Darbepoetin alfa enhances exercise performance in trained mice in a sex-specific manner

Erythropoiesis-stimulating agents (ESAs) increase hemoglobin mass and maximal oxygen uptake; however, it remains unclear whether the abuse of ESAs enhances exercise performance. Therefore, we herein investigated the effects of darbepoetin alfa (DPO), a long-acting erythropoietin analog, on exercise performance in trained male and female mice. Exercise performance was assessed as the number of arrivals at the halfway line of a flow rate-adjustable swimming pool. The DPO treatment significantly increased hematocrit levels regardless of sex, but only enhanced exercise performance in female mice. The sex-specific effect of DPO on exercise performance was not abolished by ovariectomy; the enhancing effect was more pronounced in ovariectomized (OVX) mice than in female mice. This effect of the DPO treatment was attributed to a significant increase in the gene expression of PGC-1alpha in the gastrocnemius (GASTR) muscle of OVX mice, but not female mice. In addition, myocyte hypertrophy, but not angiogenesis, was observed in the GASTR muscle of DPO-treated OVX mice. These results revealed the sex-specific enhancing effect of DPO on exercise performance in trained mice. Enhanced exercise performance did not appear to require female sex hormones and may not be due to direct effects on skeletal muscles.