Takemura Koji, Odawara Motoki, Nishi Hiroshi, Higashihara Takaaki, Yoshida Yoko, Nakazato Koichi, Fujii Nobuharu L, Ishii Naokata, Inagi Reiko, Tanaka Tetsuhiro, Nangaku Masaomi
Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Department of Exercise Physiology, Nippon Sport Science University, Tokyo, Japan.
Physiol Rep. 2025 Jul;13(13):e70464. doi: 10.14814/phy2.70464.
Increased blood hemoglobin concentration theoretically promotes oxygen delivery to the periphery. Clinically, in addition to recombinant human erythropoietin analogs, prolyl hydroxylase (PH) inhibitors to stabilize the expression of hypoxia-inducible factor (HIF) protein were recently approved for the treatment of anemia in chronic kidney disease. However, whether the new agent helps enhance physical exercise capacity remains a matter of controversy. Treatment of C57BL/6J mice via oral gavage with roxadustat of 30 mg/kg three times per week for 5 weeks elevated the blood hemoglobin concentration, upregulated the HIF-downstream gene expression of the muscle, and enhanced a high-intensity exercise performance measured with a treadmill running exhaustion test, compared to those treated with vehicle, while total body weight or skeletal muscle mass was comparable. This physical effect depended on the increase in blood hemoglobin concentration, as confirmed by mice hemodiluted to control hemoglobin concentrations through phlebotomy followed by infusion of the approximate volume of phosphate-buffered saline. In conclusion, oral administration of the HIF-PH inhibitor to mice increased high-intensity exercise capacity as well as elevated blood hemoglobin concentration. The finding implies the versatile effects on humans taking HIF-PH inhibitors, as well as the risk of them being abused for blood doping.
理论上，血液血红蛋白浓度升高可促进氧气输送至外周。临床上，除重组人促红细胞生成素类似物外，最近批准了用于稳定缺氧诱导因子（HIF）蛋白表达的脯氨酰羟化酶（PH）抑制剂来治疗慢性肾脏病贫血。然而，这种新药是否有助于提高身体运动能力仍存在争议。与给予赋形剂处理的小鼠相比，对C57BL/6J小鼠每周经口灌胃3次30mg/kg的罗沙司他，持续5周，可提高血液血红蛋白浓度，上调肌肉中HIF下游基因表达，并通过跑步机跑步耐力试验测得的高强度运动表现得到增强，而总体重或骨骼肌质量相当。通过放血使小鼠血液稀释至对照血红蛋白浓度，然后输注大致体积的磷酸盐缓冲盐水，证实这种身体效应依赖于血液血红蛋白浓度的增加。总之，对小鼠口服HIF-PH抑制剂可提高高强度运动能力以及升高血液血红蛋白浓度。这一发现意味着HIF-PH抑制剂对服用者有多种作用，也存在被滥用于血液兴奋剂的风险。
