Metabolomic responses are more sensitive in muscle than serum following 28 days of arduous exercise with erythropoietin administration

Abstract Erythropoietin (EPO) administration stimulates haematological and non‐haematological adaptations that alter substrate oxidation and enhance aerobic performance. The effects of strenuous exercise and EPO on metabolites, and whether any effect is associated with haematological and non‐haematological adaptations, has not been assessed. The objective of this study was to examine changes in serum and skeletal muscle metabolomes and explore whether changes were associated with haematological and non‐haematological adaptations to strenuous exercise and EPO. Eight males (20 ± 3 years, 25 ± 3 kg/m2) completed this longitudinal study. Participants received 50 IU/kg body mass of EPO, 3×/week for 28 days, while exercise (energy expenditure of 1200–1500 kcals/day) and diet were controlled. Before (PRE) and after (POST) EPO, V̇O2peak, time trial (TT) performance, blood volume, iron homeostasis, and untargeted metabolomics profiles in rested/fasted muscle and serum were assessed. Weighted gene correlation network analysis (WGCNA) was used to identify plasticity of metabolite networks (POST/PRE) correlated with change in V̇O2peak, TT performance, blood volume and iron homeostasis. Four serum and 51 muscle metabolites were different (P ≤ 0.05, false discovery rate ≤ 0.10) at POST compared to PRE. Of the WGCNA networks identified, two serum modules were associated with aerobic performance (P = 0.05), while five skeletal muscle modules were associated with both aerobic performance and iron outcomes (P = 0.05). Changes to the serum and skeletal muscle metabolomes indicate altered carnitine, β‐alanine and glucose metabolism metabolites, likely depicting a shift to greater fat oxidation, buffering capacity and the alteration in iron homeostasis following 28 days of EPO administration and strenuous exercise.