine this, male subjects ( n = 6) exercised to volitional exhaustion (Exh) on a cycle ergometer at 75% maximal O2 uptake. Muscle biopsies were obtained at rest, 30 min, and Exh (99 ± 10 min). At rest, total glycogen concentration was 497 ± 41 and declined to 378 ± 51 mmol glucosyl units/kg dry wt following 30 min of exercise ( P < 0.05). There were no significant changes in proglycogen, macroglycogen, glycogenin activity, or mRNA in this period ( P ≥ 0.05). Exh resulted in decreases in total glycogen, proglycogen, and macroglycogen as well as glycogenin activity ( P < 0.05). These decrements were associated with a 1.9 ± 0.4-fold increase in glycogenin mRNA over resting values ( P < 0.05). Glycogenolysis in the initial exercise period (0–30 min) was not adequate to induce changes in glycogenin; however, later in exercise when concentration and granule number decreased further, decrements in glycogenin activity and increases in glycogenin mRNA were demonstrated. Results show that glycogenin becomes inactivated with glycogen catabolism and that this event coincides with an increase in glycogenin gene expression as exercise and glycogenolysis progress.