Hibernating Belding's ground squirrels (Spermophilus beldingi) are ketotic relative to fed nonhibernators. Muscles from torpid individuals, when incubated in media containing physiological concentrations of glucose and ketone, show reduced uptake of glucose in the presence of ketone. The magnitude of the reduction is dependent on ketone concentration and reaches 60% in heart and 100% in pectoralis at 1.4 mM ketone. Fasted squirrels are also ketotic. However, ketone does not reduce glucose uptake in muscles from fed or fasted animals. Glucose utilization by muscles decreases during a long-term fast, but the reduction is independent of ketone. Thus both a long-term fast and hibernation lead to changes in muscle tissues that decrease their reliance on glucose as an energy source. Ketosis leads to glucose sparing during hibernation, whereas muscle glucose utilization is decreased independently of ketone during a fast. The glucose sparing achieved in both hibernation and fasting leads to conservation of body protein, the major source of gluconeogenic precursors in fasting mammals.