Unité de Biologie Intégrative des Adaptations à l'Exercice - INSERM 902, Genopole, F-91058, Evry, France.
BMC Med Genomics. 2012 Jun 29;5:29. doi: 10.1186/1755-8794-5-29.
Erythropoietin (EPO) is known to improve exercise performance by increasing oxygen blood transport and thus inducing a higher maximum oxygen uptake (VO2max). Furthermore, treatment with (or overexpression of) EPO induces protective effects in several tissues, including the myocardium. However, it is not known whether EPO exerts this protective effect when present at physiological levels. Given that EPO receptors have been identified in skeletal muscle, we hypothesized that EPO may have a direct, protective effect on this tissue. Thus, the objectives of the present study were to confirm a decrease in exercise performance and highlight muscle transcriptome alterations in a murine EPO functional knock-out model (the EPO-d mouse).
We determined VO2max peak velocity and critical speed in exhaustive runs in 17 mice (9 EPO-d animals and 8 inbred controls), using treadmill enclosed in a metabolic chamber. Mice were sacrificed 24h after a last exhaustive treadmill exercise at critical speed. The tibialis anterior and soleus muscles were removed and total RNA was extracted for microarray gene expression analysis.
The EPO-d mice's hematocrit was about 50% lower than that of controls (p<0.05) and their performance level was about 25% lower (p<0.001). A total of 1583 genes exhibited significant changes in their expression levels. However, 68 genes were strongly up-regulated (normalized ratio>1.4) and 115 were strongly down-regulated (normalized ratio<0.80). The transcriptome data mining analysis showed that the exercise in the EPO-d mice induced muscle hypoxia, oxidative stress and proteolysis associated with energy pathway disruptions in glycolysis and mitochondrial oxidative phosphorylation.
Our results showed that the lack of functional EPO induced a decrease in the aerobic exercise capacity. This decrease was correlated with the hematocrit and reflecting poor oxygen supply to the muscles. The observed alterations in the muscle transcriptome suggest that physiological concentrations of EPO exert both direct and indirect muscle-protecting effects during exercise. However, the signaling pathway involved in these protective effects remains to be described in detail.
促红细胞生成素（EPO）通过增加血液中的氧气运输从而提高最大摄氧量（VO2max），被认为可以改善运动表现。此外，EPO 的治疗（或过表达）可诱导包括心肌在内的多种组织产生保护作用。然而，目前尚不清楚 EPO 在生理水平下是否发挥这种保护作用。鉴于已经在骨骼肌中鉴定出 EPO 受体，我们假设 EPO 可能对该组织具有直接的保护作用。因此，本研究的目的是在 EPO 功能敲除模型（EPO-d 小鼠）中证实运动表现下降，并强调肌肉转录组的变化。
我们在代谢室内的跑步机上进行了 17 只小鼠（9 只 EPO-d 动物和 8 只近交对照）的最大摄氧量峰值速度和临界速度的衰竭跑测试。在最后一次以临界速度进行的衰竭性跑步机运动后 24 小时，处死小鼠。切除比目鱼肌和跖肌，提取总 RNA 进行微阵列基因表达分析。
EPO-d 小鼠的红细胞压积比对照组低约 50%（p<0.05），运动表现低约 25%（p<0.001）。共有 1583 个基因的表达水平发生了显著变化。然而，有 68 个基因强烈上调（归一化比值>1.4），115 个基因强烈下调（归一化比值<0.80）。转录组数据挖掘分析表明，EPO-d 小鼠的运动导致肌肉缺氧、氧化应激和蛋白水解，与糖酵解和线粒体氧化磷酸化中能量途径的破坏有关。
我们的结果表明，功能性 EPO 的缺乏导致有氧运动能力下降。这种下降与红细胞压积有关，反映了肌肉供氧不足。肌肉转录组的观察到的变化表明，生理浓度的 EPO 在运动过程中对肌肉具有直接和间接的保护作用。然而，涉及这些保护作用的信号通路仍有待详细描述。
