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Kidney Week

Abstract: PO0270

HIF Prolyl Hydroxylase Inhibitor Improves Exercise Endurance and Hardly Affects Instantaneous Force in Mice

Session Information

Category: Anemia and Iron Metabolism

  • 200 Anemia and Iron Metabolism

Authors

  • Takemura, Koji, Tokyo Daigaku, Bunkyo-ku, Tokyo, Japan
  • Nishi, Hiroshi, Tokyo Daigaku, Bunkyo-ku, Tokyo, Japan
  • Higashihara, Takaaki, Tokyo Daigaku, Bunkyo-ku, Tokyo, Japan
  • Nangaku, Masaomi, Tokyo Daigaku, Bunkyo-ku, Tokyo, Japan
Background

Erythropoietin (EPO) and hypoxia-inducible factor (HIF)
stabilizers (PH inhibitors) are efficient therapeutic modalities against anemia in CKD.
Compared to EPO and EPO receptor system, extra-renal action
of PH inhibitors has still not been fully investigated. Previous reports caution us about the actual misuse of PH inhibitors in doped athletes, but nonhematopoietic effects of PH inhibitors on skeletal muscles remain controversial. Metabolic shift from oxidative phosphorylation toward glycolysis in myotubes in vitro was previously reported. Direct pharmacological effects of PH inhibitors on skeletal muscles and exercise performance were assessed in vivo.

Methods

Roxadustat, one of PH inhibitors, was administered via oral gavage to 8-week-old C57BL6 mice. Plasma EPO levels and HIF-targeted gene expression were analyzed after a single administration. Exercise ability was also assessed by treadmill exhaustion test, forelimb grip test, and electric-pulse-induced isometric plantar flexion torque measurement after a single dose or chronic 5-week treatment, in addition to which muscle weight and muscle fiber-type were also measured.

Results

Even a single administration of roxadustat increased plasma EPO levels and gene expression downstream of HIF in skeletal muscles. Mice treated with the agent for 5 weeks showed higher blood hemoglobin levels and improved exercise endurance in treadmill exhaustion test, while the treatment provided comparable results in isometric plantar flexion torque measurement. Although PH inhibitor treatment induced fast-to-slow muscle fiber-type conversion which seem beneficial to exercise endurance, better running performance with increased hemoglobin level was blunted with forced hemodilution alone.

Conclusion

Treatment with a PH inhibitor, roxadustat, improves exercise endurance principally via pharmacological hematopoietic effect and hardly affects instantaneous force in mice although it also affects skeletal myocytes at molecular levels.