Estrogen is a hormone that regulates physiological processes and its dysregulation may relate to muscle disorders particularly in female, although the mechanism remains to be elucidated. We here show that estrogen deficiency repressed exercise endurance in female mice whereas the administration of estrogen to ovariectomized mice recovered it. Microarray analysis of mouse muscles showed that mitochondrial uncoupling protein 3 (UCP3) is upregulated by ovariectomy and downregulated by estrogen administration. Intriguingly, ectopic expression of constitutively active estrogen receptor alpha decreased UCP3 level and increased cellular ATP content in differentiated myoblastic C2C12 cells. Overall, the present study suggests that estrogen plays a critical role in the regulation of energy expenditure and exercise endurance in female. (C) 2016 Elsevier Inc. All rights reserved.